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Center for Bioethics

Dr. Susan Berry
Chair, IRB Executive Committee
University of Minnesota
D528 Mayo Memorial Building
420 Delaware St. SE
Minneapolis, MN 55455-0392

N504 Boynton
410 Church Street
Minneapolis MN 55455
612-624-9440
Fax: 612-624-9108
www.bioethics.umn.edu

January 5, 2015

Dear Sue:
I am writing to you in your capacity as Chair of the Executive Committee of the IRB. As a result
of documents acquired through state Data Practices Act requests, I have obtained information
suggesting ethical and legal violations in the conduct and oversight of a clinical trial titled
“Seroquel Extended Release for the Management of Borderline Personality Disorder”
(NCT00880919), funded by AstraZeneca and conducted from 2008 to 2013 in the University of
Minnesota’s Department of Psychiatry. The principal investigator for the study was Dr. Charles
Schulz. Co-investigators include Dr. Scott Crow, Dr. Kathryn Cullen, Dr. Michael Miller, and
Dr. Richelle Moen.
I am writing to ask the Executive Committee to investigate this trial. My chief concerns include
issues involving 1) recruitment of subjects, 2) the independence of the Data Safety Monitoring
Board, and 3) conflicts of interest.
Background
Seroquel is an antipsychotic drug approved for the treatment of schizophrenia and bipolar
disorder and as an adjunct treatment for depression. It has black box warnings for increased risk
of death in elderly patients and for increased risk of suicidal ideation in children and young
adults. In 2010, AstraZeneca paid $520 million to settle federal investigations into illegal
marketing of the drug, including the payment of kickbacks to doctors to market Seroquel for
unapproved uses. Numerous media reports have linked Dr. Charles Schulz, the Chairman of the
Department of Psychiatry, to the controversy over illegal marketing of Seroquel. 1
Seroquel is not approved for the treatment of Borderline Personality Disorder. In fact, no
medication is approved for the treatment of any personality disorder. According to a metaanalysis of pharmacological treatments for Borderline Personality Disorder conducted by the
Cochrane Collaboration in 2010, “Total Borderline Personality Disorder severity was not
1

Jeremy Olson, “U doctor scrutinized over drug research,” St. Paul Pioneer Press, March 19, 2009; Maura Lerner
and Janet Moore, “Once-secret drug company records put U on the spot,” Minneapolis Star-Tribune, March 19,
2009; Andy Mannix, “Charles Schulz under scrutiny for Seroquel study suicide,” City Pages, February 2, 2011.

significantly influenced by any drug. No promising results are available for the core Borderline
Personality Disorder symptoms of chronic feelings of emptiness, identity disturbance and
abandonment.” 2 Dr. Schulz has conducted studies of at least two other pharmacological
treatments for Borderline Personality Disorder, Zyprexa (olanzapine) and Depakote (divalproex
sodium). 3
In “Seroquel Extended Release for the Management of Borderline Personality Disorder,”
investigators at the University of Minnesota and the University of Iowa randomized subjects
diagnosed with Borderline Personality Disorder to one of three groups: 150 mg/day of Seroquel,
300 mg/day of Seroquel, or placebo. Subjects were treated for eight weeks (Appendix A.)
Concerns
1) Recruitment from sex offender facility
On May 27, 2010, Dr. Schulz filed a Reporting Form for Unanticipated Problems Involving
Risks to Subjects or Others (Appendix B). He informed the IRB of an incident involving two
subjects recruited into the study from Alpha House, “a residential program which provides high
levels of structure and supervision for sex offenders.” The report states:
“Redacted was employed as the full-time cook at Alpha House. Per Alexis on the morning of
2010 BRE cooked and served oatmeal to 1520 persons at Alpha House, 4 of which were staff
members. Some residents noticed pink particles in the oatmeal. After eating breakfast the
residents and staff reported feeling sedated and some were ‘knocked out’ for the remainder of the
day. Staff asked redacted if he had put the study medication into the oatmeal and redacted
denied it. After failing a polygraph test redacted was re-imprisoned.”
This alarming report raises at least two questions. The first is about the safety of the residents
and staff of Alpha House. Were any other residents or staff members harmed, and what steps
were taken by the investigators to determine whether any other such incidents occurred? There is
no indication of concern by the IRB in any of their communications with the investigators, and
no mention of the incident in the minutes of the Data Safety Monitoring Board.
The second question concerns the recruitment tactics employed in the study. What circumstances
led to residents of a sex offender facility licensed by the Minnesota Department of Corrections
being recruited into this study? Were any other residents enrolled? Did study investigators
recruit subjects from other facilities licensed by the Department of Corrections? The documents
I was provided do not suggest that the IRB asked investigators about any of these issues.
2

Stoffers J1, Völlm BA, Rücker G, Timmer A, Huband N, Lieb K, “Pharmacological interventions for borderline
personality disorder,” Cochrane Database Systematic Review 2010 Jun 16;(6):CD005653;
http://www.ncbi.nlm.nih.gov/pubmed/20556762

3

Zanarini MC, Schulz SC, Detke HC, Tanaka Y, Zhao F, Lin D, Deberdt W, Kryzhanovskaya L, Corya S: A dose
comparison of olanzapine for the treatment of borderline personality disorder: a 12-week randomized, double-blind,
placebo-controlled study. J Clin Psychiatry 2011; 72:1353–1362; “Depakote ER in Borderline Personality Disorder”
NCT00222482; https://clinicaltrials.gov/ct2/show/NCT00222482

Because of widespread abuses in the 1960s and 1970s, Health and Human Services (HHS)
regulations include special protections for prisoners (see 45 CFR part 46, subpart C). HHS
regulations define prisoners as "any individual involuntarily confined or detained in a penal
institution. The term is intended to encompass individuals sentenced to such an institution under
a criminal or civil statute, individuals detained in other facilities by virtue of statutes or
commitment procedures which provide alternatives to criminal prosecution or incarceration in a
penal institution, and individuals detained pending arraignment, trial, or sentencing” [see 45 CFR
part 46.303(c)].
The key questions for determining whether the subjects recruited from Alpha House count as
prisoners under 45 CFR part 46.303(c) are 1) whether their ability to leave the facility was
restricted, and 2) whether their confinement to Alpha House occurred as result of statutes or
commitment procedures which provide alternatives to criminal prosecution or incarceration in a
penal institution. Without further investigation, it is hard to know for certain whether these two
criteria were met. However, the fact that one subject was “re-imprisoned” after failing a
polygraph test suggests that his confinement to Alpha House probably was an alternative to
incarceration.
If so, then under the terms of the Federalwide Assurance (FWA) for the protection of human
subjects, the composition of the IRB panel that reviewed the study should have met the
requirements of HHS regulations at 45 CFR 46.304(a) and (b). For example, the IRB panel
reviewing the study should have included a prisoner or prisoner representative. In addition, any
research on prisoners must fall within the categories of research permissible under 45 CFR
46.306(a)(2). It does not appear that these conditions were met.
According to the Continuing Review report for December 3, 2010 through January 25, 2012
(Appendix C, page 37), one of the three initial sites for the study, McLean Hospital at Harvard
University, withdrew from the study because of its inability to recruit subjects. (This is not
mentioned in the published paper.) The University of Minnesota, in contrast, managed to exceed
its recruitment goals. On November 20, 2012, Dr. Schulz reported enrolling a total of 52
subjects with only three screening failures (Appendix C, page 52). By the end of the study, the
Minnesota site had enrolled 58 subjects (Appendix C, page 58). It would be worth investigating
how and where these subjects were recruited, what steps were taken to confirm the diagnosis of
Borderline Personality Disorder, and whether the sponsor provided financial incentives for
subject recruitment.
2) Independence of Data Safety Monitoring Board
According to documents submitted to the IRB, Dr. Scott Crow, a faculty member in the
Department of Psychiatry, served both as co-investigator for the study and as chair of the Data
and Safety Monitoring Board (DSMB.) This dual role constituted a conflict of interest and
compromised the independence of the DSMB. Every major set of research guidelines
concerning the composition of DSMBs stipulates that such boards must be independent of the
investigators and study sponsors and must not include members of the research team.

For example, the World Health Organization’s Operational Guidelines for the Establishment and
Functioning of Data and Safety Monitoring Boards state, “Members should not be affiliated with
the sponsor, investigator(s), ethics committee(s), regulatory authority(ies), site(s) or study staff.
Members should also not have vested conflicts of interest (e.g. a financial or other interest in an
intervention or product similar to the intervention being studied).” 4
The 2006 Food and Drug Administration’s Guidance for Clinical Trial Sponsors: Establishment
and Operation of Clinical Trial Data Monitoring Committees states, “We recommend that
sponsors avoid appointing to a DMC any individuals who have relationships with trial
investigators or sponsor employees that could be considered reasonably likely to affect their
objectivity.” 5
The National Institutes of Health policy for data and safety monitoring states, “Ideally,
participants in monitoring outcomes of a trial are in no way associated with the trial.” 6
The European Medicine Agency’s Guideline on Data Monitoring Committees states,
“Furthermore, in order to allow for an unbiased assessment of study data and not to bias the
further conduct of a clinical trial, any person (not only employees of the sponsor) involved in the
conduct of the clinical trial (e.g. investigators) should not serve on the DMC.” 7
At least one member of the University of Minnesota IRB appears to have recognized the
problem. In the document labelled “Continuing Review of Approved Research” dated January
26, 2011, Dr. Simone Ognjanovic asks, “Scott Crow was a member of DSMB (Data Safety
Monitoring Board) and a co-investigator?” However, the IRB apparently dismissed Dr.
Ognjanovic’s concerns. The minutes for the January 26, 2011 meeting state, “This does not
create a conflict of interest as researchers are required to monitor adverse events” (Appendix C,
pages 33-4). It is unclear what reasoning the IRB used to justify this conclusion.
3) Conflicts of interest on IRB
In the Continuing Review dated December 17, 2008, it is noted that Dr. Scott Crow was not
present for voting “due to conflict of interest” (Appendix C, page 9.) This note suggests that Dr.
Crow, in addition to directing the Data Safety Monitoring Board and serving as Co-Investigator
for the study, was also a member of the IRB panel evaluating the study. In later reviews, there is
no indication that Dr. Crow abstained from voting, and all Continuing Reviews of the study
passed with unanimous votes. If Dr. Crow continued to serve on the IRB and vote on the
4

World Health Organization, Operational Guidelines for the Establishment and Functioning of Data and Safety
Monitoring Boards, Geneva, Switzerland, 2005. See http://www.who.int/tdr/publications/documents/operationalguidelines.pdf?ua=1
5

Food and Drug Administration, Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical
Trial Data Monitoring Committees, Bethesda, Maryland, 2005. See
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf
6

http://grants.nih.gov/grants/guide/notice-files/not98-084.html

7

http://osp.od.nih.gov/sites/default/files/resources/WC500003635.pdf

Continuing Review of the study in question, his presence would constitute a clear conflict of
interest.
4) Conflicts of interest involving the Principal Investigator
In the Continuing Review dated January 26, 2011, Dr. Ognjanovic noted that Dr. Schulz was a
member of the AstraZeneca Scientific Advisory Board (Appendix C, page 33). She pointed out
that the study in question was being done to expand the use of Seroquel to unapproved
indications (Borderline Personality Disorder) and asked whether Dr. Schulz had a conflict of
interest.
According to the policy set out by the Office of Institutional Compliance, “Managing Conflicts
of Interest in Research,” serving on a sponsor’s Scientific Advisory Board does constitute a
conflict of interest. According to the policy, if the financial interest was “significant,” it should
have prohibited Dr. Schulz from serving as Principal Investigator for this study. The policy
states:
“A University professor cannot serve as PI or Co-I on human subjects research that the IRB
determines is greater than minimal risk for human participants, while simultaneously holding a
significant financial or business interest in a business entity that could benefit from the research
project.” 8
However, the IRB appears to have taken no action. Schulz remained Principal Investigator for
the study. The Continuing Review form states: “The IRB committee notes that the Pl's conflict
of interest management plan has been reviewed previously by the IRB Committee. The
committee acknowledges current, IRB approved language in the consent form that references the
Pl's role on the Scientific Advisory Board.”
However, there is no indication of what this conflict of interest management plan might be. In
addition, the consent form that was provided to me by the Department of Psychiatry contains no
mention of the role of Schulz on the AstraZeneca Scientific Advisory Board (Appendix D). It is
unclear whether the IRB Committee was mistaken about the consent form, or whether the
Department of Psychiatry used a different version of the consent form than the one it submitted
to the IRB.
I would appreciate the opportunity to discuss these issues with you at your earliest convenience.
Yours sincerely,

Carl Elliott
Professor, Center for Bioethics

8

http://www.compliance.umn.edu/conflictResearch.htm

Appendix A

Article

Comparison of Low and Moderate Dosages of ExtendedRelease Quetiapine in Borderline Personality Disorder:
A Randomized, Double-Blind, Placebo-Controlled Trial
Donald W. Black, M.D.
Mary C. Zanarini, Ed.D.
Ann Romine, R.N.
Martha Shaw, B.A.
Jeff Allen, Ph.D.
S. Charles Schulz, M.D.

Objective: The authors compared the
efficacy and tolerability of low and moderate dosages of extended-release quetiapine in adults with borderline personality
disorder.
Method: Ninety-five participants with
DSM-IV borderline personality disorder were
randomly assigned to receive 150 mg/day of
quetiapine (the low-dosage group; N=33),
300 mg/day of quetiapine (the moderatedosage group; N=33), or placebo (N=29).
Total score over time on the clinician-rated
Zanarini Rating Scale for Borderline Personality Disorder (“Zanarini scale”) was analyzed
in a mixed-effects model accounting for informative dropout.
Results: Participants in the low-dosage
quetiapine group had significant improvement on the Zanarini scale compared with
those in the placebo group. Time to response (defined as a reduction of 50% or
more on the Zanarini scale total score) was
significantly shorter for both the low-dosage
quetiapine group (hazard ratio=2.54, p=0.007)

and the moderate-dosage quetiapine group
(hazard ratio=2.37, p=0.011) than for the
placebo group. Among participants who
completed the study, 82% in the lowdosage quetiapine group were rated as
“responders,” compared with 74% in the
moderate-dosage group and 48% in the
placebo group. Treatment-emergent adverse events included sedation, change
in appetite, and dry mouth. The overall
completion rate for the 8-week doubleblind treatment phase was 67% (67% for
the low-dosage quetiapine group, 58% for
the moderate-dosage quetiapine group,
and 79% for the placebo group). Participants who experienced sedation were
more likely to drop out.
Conclusions: Participants treated with
150 mg/day of quetiapine had a significant
reduction in the severity of borderline
personality disorder symptoms compared
with those who received placebo. Adverse
events were more likely in participants
taking 300 mg/day of quetiapine.
(Am J Psychiatry 2014; 171:1174–1182)

B

orderline personality disorder is characterized by mood
instability, cognitive symptoms, impulsive behavior, and
disturbed relationships (1–3). A variety of psychotherapies
have been developed (4–6) and, while research on the use
of medication is ongoing, no drug has been approved in
the United States or elsewhere for its treatment (7). Secondgeneration antipsychotics have been the most intensively
studied, but randomized controlled trials of aripiprazole,
olanzapine, and ziprasidone have produced mixed results
(8–11). Five open-label studies found that quetiapine may
be effective in treating a range of borderline symptoms
(12–16). While encouraging, these studies involved small
samples, and four of them (12–15) focused on impulsivity/
hostility, not more general borderline psychopathology.
This study was designed to provide a rigorous test of
extended-release quetiapine in the treatment of borderline personality disorder. Quetiapine is approved by the
U.S. Food and Drug Administration for the treatment of

schizophrenia and for acute and maintenance treatment
of bipolar disorder. There is some evidence suggesting that
quetiapine could be effective in treating borderline personality
disorder. First, it is effective in treating bipolar disorder,
and mood shifts observed in bipolar patients resemble
affective instability in borderline patients (17). Second,
research suggests that quetiapine may curb impulsivity
and self-harm (14, 18). Furthermore, open-label studies
have suggested that the drug has promise in treating borderline patients (12–16).
We report the results of a randomized controlled trial
that compared low (150 mg/day) and moderate (300 mg/day)
dosages of quetiapine in the treatment of borderline personality disorder. Two active treatment arms were used in
order to determine the best dosage of quetiapine relative
to its adverse effects. We expected that both dosages would
be superior to placebo, but that the higher one would have
more adverse effects.

This article is featured in this month’s AJP Audio, is an article that provides Clinical Guidance (p. 1182),
and is discussed in an Editorial by Dr. Tohen (p. 1139) and Video by Dr. Pine

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Am J Psychiatry 171:11, November 2014

BLACK, ZANARINI, ROMINE, ET AL.

Method
The trial was conducted from January 2010 to March 2013 at
three academic medical centers. Participants gave written informed
consent according to procedures approved by a university-affiliated
institutional review board.
The study proceeded in three phases: a screening period
lasting up to 2 weeks overall (visits 1–2); an 8-week double-blind
treatment phase with weekly visits (visits 2–10); and a 1-week
discontinuation phase (visit 11). The 8-week treatment phase was
considered sufficient to show a difference between groups.
Participants who met enrollment criteria at both visits 1 and 2
were randomly assigned to receive treatment with 150 mg/day of
extended-release quetiapine, 300 mg/day of extended-release
quetiapine, or placebo. Participants, site personnel, and investigators were blind to treatment group assignment.
Quetiapine was started at 50 mg/day and adjusted to 150 mg/
day after 1 week. For participants assigned to the higher dosage,
the dosage was raised to 300 mg/day after 4 weeks. To preserve
blinding, all participants received one bottle of 150-mg quetiapine (or placebo) tablets initially, and then after 4 weeks received
two bottles; the second bottle contained either 150-mg quetiapine tablets (for the moderate-dosage group) or placebo tablets
(for the low-dosage and placebo groups).

Inclusion and Exclusion Criteria
Persons 18–45 years of age with moodiness, impulsivity, distrustfulness, and difficult relationships were recruited through referral, advertisements, and word of mouth. After screening with
the Diagnostic Interview for DSM-IV Personality Disorders (19) to
confirm the presence of DSM-IV borderline personality disorder,
we administered the Structured Clinical Interview for DSM-IV to
assess comorbid disorders (20). Participants had to meet Revised
Diagnostic Interview for Borderlines criteria (21) for borderline personality disorder and could not meet current criteria for major depressive disorder, posttraumatic stress disorder, panic disorder, or
obsessive-compulsive disorder. They were required to have a total
score $9 on the Zanarini Rating Scale for Borderline Personality
Disorder (“Zanarini scale”) (22) at visit 2. Individuals were excluded
if they had ever met criteria for a psychotic disorder, had a primary
neurological condition, or were cognitively impaired; had current
substance dependence or had recently abused opiates, amphetamine, barbiturates, cocaine, or hallucinogens; were medically
unstable; had a history of lack of response to an atypical antipsychotic; were pregnant or lactating; or were acutely suicidal.
Participants entering the study could not begin any type of psychotherapy during the study. Concomitant use of benzodiazepines
was allowed at dosages equivalent to #1.0 mg/day of lorazepam;
only one participant (in the placebo group) took benzodiazepines
during the study. Episodic use of anticholinergics was allowed for
sleep. No other psychotropic medication was permitted.

Efficacy Assessments
Rater-administered scales included the Zanarini scale (22), the
Montgomery-Åsberg Depression Rating Scale (MADRS) (23), the
Modified Overt Aggression Scale (24), the Young Mania Rating
Scale (25), and the Global Assessment of Functioning Scale (GAF).
Self-administered measures included a self-report version of the
Zanarini scale (26), the Borderline Evaluation of Severity Over Time
(27), the Barratt Impulsiveness Scale (28), the Symptom Checklist–
90–Revised (SCL-90-R) (29), and the Sheehan Disability Scale (30).
The primary outcome measure was the Zanarini scale total
score. This semistructured interview has anchored ratings (0=no
symptoms, 4=severe symptoms) on nine items that correspond
to the DSM-IV borderline personality disorder criteria. Its subscales
were considered secondary efficacy measures. Other secondary

Am J Psychiatry 171:11, November 2014

measures included the self-rated version of the Zanarini scale, the
MADRS, the Borderline Evaluation of Severity Over Time, the
Modified Overt Aggression Scale, the GAF, the Barratt Impulsiveness Scale, the SCL-90-R, the Young Mania Rating Scale, and the
Sheehan Disability Scale.

Safety Measures
Adverse events, vital signs, electrocardiogram findings, laboratory values, and extrapyramidal symptoms were assessed. Laboratory tests included clinical chemistry, electrolyte levels, lipid
profile, prolactin level, and hematology panels. A urine drug screen
and pregnancy test were performed. These tests were performed
at protocol-specified time points and when clinically indicated.
Extrapyramidal symptoms were assessed with the Simpson-Angus
Rating Scale (31), the Barnes Akathisia Scale (32), and the Abnormal
Involuntary Movement Scale (33).

Statistical Analysis
A sample size of 33 in each group was considered sufficient for
detecting an effect size greater than 0.68 with a power of 0.80, an
alpha of 0.05 (two-tailed), and a 15% dropout rate. The numbers of participants assigned to 150 mg/day of quetiapine (N=33),
300 mg/day of quetiapine (N=33), and placebo (N=29) were close
to those planned.
The analyses included comparisons of baseline (visit 2) severity
and background variables, time to adverse events, time to study
discontinuation, and treatment response. All participants who
were assigned to a treatment group and met study inclusion
criteria were included in each analysis. Statistical tests were performed using a two-sided alpha of 0.05.
Pearson’s chi-square test (or Fisher’s exact test) was used to
test for categorical baseline group differences. The Kruskal-Wallis
test was used to test for dimensional baseline group differences.
Mean severity scores from the baseline visit were compared using analysis of variance.
Adverse events were recorded as mild, moderate, or severe,
with additional notations if an adverse event was thought to be
related to the study medication. Time to adverse event was defined as the first postscreening visit with an adverse event reported, with censoring occurring if an event was not reported by
the time of study discontinuation or study completion. In addition, we considered time to different types of adverse events (e.g.,
appetite change, bodily pain). Cox proportional hazards regression analysis was performed to compare the treatment groups on
time to each definition of adverse event.
Time to discontinuation was defined as the last postscreening
visit attended during the treatment phase, with censoring occurring if the participant attended visit 10. The analysis examined
predictors of time to discontinuation. First, the three groups were
compared with no covariates. Next, we examined severity of adverse events as time-dependent predictors of discontinuation.
The analysis included any event, as well as the different types of
adverse events. In addition, we examined illness severity (based
on Zanarini scale score) as a time-dependent predictor. This was
done to provide a better understanding of factors related to discontinuation. Cox proportional hazards regression analysis was
used to model time to discontinuation.
For the primary efficacy variable, a mixed-effects model was
used that included terms for treatment group, linear time effect
(weeks since visit 2 [baseline]), quadratic time effect, site, and
treatment-by-time interactions. (Because one site enrolled only
three participants, those participants were pooled with the smaller
of the two remaining sites.) Each participant’s outcome profile
during the 8-week treatment phase (visit 2 to visit 10) was summarized with a subject-specific intercept and slope. We fitted
a shared parameter model, where the treatment-response model

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QUETIAPINE IN BORDERLINE PERSONALITY DISORDER

(the mixed-effects model) and a time-to-discontinuation model
were fitted simultaneously, with the subject-specific intercepts and
slopes from the response model used as predictors of discontinuation (34). The shared-parameter model reduces bias in treatment
effects caused by informative dropout (35). The NLMixed procedure
in SAS was used to fit the shared parameter model (36, 37). The
same model was also used for all other response measures for
which data were collected at each visit. The mixed-effects model
was used for measures collected at visits 2, 6, and 10.
The statistical tests for the null hypothesis were performed by
testing differences in mean change from baseline for the groups
receiving 150 mg/day or 300 mg/day of quetiapine compared
with the placebo group. For each group, mean change from
baseline (visit 2) to week 8 of treatment (visit 10) was calculated
as a function of the group’s linear and quadratic coefficients.
Effect size (d) was defined as the group difference from placebo
in change from visit 2 to visit 10, expressed in standard deviation
units. The same procedure was applied to secondary efficacy variables and measures of extrapyramidal symptoms, as well as to
evaluate changes in blood pressure and heart rate. Participants
were classified as responders if they had a reduction of $50% in
Zanarini scale total score; the Cox proportional hazards regression
model was used to model time to response. Among participants
who completed the study, number needed to treat was calculated
based on the proportion of participants whose Zanarini scale total
score at visit 10 represented a reduction of $50% relative to visit 2.
Levels of serum electrolytes, glucose, lipids, and prolactin were
assessed at visit 2 and visit 10, and group differences in changes
were tested using analysis of variance.

Results
A total of 111 individuals were screened for the study,
and 95 were randomly assigned to a treatment group: 33
were assigned to receive 150 mg/day of quetiapine (the lowdosage group), 33 were assigned to receive 300 mg/day of
quetiapine (the moderate-dosage group), and 29 were assigned to receive placebo (N=29). Of those not assigned,
eight did not meet inclusion or exclusion criteria, five failed
to appear after visit 1, and three withdrew consent. Baseline characteristics were similar for the three treatment
groups (Table 1). While the rates of lifetime psychiatric disorders were not significantly different between the groups,
presence of a mood disorder was included as a covariate in
the treatment response models.
Between-group differences were observed for baseline
illness severity as measured by the Zanarini scale total score
(clinician- and self-rated versions); the Borderline Evaluation of Severity Over Time total score as well as the thoughts
and feelings and negative behaviors subscales; the Modified
Overt Aggression Scale; the SCL-90-R general severity index score; and the Sheehan Disability Scale scores (Table 2).
Baseline severity was greatest for the group receiving 300
mg/day of quetiapine and least for the placebo group. The
mixed-effects model accounts for the imbalance in baseline
severity because intercepts vary by group and individual.
Adverse Events
The numbers of participants reporting adverse events
are presented in Table 3. Overall, 88% reported at least one
adverse event, with 82% reporting an adverse event thought

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to be related to the study medication. Among all adverse
events, 68% were suspected to be related to the study drug.
No serious adverse events occurred.
Cox proportional hazards regression models were used
to test for group differences in time to adverse events. Risk
of any type of adverse event was not significantly different
for the quetiapine groups compared with the placebo
group. Risk of an adverse event thought to be related to the
study medication was higher for the moderate-dosage
quetiapine group (hazard ratio=1.73), but the result was
not significant (p=0.074). For the moderate-dosage quetiapine group, risk was elevated for sedation (hazard
ratio=2.16, p=0.021), change in appetite (hazard ratio=3.89,
p=0.018), and dry mouth (hazard ratio=16.77, p=0.007). For
the low-dosage quetiapine group, risk was higher for dry
mouth (hazard ratio=9.32, p=0.034). The hazard ratios
suggest that sedation, change in appetite, dry mouth, and
dizziness are more likely with higher dosages of quetiapine.
Study Discontinuation
Of all participants assigned to a treatment group, 64 (67%)
completed the study, 23 of them in the placebo group, 22 in
the low-dosage quetiapine group, and 19 in the moderatedosage quetiapine group. Eight participants dropped out
before a postbaseline assessment. Risk of discontinuation
was higher among participants who received quetiapine,
but the differences from placebo were not significant for
either dosage group. Illness severity (measured by the
Zanarini scale total score as a time-varying predictor) was
not associated with discontinuation. Risk of discontinuation increased with severity of any adverse event (hazard
ratio=1.74, p=0.018). Sedation was predictive of discontinuation (hazard ratio=1.77, p=0.025).
Efficacy Results
For all treatment groups, Zanarini scale total score improved during the treatment phase (Figure 1). For the
quetiapine groups, the rate of improvement was highest
from visit 2 to visit 6; after that, improvement plateaued.
For this reason, the model included a quadratic effect for
time. Efficacy results (Table 4) are based on the shared
parameter model, which estimates each treatment group’s
change from baseline, accounting for informative dropout.
The difference in improvement between the low-dosage
quetiapine group and the placebo group was statistically
significant (d=20.79, p=0.031); the difference between the
moderate-dosage quetiapine group and the placebo group
was not (d=20.41, p=0.265). The mean score decreased by
1.22 points per week for the low-dosage quetiapine group,
0.99 points per week for the moderate-dosage quetiapine
group, and 0.75 points per week for the placebo group. The
difference between the two quetiapine groups was not
significant. Time to treatment response was faster for the
quetiapine groups relative to the placebo group (low-dosage
group: hazard ratio=2.54, p=0.007; moderate-dosage group:
hazard ratio=2.37, p=0.011). Including participants who
Am J Psychiatry 171:11, November 2014

BLACK, ZANARINI, ROMINE, ET AL.

TABLE 1. Demographic and Clinical Characteristics of Study Participants With Borderline Personality Disorder Who Received
Quetiapine or Placebo

Variable
Age (years)
Age at onset (years)
Duration of illness (years)
Education (years)
Male
Race/ethnicity
European-Caucasian
Other
Marital status
Single
Married
Other
Any past psychiatric hospitalization
Lifetime psychiatric axis I disorders
Mood disorders
Anxiety disorders
Substance use disorders
Any axis I disorder

Low-Dosage
Quetiapine
(150 mg/day)
(N=33)

Placebo (N=29)

Moderate-Dosage
Quetiapine
(300 mg/day)
(N=33)

Mean
30.1
14.6
16.2
14.5
N
10

SD
8.8
6.6
8.9
1.7
%
34

Mean
28.2
12.2
15.4
14.3
N
8

SD
8.0
3.7
9.4
2.7
%
24

Mean
30.2
12.2
17.9
14.1
N
10

SD
8.1
5.0
8.5
3.0
%
30

22
6

79
21

26
7

79
21

26
7

79
21

20
2
5
7

74
7
19
24

26
4
3
13

79
12
9
39

18
6
8
13

56
19
25
39

14
5
6
19

48
17
21
66

25
5
11
29

76
15
33
88

19
5
13
28

58
15
39
85

discontinued before visit 10, the percentage classified as
responders for at least one postbaseline visit was 82% for the
low-dosage quetiapine group, 67% for the moderate-dosage
quetiapine group, and 62% for the placebo group. (Some
participants were classified as responders but were reclassified as nonresponders by their last visit.) Among the 31
participants who did not complete the study, 10 (32%) were
responders. Among participants who completed the study,
the visit 10 response rates were 82% for the low-dosage
quetiapine group, 74% for the moderate-dosage quetiapine
group, and 48% for the placebo group. From these rates,
number needed to treat is estimated at 2.9 for 150 mg/day of
quetiapine and 3.9 for 300 mg/day of quetiapine.
Both quetiapine dosages were superior to placebo for
many secondary efficacy measures, including the selfrated Zanarini scale total score and subscale scores (except
impulsivity); the Borderline Evaluation of Severity Over
Time total score as well as the thoughts and feelings
subscale; the Modified Overt Aggression Scale score; and
work or school days lost because of symptoms (from the
Sheehan Disability Scale). Neither quetiapine dosage was
superior to placebo with regard to the Barratt Impulsiveness Score, but the moderate-dosage group had better
scores on the Young Mania Rating Scale (d=20.50, p=0.019)
and the SCL-90-R general severity index (d=20.62, p=0.033)
(Table 4).

decrease in systolic blood pressure (0.53 mmHg/week).
From visits 1 to 10, triglyceride levels increased 9.8 mg/dL
on average (SD=52.1), with no significant group differences. There were no significant group differences for
serum levels of electrolytes, glucose, lipids, and prolactin.
There were no significant group differences with respect to
changes in extrapyramidal symptoms from baseline to
endpoint. Urine pregnancy tests were conducted at visits
1, 6, and 10. One woman tested positive at visit 6 and
discontinued study participation; all other results were
negative.
Among participants who completed the study, the mean
weight gained between visit 1 and visit 10 was 1.0 lb (SD=4.4)
for the placebo group, 1.0 lb (SD=7.2) for low-dosage
quetiapine group, and 3.0 lb (SD=9.2) for moderate-dosage
quetiapine group. Standard deviations for weight gain
were greater for the quetiapine groups relative to the
placebo group (p=0.028 for the low-dosage group, and
p=0.001 for the moderate-dosage group). Median weight
gain was not significantly different between groups.
Sixty participants (63%) attended visit 11, which occurred
1 week after study medication was discontinued. Twelve
participants (20%) reported a new adverse event, with three
reports of increased moodiness or irritability and three of
trouble sleeping. All adverse events were rated as mild.

Safety Results

Discussion

The moderate-dosage quetiapine group experienced
a significant increase in heart rate (1.03 bpm/week). The
low-dosage quetiapine group experienced a significant

The results show that low-dosage extended-release
quetiapine was superior to placebo in reducing the overall
severity of borderline personality disorder. The estimated

Am J Psychiatry 171:11, November 2014

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QUETIAPINE IN BORDERLINE PERSONALITY DISORDER

TABLE 2. Baseline Clinical Measures for Study Participants With Borderline Personality Disorder Who Received Quetiapine or
Placebo
Low-Dosage
Quetiapine
(150 mg/day)
(N=33)

Placebo (N=29)
Measure

Moderate-Dosage
Quetiapine
(300 mg/day)
(N=33)

Analysis

Mean

SD

Mean

SD

Mean

SD

F

df

p

14.6
6.3
3.1
1.7
3.5

4.8
2.0
1.7
0.9
1.4

15.8
6.4
3.5
1.8
4.0

3.4
1.3
1.4
1.1
1.4

17.7
7.2
4.0
2.2
4.3

5.3
1.8
1.9
1.3
1.5

3.7
2.5
2.1
2.2
2.4

2,92
2,92
2,92
2,92
2,92

0.029
0.092
0.130
0.115
0.093

11.8
5.3
2.4
1.5
2.6

6.6
2.5
2.2
1.4
1.8

14.4
6.1
3.1
1.5
3.8

5.1
2.2
2.2
1.3
1.7

17.8
7.7
3.7
2.3
4.2

6.3
2.5
2.1
1.6
2.2

7.7
7.7
2.5
2.9
5.7

2,92
2,91
2,91
2,91
2,91

0.001
0.001
0.088
0.061
0.005

32.6
18.7
7.1
8.3
15.0
11.3
3.6
62.3
74.8
1.0

10.6
7.1
2.7
3.0
6.7
9.2
2.9
6.0
9.3
0.7

36.6
21.7
8.8
8.9
16.9
18.7
3.3
61.1
71.7
1.3

9.6
6.1
3.0
2.5
5.6
14.9
2.8
7.9
14.5
0.6

40.9
24.2
9.9
8.2
18.8
22.6
4.4
58.4
79.9
1.7

12.0
8.0
3.8
2.5
7.2
17.8
3.6
6.4
17.4
0.7

4.6
4.5
5.8
0.7
2.7
4.7
1.1
2.6
2.7
7.3

2,92
2,92
2,92
2,92
2,91
2,91
2,91
2,91
2,91
2,91

0.013
0.014
0.004
0.505
0.075
0.011
0.346
0.078
0.070
0.001

13.0
3.3
0.1
4.9
5.2
1.2

5.5
2.1
0.3
2.4
2.3
1.7

16.7
4.5
0.1
6.0
6.6
4.0

5.2
2.7
0.4
2.4
2.2
6.5

17.2
5.3
0.2
6.3
6.3
5.6

6.2
2.8
0.4
2.5
2.7
7.6

4.8
4.2
0.6
2.9
3.0
4.2

2,91
2,81
2,79
2,92
2,92
2,87

0.010
0.019
0.538
0.058
0.054
0.018

a

Zanarini scale
Total score
Affective disturbance score
Cognitive disturbance score
Impulsivity score
Disturbed relationship score
Zanarini scale,a self-rated
Total score
Affective disturbance score
Cognitive disturbance score
Impulsivity score
Disturbed relationship score
Borderline Evaluation of Severity Over Time
Total score
Thoughts and feelings score
Negative behaviors score
Positive behaviors score
Montgomery-Åsberg Depression Rating Scale
Modified Overt Aggression Scale
Young Mania Rating Scale
Global Assessment of Functioning Scale
Barratt Impulsiveness Scale
Symptom Checklist–90–Revised
Sheehan Disability Scale
Total score
Work/school
Social life
Family life/home responsibilities
Days lost
Days unproductive
a

Zanarini scale=Zanarini Rating Scale for Borderline Personality Disorder.

TABLE 3. Adverse Events Reported by Study Participants With Borderline Personality Disorder Who Received Quetiapine or
Placebo

Placebo (N=29)

Low-Dosage
Quetiapine
(150 mg/day)
(N=33)

Moderate-Dosage
Quetiapine
(300 mg/day)
(N=33)

Related to
Study Drug

Total

Event

N

%

N

%

N

%

N

%

N

%

Any adverse event
Sedation
Change in appetite
Dry mouth
Headache
Bodily pain
Hypersomnia
Dizziness
Forgetfulness or confusion
Nausea or vomiting
Cold/flu symptoms

25
15
4
1
8
12
3
1
3
8
4

86
52
14
3
28
41
10
3
10
28
14

29
25
9
9
7
11
5
5
6
8
8

88
76
27
27
21
33
15
15
18
24
24

30
28
13
14
13
12
8
7
5
9
7

91
85
39
42
39
36
24
21
15
27
21

84
68
26
24
28
35
16
13
14
25
19

88
71
27
25
29
37
17
14
15
26
20

78
67
25
24
23
20
15
13
12
12
0

82
70
26
25
24
21
16
14
13
13
0

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Am J Psychiatry 171:11, November 2014

BLACK, ZANARINI, ROMINE, ET AL.

FIGURE 1. Changes in Mean Total Score on the Zanarini Rating Scale for Borderline Personality Disorder Among Study
Participants Who Received Quetiapine or Placeboa
Mean Change From Baseline in Zanarini Scale Total Score

0

–4

–6

–8

–10

–12

a

Quetiapine, 300 mg (N=33)
Quetiapine, 150 mg (N=33)
Placebo (N=29)

–2

2

3

4

5

6
Visit

7

8

9

10

Solid lines represent least-square mean estimates; dashed lines represent estimates from the shared parameter model with linear and
quadratic effects. Results do not align completely because of differences in how group means are modeled and because the shared
parameter model corrects for informative dropout.

effect size (20.79) indicates that the drug had a large effect
on the primary outcome; improvement was greatest
between visit 2 and visit 6. The Zanarini scale total score
decreased 9.8 points (1.22 points per week) for the lowdosage (150 mg/day) quetiapine group, 7.9 points (0.99
points per week) for the moderate-dosage quetiapine (300
mg/day) group, and 6.0 points (0.75 points per week) for
the placebo group. Improvement of this magnitude is
comparable to or exceeds that seen in other treatment
trials in which the Zanarini scale was used (6, 7, 9, 12).
Improvement for the moderate-dosage quetiapine group
mirrored that of the low-dosage group through visit 6, but
then regressed (Figure 1). Because the moderate-dosage
quetiapine group did not receive the full 300-mg/day
dosage until after visit 6, this finding was not unexpected.
The low and moderate dosages were both superior to
placebo on many of the secondary efficacy variables. Thus,
this study joins a growing body of evidence showing that
a relatively brief course of quetiapine can provide clinically
meaningful benefit to borderline patients (12–16).
Improvement on the Modified Overt Aggression Scale
further suggests that quetiapine is superior to placebo in
treating verbal and physical aggression. This finding is
consistent with the improvement we observed among
participants in the moderate-dosage group on the Young
Mania Rating Scale, which taps irritability, aggression, and
verbal outbursts. We were surprised that there were no
significant differences on measures of impulsivity and
Am J Psychiatry 171:11, November 2014

depression between the groups because these symptoms
have been shown to improve in medication and psychotherapy trials (8, 14).
Low-dosage bested moderate-dosage quetiapine on the
primary outcome variable, but when all efficacy variables
are considered, the advantage of the lower dosage becomes
less apparent. Perhaps because the moderate dosage is
associated with greater levels of sedation, patients may
report feeling “worse” and thus be rated as more symptomatic. Or it could be that the moderate dosage is not as
effective and that the lower dosage is optimal.
Overall, 67% of participants completed the study, and
the differences between groups in study completion were
not significant. Adverse events were consistent with those
reported in previous studies in mixed groups of patients
(38), including sedation, change in appetite, dry mouth,
and dizziness; only sedation predicted discontinuation.
Changes in weight, serum glucose level, and lipid levels
were inconsistent and not significantly different between
groups, perhaps because of the relative brevity of the study.
Improvements were also observed in 62% of placebo
recipients. High placebo response rates have been a feature of controlled trials of borderline personality disorder
(14), so this rate was not surprising. Nonetheless, high
rates can lower statistical power and interfere with interpretation of study results. It is possible that placebo
recipients improved from the nonspecific psychological
support given during the study. One potential solution is
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QUETIAPINE IN BORDERLINE PERSONALITY DISORDER

TABLE 4. Comparison of Efficacy Measures for Study Participants With Borderline Personality Disorder Who Received
Quetiapine or Placeboa
Mean Change per Week
Low-Dosage
Quetiapine
(150 mg/day)

Placebo
Measure
Zanarini scale
Total score
Affective disturbance
Cognitive disturbance
Impulsivity
Disturbed relationship
Zanarini scale, self-rated
Total score
Affective disturbance
Cognitive disturbance
Impulsivity
Disturbed relationship
Borderline Evaluation of
Severity Over Time
Total score
Thoughts and feelings
Negative behaviors
Positive behaviors
Montgomery-Åsberg Depression Rating Scaleb
Modified Overt Aggression Scaleb
Young Mania Rating Scaleb
Global Assessment of Functioning Scaleb
Barratt Impulsiveness Scaleb
Symptom Checklist–90–Revised
Sheehan Disability Scaleb
Total score
Work/school
Social life
Family life/home responsibilities
Days lost
Days unproductive
a
b

ModerateDosage
Quetiapine
(300 mg/day)

Low-Dosage
Quetiapine Versus
Placebo

Moderate-Dosage
Quetiapine Versus
Placebo

Estimate

SE

Estimate

SE

Estimate

SE

d

SE

p

d

SE

p

–0.75
–0.32
–0.21
–0.09
–0.18

0.15
0.06
0.04
0.03
0.05

–1.22
–0.48
–0.34
–0.14
–0.32

0.15
0.07
0.04
0.03
0.05

–0.99
–0.38
–0.30
–0.13
–0.27

0.16
0.07
0.04
0.03
0.05

–0.79
–0.78
–0.63
–0.37
–0.75

0.36
0.42
0.28
0.26
0.38

0.031
0.068
0.023
0.156
0.051

–0.41
–0.32
–0.43
–0.30
–0.48

0.36
0.43
0.28
0.27
0.38

0.265
0.456
0.127
0.269
0.204

–0.58
–0.25
–0.15
–0.10
–0.14

0.18
0.08
0.06
0.04
0.05

–1.29
–0.47
–0.34
–0.17
–0.36

0.18
0.08
0.06
0.04
0.05

–1.28
–0.53
–0.35
–0.16
–0.32

0.19
0.09
0.06
0.04
0.05

–0.88
–0.70
–0.71
–0.39
–0.86

0.32
0.34
0.29
0.30
0.27

0.006
0.040
0.016
0.191
0.002

–0.87
–0.87
–0.73
–0.35
–0.73

0.32
0.34
0.29
0.29
0.27

0.007
0.013
0.013
0.232
0.008

–0.91
–0.46
–0.18
0.25
–0.59
–0.37
–0.11
0.62
–0.59
–0.07

0.31
0.20
0.08
0.08
0.18
0.43
0.06
0.19
0.26
0.02

–2.10
–1.29
–0.41
0.42
–0.85
–1.92
–0.26
1.05
–0.73
–0.11

0.32
0.20
0.08
0.08
0.19
0.42
0.06
0.20
0.27
0.02

–1.97
–1.21
–0.39
0.35
–1.05
–1.82
–0.30
1.04
–0.83
–0.12

0.33
0.21
0.08
0.09
0.19
0.43
0.06
0.21
0.27
0.02

–0.85
–0.90
–0.55
0.52
–0.31
–0.82
–0.40
0.49
–0.08
–0.47

0.32
0.31
0.28
0.35
0.32
0.32
0.21
0.33
0.21
0.28

0.009
0.004
0.054
0.146
0.328
0.014
0.060
0.135
0.719
0.099

–0.75
–0.82
–0.49
0.30
–0.56
–0.76
–0.50
0.49
–0.13
–0.62

0.32
0.31
0.28
0.36
0.32
0.32
0.21
0.33
0.21
0.29

0.020
0.009
0.079
0.407
0.083
0.020
0.019
0.141
0.536
0.033

–0.58
–0.10
–0.22
–0.25
0.05
–0.33

0.18
0.07
0.08
0.07
0.11
0.21

–0.85
–0.28
–0.27
–0.31
–0.33
–0.58

0.19
0.08
0.09
0.08
0.12
0.23

–1.11
–0.28
–0.36
–0.45
–0.36
–0.88

0.20
0.08
0.09
0.08
0.12
0.23

–0.38
–0.56
–0.17
–0.19
–0.49
–0.26

0.37
0.32
0.40
0.36
0.21
0.32

0.310
0.081
0.679
0.591
0.025
0.424

–0.72
–0.55
–0.46
–0.66
–0.54
–0.55

0.37
0.31
0.40
0.36
0.21
0.31

0.054
0.088
0.255
0.073
0.012
0.086

d=group difference mean change from baseline, divided by pooled baseline standard deviation; Zanarini scale=Zanarini Rating Scale for
Borderline Personality Disorder.
Shared parameter not used for outcomes that were measured only at visits 2, 6, and 10. Mean change per week was calculated using each
group’s linear and quadratic effects.

to conduct longer trials, but patients would have to be
willing to participate in lengthier trials. Alternatively, studies could benefit from an extended lead-in period to minimize
the impact of the placebo effect, since early responders would
not be randomized.
The study had several methodological limitations. First,
the noncompletion rate was 33%. While this rate is not
unusual for trials of borderline personality disorder (8, 13),
investigators need to address the issue of attrition. Second,
stringent criteria excluded people with current major
depression, posttraumatic stress disorder, panic disorder,
obsessive-compulsive disorder, and substance dependence to ensure a greater focus on changes in borderline
symptoms rather than in comorbid disorders. For that

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reason, the results may not generalize to borderline
patients with these disorders. Finally, while quetiapine
was effective in treating many symptoms of borderline
personality disorder, its adverse effects must be taken into
consideration. We believe the results should generalize
to the use of immediate-release quetiapine because the
active ingredient is identical to that in extended-release
quetiapine.
Additional trials are needed to confirm the efficacy of
quetiapine in borderline personality disorder. Trials in
which quetiapine is tested against other psychotropic
agents and combination trials in which quetiapine is
added to an evidence-based psychotherapy could also be
helpful.
Am J Psychiatry 171:11, November 2014

BLACK, ZANARINI, ROMINE, ET AL.

Received Oct. 12, 2013; revisions received March 17 and April 28,
2014; accepted May 6, 2014 (doi: 10.1176/appi.ajp.2014.13101348).
From the Department of Psychiatry, University of Iowa Carver College
of Medicine, Iowa City; McLean Hospital, Harvard Medical School,
Belmont, Mass.; and the Department of Psychiatry, University of
Minnesota Medical Center, Fairview, Minneapolis. Address correspondence to Dr. Black (donald-black@uiowa.edu).
Dr. Black receives royalties from American Psychiatric Publishing,
Oxford University Press, and UpToDate. Dr. Schulz has received
research support from Forum, Myriad RBM, and Sunovion and has
served as a consultant to Eli Lilly, Forum, Genentech, and Teva. Dr.
Zanarini receives royalties from American Psychiatric Publishing and
Jones & Bartlett. The other authors report no financial relationships
with commercial interests.
Supported by a grant from AstraZeneca to Dr. Schulz, with
subcontracts to Drs. Black and Zanarini.
The authors thank Drs. Michael Burgard, Katherine Gilligan, Jeffrey
Jacobson, Dustin DeYoung, Tom Salter, and Siddharth Bajpai for
assisting with the study.
Clinicaltrials.gov identifier: NCT00880919.

12.

13.

14.

15.

16.

17.

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E, Pérez V: Ziprasidone in the treatment of borderline personality

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open-label trial. Ann Clin Psychiatry 2008; 20:219–226
Perrella C, Carrus D, Costa E, Schifano F: Quetiapine for the
treatment of borderline personality disorder; an open-label
study. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:
158–163
Van den Eynde F, Senturk V, Naudts K, Vogels C, Bernagie K,
Thas O, van Heeringen C, Audenaert K: Efficacy of quetiapine
for impulsivity and affective symptoms in borderline personality disorder. J Clin Psychopharmacol 2008; 28:147–155
Villeneuve E, Lemelin S: Open-label study of atypical neuroleptic
quetiapine for treatment of borderline personality disorder: impulsivity as main target. J Clin Psychiatry 2005; 66:1298–1303
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quetiapine in the treatment of borderline personality disorder:
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Zanarini MC, Frankenburg FR: Self-Report Version of the
Zanarini Rating Scale for Borderline Personality Disorder. Belmont, Mass, Mclean Hospital, 2008
Pfohl B, Blum N, McCormick B, St John D, Allen J, Black DW:
Reliability and validity of the Borderline Evaluation of Severity
Over Time (BEST): a self-rated scale to measure severity and
change in persons with borderline personality disorder. J Pers
Disord 2009; 23:281–293
Barratt E: Anxiety and impulsiveness related to psychomotor
efficiency. Percept Mot Skills 1959; 9:191–198
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Guy W (ed): ECDEU Assessment Manual for Psychopharmacology: Publication ADM 76-338. Washington, DC, US Department
of Health, Education, and Welfare, 1976, pp 534–537

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34. Mori M, Woolson RF, Woodworth GG: Slope estimation in the
presence of informative right censoring: modeling the number
of observations as a geometric random variable. Biometrics
1994; 50:39–50
35. Mazumdar S, Tang G, Houck PR, Dew MA, Begley AE, Scott J,
Mulsant BH, Reynolds CF 3rd: Statistical analysis of longitudinal
psychiatric data with dropouts. J Psychiatr Res 2007; 41:1032–
1041

36. Fitzmaurice GM, Laird NM, Ware JH: Applied Longitudinal
Analysis. New York, John Wiley & Sons, 2004
37. SAS Institute: SAS/STAT 9.1: Users Guide. Cary, NC, SAS Institute, 2004
38. Calabrese JR, Keck PE Jr, Macfadden W, Minkwitz M, Ketter TA,
Weisler RH, Cutler AJ, McCoy R, Wilson E, Mullen J BOLDER Study
Group: A randomized, double-blind, placebo-controlled trial of
quetiapine in the treatment of bipolar I or II depression. Am J
Psychiatry 2005; 162:1351–1360

Clinical Guidance: Quetiapine for Borderline Personality
Disorder
Six weeks of extended-release quetiapine at a dosage of 150 mg/day significantly
reduces symptoms of borderline personality disorder. In the trial by Black et al.,
300 mg/day was not significantly superior to placebo and produced more side
effects than low-dosage quetiapine. In an editorial, Tohen (p. 1139) cites the 3-lb
weight gain in the group receiving 300 mg/day of quetiapine—compared with 1 lb
for placebo and low-dosage quetiapine—and stresses the need for consideration of
long-term effects.

1182

ajp.psychiatryonline.org

Am J Psychiatry 171:11, November 2014

Appendix B

-’I
for Unanticipated Problems Involving Risks t

ectsor Others

0709M16844
[Charles Schulz, MD
Seroquel XR for the Management of Borderline
Personality Disorder (BPD) ____

IRB S tudy Number:
Current Principal Investigator.
Primary Title:

Provide the following information for each unanticipated problem/event that is serious and
possibly related to the research procedures. Attach any summary or report from sponsor or
DSMB with corresponding reference #.

Reference
Date of Event:
Date of Report:
On-site

0

Astrazeneca Study #IRUSQUET0454
2010
2010
Off-site

M

Initial report

Z

Follow up report

Describe problems/event:
Misuse of study medication: study medication misused by two study subjects and given to others.
Incident report included with this document.
Possibly related LIII Probably related LII Definitely related
Does this problem/event alter risk to past, present or future subjects?
Yes III
Don’t Know (Insufficient Information)
No El

E]

Based on your, the local investigator’s judgment, should this problem/event be added to the
consent form as a potential risk?
Yes
LIII Provide revised consent form with changes highlighted.
Z Explain why not:
No
The incident did involve a direct risk to study subjects taking the study medication.

Based on your, the local investigator’s, analysis of this problem/event,
should currently enrolled subjects be notified?
YeSEI
should subjects who have completed the study be notified?
Yes [11111
Explain:
The safety of the two study subjects was not affected by this incident.

Principal InvestigatorSit

Date

No
No

Study: Seroquel XR for the Management of Borderline Personality Disorder
(BPD)

1YJ (1

P: S. Charles Schulz, MD

till,’
l,i1iIItrr1Th
Date of Report:

ISIISJ

Study patient
was enrolled into study on
2010 and
randomized to study medication (Seroquel XR or placebo) on
2010,
current residence was Alpha House Residence. Alpha House is a
residential program which provides high levels of structure and supervision for
sex offenders within a therapeutic community setting and is licensed and certified
by the Minnesota Department of Corrections.
Study patient
was enrolled in study on
2010 and
randomized to study medication on
2010.
current residence was
Alpha House Residence,
returned to research clinic for study visit 3 on
2010.
did not return visit 2 study medication bottle stating he forgot
it at home.
’eminded to return study med bottle at next visit and he agreed.
received visit 3 assessments and new bottle of study medication was
dispensed to him, Seroquel XR or placebo, 30 tablets with instructions to take 3
tablets at bedtime (150mg or placebo).
did not return to study visit 4 on
2010. Study coordinator phoned Alpha House residence line and
was not available. Study coordinator left message regarding
missed
appointment. Study coordinator then received a phone call from
who was
calling in for final follow-up after study withdrawal,
informed study
coordinator that
had ’gone back to prison’ on
2010.
On Tuesday
2010 Study coordinator received phone call from
acquaintance of
stating
iad ’got locked up again.’ Study coordinator
received second phone call from Alpha House staff person Alexis stating
had signed a release of information for study staff. Alexis stated
had been
re-imprisoned due to an incident involving the study medication as follows.
reported to Alpha House staff that he had only taken 1 dose of his study
medication (1 tablet of Seroquel XR 50mg or placebo) and did not like the effects
of the medication. He then gave
6 tablets of his study medication.
returned to research clinic for visit 3 on 18 MAY 2010 and returned his bottle of

stated he felt overly sedated by
study medication with 3 tablets remaining,
the study medication, and did not wish to continue in the study.
was employed as the full-time cook at Alpha House, Per Alexis on the
morning of
2010 BRE cooked and served oatmeal to 1520 persons at
Alpha House, 4 of which were staff members. Some residents noticed pink
particles in the oatmeal. After eating breakfast the residents and staff reported
feeling sedated and some were knocked out’ for the remainder of the day.
Staff asked
if he had put the study medication into the oatmeal and
denied it. After failing a polygraph test
was re-imprisoned.
Study medication blind was broken by Investigational Drug Services (IDS)
pharmacy at the University of Minnesota on
2010. Blind reveals
was randomized to Seroquel 150mg arm and
was randomized to
Seroquel 300mg arm. Both arms start out on daily dose of Seroquel XR 50mg at
bedtime for I week, and then increase to 150mg at bedtime for 2 weeks.
Remaining study drug for kits
pharmacy for destruction.

and

to be returned to IDS

2

UNIVERSITY OF MINNESOTA
Twin Cities Campus

Human Research Protection Program

011ice ofthe Viii I’,rsjclejt! fm Research

/)528 Maya Memorial Building
420 Delawase Street S. E
MMC 820
Minneapolis. MN 55455
Office: 6/2-626-5654
Icv. 612-620-6061
E-mail: jib @ scm/s. edo or jbc @ cmiii es/is
IVebsile: Iinp://researcli. (s,,in.edf/sisbfcts/

06/21/2010
Sellmann C Schulz
Psychiatry Department
F282/2A West-B
2450 Riverside
Minneapolis, MN 55454
RE: "Seroquel XR for the Management of Borderline Personality Disorder: A Randomized
Double-Blind Comparison with Placebo’
IRB Code Number: 0709M16844
Dear Dr. Schulz:
At its meeting on June 17, 2010 the Institutional Review Board (IRB) reviewed and noted
unanticipated problem and adverse event report for the referenced study. The following reports
were included in this review: AstraZenica Study #IRUSQUET0454, event date: May 17, 2010,
report date: May 27, 2010.
Thank you for keeping the IRB informed of the status of your research.
As Principal Investigator of this project, you are required by federal regulations to inform the
IRB of any proposed changes in your research that will affect human subjects. Changes should
not be initiated until written IRB approval is received. Unanticipated problems and adverse
events should be reported to the IRB as they occur. Research projects are subject to continuing
review and renewal.
If you have any questions, call the IRB office at 612-626-5654.

We have created a short survey that will only take a couple of minutes to complete. The
questions are basic, but will give us guidance on what areas are showing improvement and what
areas we need to focus on:
httt)s://umsurvev.umn.e.du/index.t)ho?sid=36122&langfum
Sincerely,

*rt--

Andrew Allen
Research Compliance Supervisor
AAIks
CC: Scott Crow, Peter Milev, Michael Miller, Richelle Moen, Ann Romine, John Vuchetich

Appendix C

University of Minnesota

Review Period:

01/10/2008-01/09/2009

-Continuing-Rev-iew-of-IRB-^Pending-

Rev; 03/01/2005

:M.e.dica,LResearch ..—-=^

-Study" Number:-0709M168-44- --- - -..----.-

Principal Investigator: Sellmann C Schulz
Title(s): Seroquel XR for the Management of Borderline Personality Disorder:
A Randomized Double-Blind Comparison with Placebo !
Study Status
Active (Enrolling Subjects)

Funding Source(s)

AGENDA.

i^M JMSL

Funding Source:
Funding Type:
Funding Source: AstraZeneca

Funding Type: OTHER
Personnel

Schulz, Selimann (P. I.)
Crow, Scott (Co-lnvestigator)
Milev, Peter (Co-lnvestigator)
Miller, Michael (Co-lnvestigator)
Moen, Richelle (Co-lnvestigator)
Romine, Ann (Correspondent)

Investigational Drug(s)
IND Number: 45,456
IND.Holder: AstraZeneca (Sponsor)

IDS Number: 3462

Study Enrollment
Number of Subjects Approved for study:

50

Number of subjects enrolled this review period:
Male Female Unknown

T

T

Total

0 ~T2~

The University of Minnesota is an equal opportunity educator & employer.
© 2004 by the Regents of the University of Minnesota,

Page 2

Page 1

Number of subjects enrolled to date:
-Male- —- —-Female- ~~~" "Unkn'own •

^_1=1———\-0 —^2=^.
Is this a multi-center study?
Yes
Total national accrual to date; 2

Unanticipated Problem Reporting
Since the most recent IRB continuing review approval, have any participants withdrawn from the
research?

No
Since the most recent IRB continuing review approval, have any participants complained about the
research?

No
Have any serious and unexpected adverse events been reported to the IRB?
No

Study Suimmary
Summarize preliminary information about any results and/or trends:
In beginning phases of enrollment with 2 subjects enrolled.

Have there been any changes in protocol approved by the IRB since last continuing review?
No
Since the most recent IRB continuing review approval, have there been any progress reports on the
research?

No
Since the most recent IRB continuing review approval, have there been any multi-c.enter trial reports?

No
Since the most recent IRB continuing review approval, have there been any other information
relevant to this research discovered, especially information about the risks and benefits associated
with the research?

The University of Minnesota is an equal opportunity educator & amployer. Page 2
© 2004 by the Regents of the University of Minnesota.

PageS

No
Since the most recent IRB continuing review approval, have subjects experienced any benefits?
Yes
2 acti.ve subjects report receiving benefit frpm.stydy.participatjon {.hys_far,

External Findings
Is there anything in the relevant recent literature that the IRB should know about concerning this
research?

No

Consent/Assent Forms
Have there been any changes to the consent and/or assent form(s) since the last IRB approval?
No
Have. translated consent short forms been used in conjunction with an interpreter to obtain consent

for this study?
No

Other Comments
Study start has been slgnigicantly delayed by contract hold-ups.

The University of Minnesota is an equal opportunity educator & employer. Page 3
© 2004 by the Regents of the UnlvsrsityofMlnnssota.

Page 4

rP-Tr"—-—S-cbulz,:Sellman=^—•^""—=—'O.TiiveFsity^'f-M:imeso'^

HSC#; 0709M16844 Research Subject's Protections Programs
Reviewer: • Institutional Review Board

-Meeting-Date:- -—— • — — - -- "—-———- - —- — - —• — •-—
Full Committee Review—Continuing Review of Approved Research
If you choose to submit this form eleytt-onically, please send to u-b(%umn.edu.
"/in IRS shall conduct 'continuing review of research covered by this policy ut inte.n'als appropriate to the
degree ofmk, but not less than once per year, andfsha/i have the aulhorUy to ohaen'e or have a third party
ohseri'e the consent process and the research."

21CFRS6.109 and 45CFR46.109
"Continuing, review ofresuurch must be siibslcuiiive and meamngfiil."
OffRP Guidance on Continumg Review 1-15-07

Study status: [X] Enrolling subjects
Following subjects

D On hold

Closed to enrollment
Study Enrollment: Note any issues. Is enrollment as expected, has PI overenroHed, is
there a lack of subjects or are they nearing approved totals? Is the PI requesting more
subjects OR should PI request more subjects?

2 of 50
Funding; Any changes in the last year? Q Yes • D No

Federally funded? . D Yes D No
Study personnel; Any personnel changes in the last year? Q Yes Q No
Are personnel lists in agreement with recent Con Ren form and consent forms?

D Yes D No
List discrepancies: Nathalie Vizueta, MA. listed on consent - not listed on con rev form
Conflict of Interest: Have there been any change in COI in the last year?

Yes Q No
Investigation al Drugs or Devices: Have there been any changes or additions in the

last

year?

Q

Yes

Q

No

UPTRTSOS (unanticipated problems or serious adverse events): Since the most recent
IRB continuing review approval have there been any UPIRTSOS to report?

D Yes D No
List issues or concerns: none given

Page 22

Study Summary: Is the summary descriptive enough to assess ongoing risk and
benefit -in relation to the length and complexity of the study?
l-.Y-es-"" Q-No-

Comments: study just started enrollment - two patients receiving medication have reported benefit
External Findings (such as interim analysis or DSMB reports, etc.): Tins report
should reflect how long the study as been open.

Yes Q No
Comments: none to report
Consent and Assent Forms: Are forms current for 1KB practice and/or standards?

D Yes D No
If the risks and/or benefits are not described accurately the committee should discuss and
make a determination. (Please edit forms and hand in edited, forms to IRB staff.)
Comments:

Inclusion of Children in Research:
If children are included in this research confirm that they should still be included m this

research. Q Yes D No [X] NA
(According to Subpart D and tlie requirements for pennisyion by parents or guardians and
for assent by children, 45CFE46.408, see yellow sheets).
If children are included this inclusion must meet one of the following criteria for
risk/beuefit assessment according to federal regulation (21CFR56 and 45CFR46 Subpart
D, see yellow sheets),

[_] (404) Minimal risk
Ij (405) Greater Ami minimal risk; but holds prospect of direct benefits to subjects.
(406) Greater than minimal risk; no prospect of direct benefit to subjects, but likely to
yield generalizable knowledge about the subject's disorder or condition.

Page 23

Criteria for IKB_AKProva]:

Confirm that the criteria for IRB approval are still met.
(21CFR56.111 and45CJ?R46.ni)
II Risks to subjects arc minimi/.ed
[_] Risks to subjects are reasonable in relation to anticipated benefit, If any, to subjects,
and the importance of the knowledge that may be expected to result
Q Selection of subjects is equitable
II Informed consent will be sought from each prospective subject or the subject's legally
authorized representative, in accordance with 21CFR50 and/or 454CFR46.116
Q Informed consent will be appropriately documented, in accordance with 21CFR50.27

and/or45CTR46.U7
Where appropriate, research plans make adequate provisions for monitoring the data
collected to ensure the safety of subjects, QYes |[ NA
Where appropriate, there arc adequate provisions to protect the privacy of subjects and to
maintain confidentiality of data. • QYes D NA
Where appropriate, vzilncrable populations have adequate protection; risk and benefit
analysis confirms their inclusion in the research. [_JYes Q NA

General questions:
**m' questions 1-4 are YES please address and document in the comments and
discussion section.

1. Does the ongoing continuing review information indicate any alteration in the risk and
benefit balance or ratio from previous reviews? Q Yes Q No
2. Does the consent or assent form(s) require revision or updating? Q Yes ' || No
3. Does the ongoing continuing review information prompt notification ofstudy subjects

already enrolled? Q Yes Q No
4. Should the committee request or seek verification of information from other sources,
such as DSMB, fonder, sponsor, or literature search? [_] Yes D No
If question 5 is NO please address and document in the con-iments and discussion section.

5. If vulnerable populations previously were subjects should they continue to be included

in this research? Q Yes • Q No DNA

Page 24

-I.s-lh v-i'-vy-i tiW—iutciLv.d 1-s ti ll-ap.p r-o.pEiii.te-toi—this^s.tu.dy-i

For continuing review approval federal regulations state that studies need to be reviewed
no-iess-that yearly-but the-committcc may-set continuing-feview-at-a-morefi'equentinterval.

Check the review interval appropriate for tllis study:
Annually
D Every 6 months

Q Quarterly
Other interval (state specific renewal interval and provide justification)

Committee Determination:
Cannot make "suggestions " due to automatic email, suggestions must be listed as

stipulations
Q Approved as Submitted: no change required in ongoing approval
Approved with Stipulations: as noted
Response to original reviewer
Q Response can be reviewed by expedited review (by senior staff)
Approval Deferred: additional information required. This is a serious decision as
deferral halls all research processes. Committee should 'consider subject status and

funding issues. Response will go back to the continuing review committee for review
Common stipulations:

Update Contacts and Questions section information on the consent forms;
i.e. "University of Minnesota Medical Center Fairview"

D Add HIPAA reference on the consent form.
D Add the human subject code numbcr/page numbers/version date to all pages of the
consent forms,

The 1RB should observe the consent process or the research,
n Reapply as required every 5 years,
I have completed a substantive and meamngfyl review based ou.the information
made available at this time.
Print name of reviewer: KG Johnson

Signed name of reviewer;

Date: 12/17/2008

PagaZb

-D o Gum ent-items-fo i^eommittee-iidis cus sioti^-b elo w:-

Document "comments, changes, and stipulations" below:
(write out stipulations clearly)

Nathalie Vizueta, MA. listed on consent and not listed on con rev form
Correct address for out-of study contact Information - remove room number, and correct street
number

Page 26

Committee Meeting Minutes
December 17, 2008

Agenda Item:i
Continuing Review-Medical

PI: Schulz, Sellmann

Reviewer: Johnsotf
Reviewer; Belew

Agenda Item: None
Agenda Item: None

Protocol Title arid HSC#:"Seroquel^^^^fo^
ARandomiZed^ouble^UudG^mparuoni?^Placebo^
Item Description:
None;.l"?;

(Discussion of Controverted Issues Summary:
There were no controverted issues.

iRevisiftnSt<31anlications.ibr'StipuIatwns^yW^
• Correct the following standard language in the Contacts and Questions section of the consent form: If you
have any questions or concerns regarding the study and would like to talk to someone other than the researcher(s),
you are encouraged to contact the Fairview Research Helpline at telephone number 612-672-7692 or toll free at 866508-6961. You may also contact this office in writing or in person at University of Minnesota Medical Center,
Fairview Riverside Campus, 2200 Riverside Avenue, Minneapolis, MN 55454.

]Ghange in Risk/Benefit Balance:
None

Committee Must Address:

B 21CFR56.111 &45CFR46.111
(Applicable Criteria Met)

D45CFR46-SubpartB
(Research Involving Pregnant Women or Fetuses)

D 21CFR50.23 &45CFR.116

D 45CFR46-Subpart C

(Waiver or Alteration of Consent Process)

(Research Involving Prisoners—Indicate Level of Risk, e.g. Minimal or
Greater Than Minimal)

D 21CFR50.27 &45CFR46.117
D 21CFR50 & 45CFR46-Subpart D

(Waiver of Consent Documentation)

(Research Involving Children—Detail Inclusion or Exclusion Justification
and Indicate Level of Risk, e.g. Minimal or Greater Than Minimal,
Describe Consent Requirements as Specified in 21CFR50.55 and

45CFR46.408)

Determinations and Justifications Required by Regulations and Guidelines;
None

IRB Decision:

Length of Approval: One Year

Approve Continuing Review with Stipulations
Additional Info: None

Vote Yes: 6

No: 0

Abstain: 0

Members Not Present for Vote Due to Conflict of Interest: Dr. Scott Crow

Not Present:

12/19/2008
...S.e;llmann.C.S.chulz._

.

,

\..^-

:fM^

Psychiatry Department \ \^'^
'

F282/2AWest-B

.

^

2450 Riverside
Minneapolis, MN 55454

RE; "Seroquel XR for the Management of Borderline Personality Disorder: A Randomized
Double-Blind Comparison with Placebo"

IRB Code Number: 0709M16844
Dear Dr. Schulz,

.At the meeting on December 17, 2008, the IRB; Human Subjects Committee reviewed the
referenced study. The following stipulations must be resolved, mid written approval should be
received, before renewed approval is confirmed,
The following changes to the consent form are stipulated;
• Correct the following standard language in the Contacts and Questions section of the
0 consent form: If you have any questions or concerns regarding the study and would like to
talk to someone other than the researcher(s), you are encouraged to contact the Fairview
Research Helpline at telephone number 612-672-7692 or toll free at 866-508-6961, You
may also contact this office in writing or in person at University of Minnesota Medical
Center, Fairview Riverside Campus, 2200 Riverside Avenue, Minneapolis, MN 55454.
^

..

.

,

...

.•

Please provide a copy of the revised consent form for review.

We cannot confirm the renewal of the referenced study until these conditions are met, If your
response is not received within ninety days, the study will be filed inactive.
Please send your response to RSPP (Mayo Mail Code 820; D-528 Mayo Memorial Building; 420
Delaware St, SE; Mmncapolis, MN 55455) The entire application does not need to be resubmitted;
your, response should address the sections requiring change. The signature of the Principal
Investigator is the only signature required with the response. Only one copy of the response is
necessary,

If you have any questions, please contact the IRB office at 612-626-5654.
Sincerely,

Andrew Alien
Research Compliance Supervisor

AA/mq
CC: Scott Crow, Peter Milev, Michael Miller, Richelle Mocn, Ann Romine, Nathalie Vizueta

Page 1

Date: 01/06/2009
To: S. Charles, Schulz (scs@umn.edu)
From: irb@umn.edu

Subject: #STUDYNBR# - PI #PILASTNAME# - IRB - APVD Continuing Review
Message: TO : crowx002@umn.edu, scs@umn.edu, romi0004@umn.edu, nvizueta@umn.edu,
moenx008@umn.edu, mjmiller@umn.edu, milev002@umn.edu,

The IRB: Human Subjects Committee renewed its approval of the referenced stidy
listed below:

Study Number: 0709M16844
Principal Investigator: Sellmann Schulz

Expiration Date: 12/16/2009
Approval Date: 12/17/2008
Title(s):
Seroquel XR for the Management of Borderline Personality Disorder: A Randomized
Double-Blind Comparison with Placebo
This e-mail confirmation is your official University of Minnesota RSPP notification of
continuing review approval. You will not receive a hard copy or letter.

This secure electronic notification between password protected authentications has
been deemed by the University of Minnesota to constitute a legal signature.
You may go to the View Completed section of http://eresearch.umn.edu/ to view or
print your continuing review submission.

For grant certification purposes you will need this date and the Assurance of
Compliance number, which is FWA00000312 (Fairview Health Systems Research

FWA00000325, Gillette Childrens Specialty Healthcare FWA00004003). Approval
will expire one year from that date. You will receive a report form two months before
the expiration date.

In the event that you submitted a consent document with the continuing review form, it
has also been reviewed and approved. If you provided a summary of subjects'
experience to include non-UPBRTSO events, these are hereby acknowledged.

As Principal Investigator of this project, you are required by federal regulations to
inform the IRB of any proposed changes in your research that will affect human
subjects. Changes should not be initiated until written IRB approval is received.
Unanticipated problems and adverse events should be reported to the IRB as they
occur. Research projects are subject to continuing review.

If you have any questions, please call the IRB office at (612) 626-5654. The IRB
wishes you continuing success with your research.

University of MinneAQta.

KUVIBW Pertofl'

10/29/2008-12/16/2009

GontinuingReview-of-lRB-- Pending

Rev: 03/01/2005

Medical Research

Study Number: 0709M16844
Principal Investigator: Sellmann C Schulz
Title(s): Seroquel XR for the Management of Borderline Personality Disorder:
A Randomized Double-Blind Comparison with Placebo
Study Status
Active (Enrolling Subjects)

AGENDA

Funding Source(s)
Funding Source: AstraZeneca

,_£^^0^

Funding Type: OTHER
PersonneS
Schulz, Sellmann (P. I.)
Crow, Scott (Co-lnvestigator)
Milev, Peter (Co-lnvestigator)

Miller, Michael (Co-lnvestigator)
Moen, Richelle (Co-Investigator)
Romine, Ann (Correspondent)
Thompson, Marian (Co-lnvestigator)

Study Enrollment
Number of Subjects Approved for study;
50
Number of subjects enrolled this review period:

Male Female Unknown Total

K

]1

-E

Number of subjects enrolled to date:
Male Female Unknown
10^

-n

Total

Is this a multi-center study?
Yes
The University of Minnesota Is an equal opportunity educator & employer,
© 2004 by the Regents of the University of Minnesota.

Page 1

Total national accrual to date: 14

Unanticipated Problem Reporting
Since the.most recent IRB conlinuing review approval, have any participants withdrawn from the
research?
Yes-

2 subjects have withdrawn due to intolerability of study medication. 1 subject withdrew at visit 10 for reasons
unknown,

Since the most recent IRB continuing review approval, have any participants complained about the
research?

No
Have any serious and unanticipated problems been reported to the IRB?

No

Study Summary
Summarize preliminary information about any results and/or trends;
Majority of subjects enrolled have completed study or are currently active In study. Many have reported and
presented reduction in symptoms of BPD. Medication intolerabllity reported by at least 2 subjects in the form of
sedation.

Have there been any changes in protocol approved by the IRB since last continuing review?
Yes
We are developing protocol amendment #2 and will submit in paper copy with this form.

Since the most recent IRB continuing review approval, have there been any progress reports on the
research?

No
Since the most recent IRB continuing review approval, have there been any multi-center trial reports?

No
Since the most recent IRB continuing review approval, have there been any other information
relevant to this research discovered, especially information about the risks and benefits associated
with the research?
No
Since the most recent IRB continuing review approval, have subjects experienced any benefits?

The University of Minnesota is an equal opportunity educator & employer. Page 2

©2004 by tha Regents of the UnivgrsllyofMlnnBsota.

Page 4

Yes
-Many~subJe'cts-h'aVB-re'po'rted-aTTd presenteclTecluctlomn symptoms of'BPD7

External Findings
Is there anything in the relevant recent literature that the IRB should know about concerning this
research?
No

Consent/Assent Forms
Have there been any changes to the consent and/or assent form(s) since the last IRB approval?
Yes
We are submitting a revised consent uploaded with this form, dated 30 SEP 2009. The revision is on p. 9,
highlighted in yellow, change form Signature of Investigator to Signature of Person Obtaining Consent.

Have translated consenl short forms been used in conjunction with an interpreter to obtain consent

for this study?
No

Other Comments

The Unlvarsity of Minnesota is an equal opportunity educator & employer. Page 3

© 2004 by tha Regents of (he Univeralty of Minnesota,

Page 6

I

PI: Schulz University of Minnesota

HSC #: 0709M 16844 Human Research Protection Program
Reviewer: Dees Institutional Review Board
-Meetmg-Date; 1-ZT6/2009 —

Full Committee Review—Conitmiuiing Review of Approved Research
••»••!

"An IRB shall conduct mntinuing revie\v of research covered by this policy at intervals appropriate fo the degree of
mk, but not less than once per year, and shall have the authority to observe or have a third party obsewe the
consent process and the research. " 2!CFR56.J09 and45C.FR46.109
"Contmnlng review of research must be substantive and meaningfid," OIIRP Guidance 1-15-07

Short Title: To determine the safety and efficacy of Seroquel XR for treatment of Borderline
Personality Disorder
Enrollment: ^ Open Q Closed Q On hold
Treatment: ^ Continues Q Complete [_| Not a treatment study
Follow-up: [3 Continues d Complete D No follow-up required
Funding; Q Federal [X] Sponsored Q Foundation Q Departmental
Enrollmient Numbers: Approved: 50 Enrolled: 6 Years active: 2

UPIRTSOs (Unanticipated Problem Involving Risk to Subjects or Others):
Have any UPIRTSOs been reported in the last year? Q Yes ^ No
Are there concerns to be discussed by the Committee? |_| Yes DO No

Study Summary: Q Adequate D Deficient
None - too early Q None - data analysis elsewhere

External Findings: D DSMB letter D Progress report Q Action letter
Consent and Assent Forms: ^ Submitted Q Missing Q Waived or not applicable
HIPAA Forms; 0 Submitted ^ Missing Q Waived or not applicable
Closed to enrollment - forms are no longer pertinent
Are all persons listed on consent form also listed on the 1RB roster? Q Yes Q No

Inclusion of Children in Research;
If children are included in this research confirm that they should still be included,

Yes D No [X] NA - children excluded
If children are included this inclusion must meet one of the following criteria for risk/bcnefit
assessment according to federal regulation (21CFR56 and 45CFR46 Subpart D),

(404) Minimal risk
.D.(4P5).<Jreaterthanmlmmal nsk; buthplds prospect of direct benefits to subjects.
Q (406) Greater than minimal risk; no prospect of direct benefit to subjects, but likely to
yield generalizable knowledge about the subject's disorder or condition,

University ol'Minnesotn JRB
Continuing Review Form

Version 10/27/09
Page 26

Substantive Changes: If any of the following are evident from the continuing review,
describe the changes for Committee discussion,

D Change in funding
Q Change in conflict of interest

D Change in risk or benefit
Q Change in subject population

Change in data management

Minor changes in consent form
II Major changes in consent form

Items for Committee Discussion:
1. Staff-Note that second consent form that appears on the flash drive and displaying IRB Approval; 30
Sep 2009 in footer is the most recent version
2. Was Appendix A completed and submitted with the original appl,? It is not in the circulation copy on the

flash drive," ' ' "^\\\^\^^t.

2. Consent form-ls there a reason why the standard research related injury wording was previously
approved rather the the language for a sponsored study?
Recommended Stipulations:
1. Submit copy of current HIPAA form
2.^CooseftHorm7R151<s7D!scomfoiS-and Incovgntences secttCTnTp, 5, 6th paragraph
_Eroyide_aD-fixpteftatien-of lliu lytin''yxtrapyrafflidaP-er-substitute a wer4^Mvordstclay language

Recommended Suggestions:
1, Consent form, Alternative Treatment section, p, 7

Delete the '0" that appears between the first and second sentences
Recommended Action:
Click to Show
Criteri.a for
Approval

Approve as Submitted
Approve with Suggestions
Approve with Stipulations as noted
D Response to original reviewer
Response can be reviewed by IRB staff
Approval Deferred - additional information required

Continuing Review Interval: ^ Annually
Every 6 months

D Quarterly
D Other interval;
I have completed a substantive and meaningful feview based on the information made available
at this time,

Print name of reviewer Alfred Dees Date: 12/16/2009

Signed name of reviewer:
If you choose to submit this form electronically, please send to irb(%umn.edu.
Forms submitted from a umn.edu account do not need a hard-copy signature,

University of Minnesota IRB
Continuing Review Form

Version 10/27/09
Page 27

•. ^

PI; Schulz University of Minnesota
HSC#: 0709M16844 , Human Research Protection Program
Reviewer: Kracn Institutional Review Jjoard

"MeefmifDaie:—T2/T6?2009Full Committee Review—Continumg Review of Approved Research
•••••••

"An 1RB shall conduct continumg, review of research covorsdby {his policy at intervals appropriate to the degree of
rink, hut no! less than once. per year, and shall have the.authwily to observe or have a third party ohsei've the
cement process and the research. " 2JCFR56. f Off and 45CFR46.109
"Continuing review of research nmst be substantive and meaningful." OIIRP Guidance 1-15-07

••« un • i

Short Title: Seroquel XR for the management of borderline personality disorder: RCT

Enrollment: [^ Open Q Closed [_] On hold
Treatment: [x] Continues Q Complete [_] Not a treatment study
Follow-up; ^ Continues D Complete Q No follow-up required
Funding; Q Federal ^ Sponsored Q Foundation Q Departmental
EmrommentNmmbers: Approved: 50 Enrolled: 6 Years active: 2

UPIRTSOs (Unanticipated Problem Involving Risk to Subjects or Olhers):
Have any UPIRTSOs been reported in the last year? Q Yes [El No
Are there concerns to be discussed by the Committee? Q Yes |^ No

Study Summary: 13 Adequate D Deficient
None - too early [_] None - data analysis elsewhere

External Findings; Q DSMB letter Q Progress report Q Action letter
Consent and Assent Forms: [^ Submitted Q Missing Q Waived or not applicable

HIPAA Forms: Q Submitted |E1 Missing Q Waived or not applicable
Q Closed to enrollment - forms are no longer pertinent
Are all persons listed on consent form also listed on the IRB roster? [^ Yes D No

Inclusion of Children in Research:
If children are included in this research confirm that they should still be included.

Yes I I No DO NA - children excluded
If children are included this inclusion must meet one of the following criteria for risk/benefit

assessment according to federal regulation (21CFR56 and 45CFR46 Subpart D).
(404) Minimal risk
D (405) Greater than minimal risk; but holds prospect of direct benefits to subjects.
(406) Greater than minimal risk; no prospect of direct benefit to subjects, but likely to
yield generalizable knowledge about the subject's disorder or condition,

University of Minnesota IRB
Continuing Review Form

Version 10/27/09
Page 29

Siabstamtive Changes: If any of the following are evident from the continuing review,
describe the changes for Committee discussion.

Q Change m risk or benefit [~} Change in funding
II Change in subject population D Change in conflict of interest
II Minor changes in consent form D Change in data management
II Major changes in consent form

Items for Committee Discussion:
1, Three subjects have withdrawn-2 did not tolerate drug (sedatlon), one reason unknown,
2. Protocol Amendment 2 being developed, Not along with this form,
3, Minor change to consent form-sig nature of person obtaining consent rather than Pi

Recommended Stipulations:
1. Provide HIPAA form
Recommended Suggestions;

Reconn mended Action: Q Approve as Submitted
Approve with Suggestions
c"ck.tosh-ow ! IS! Approve with Stipulations as noted
Criteria for I '"' "l'Ilr—i '^ •— - -r -—^-^-—^ — -

VA'pP'rovaT | U Response to original reviewer
Response can be reviewed by TRB staff
Q Approval Deferred " additional information required

Continuing Review Interval: [X] Annually
Every 6 months

II Quarterly
[_j Other interval;
/ have completed a substantive and meaningful review based on the information made available
at this time.

Print name of reviewer; Lidna E, Krach, MD Date: 12/16/2009

Signed name of reviewer:
If you choose to submit this form electronically, please send to irb(Sl,umn.edu.
Forms submitted from a umn.cdu account do not need a hard-copy signature,

University of Minnesota IRB
Continuing Review Form

Version 10/27/09
Page 30

Committee Meeting Minutes
December 16,2009

Agenda Item;
Continuing Review-Medical

Pt; Schub, Sellmann

Kevie'wejft Krach
'Iteyie'wer;:i?(Dees?:

Agenda If eni:; None
Agenda Item; None

Protocol Title and MSC?#:''Sei^q^
AR^domizedDouble^luidCompansonmtKP 1^^:,^ Kii?l^^:®'l{:-,:l-|::i
Item Description: X - .,1,"::1;;- ^~,'::x^

M revises consent form with a m^
^Discussion of Gontrovertea Issues Summai-y;
There were no controverted issues.

|Reyisions,>CIaril^atipiMorStipuIatiQns::^^<IT1^^^^^^^^
• Please submit the most current version of your HIPAA Authorization Form for review. This form is now
required at the time of continuing review. The IRB has initiated this new requirement to help maintain substantive
and meaningful review of all continuing review submissions.
The following changes to the consent form are stipulated:
• As this study is funded by a corporate sponsor, the following standard 'sponsor-funded' injury compensation
language should be used in the consent form:
'In the event that this research activity results in an injury, treatment will be available, including first aid, emergency
treatment, and follow-up care as needed. Care for such injuries will be billed in the ordinary manner, to you or your
insurance company. The sponsor of the study has some funds available to pay for care for injuries resulting directly
from being in this study. If you think that you have suffered a research related injury and that you may be eligible for
reimbursement of some medical care costs, let the study physicians know right away.'
-If the research contract makes an exception for the corporate sponsor not to be liable for research related injury
payment, then please provide documentation (pertinent section of the contract) to support this.

|C?hahge;i&Risk/BenefiiBatancei
None

Committee Must Address;

S 21CFR56.111 &45CFR46.1U
(Applicable Criteria Met)

D45CFR46-SubpartB
(Research Involving Pregnant Women or Fetuses)

D 21CFR50.23 & 45CFR.116

D 45CFR46-Subpart C

(Waiver or Alteration of Consent Process)

(Research Involving Prisoners—Indicate Level of Risk, e.g. Minimal or
Greater Than Minimal)

D 21CFR50.27 &45CER46.117
(Waiver of Consent Documentation)

D 21CFR50 & 45CPR46-SubpartD
(Research Involving Children—Detail Inclusion or Exclusion Justification
and Indicate Level of Risk, e.g. Minimal or Greater Than Minimal,
Describe Consent Requirements as Specified in 21CFR50.55 and

45CFR46.408)

Committee Meeting Minutes
December 16, 2009
Determinations and Justifications Required by Regulations and Guidelines:
None

Length of Approval: One Year

IRB Decision:
Approve Continuing Review with Stipulations
Additional Info: None

Vote Yes: 9

No: 0

Abstain: 0

Members Not Present for Vote Due to Conflict of Interest: None

Not Present:

12/17/2009
Selhnaim C Schulz

Psychiatry Department83 93 ^
F282/2A West-B
2450 Riverside
Minneapolis, MN 55454

RE: "Seroquel XR for the Management of Borderline Personality Disorder: A Randomized
Double-Blind Comparison with Placebo"

IRB Code Number: 07(»9M16844

Dear Dr. Schulz,

At the meeting on December 16,2009, the Institutional Review Board (TRB) reviewed the
referenced study, Tlie following stipulations must be resolved, and written approval should be
received before renewed approval is confirmed.
• Please submit the most current version of your HIPAA Authorization Form for review.
This form is now required at the time of continuing review, The IRB has initiated this
new requirement to help maintain substantive and meaningful review of all continuing
review submissions.

The following changes to the consent form are stipulated:
• As this study is funded by a corporate sponsor, the following standard 'sponsor-funded'
injury compensation language should be used in the consent form:
'In the event that this research activity results hi an injury, treatment will be
available, including first aid, emergency treatment, and follow-up care as needed,
Care for such injuries will be billed in the ordinary manner, to you or your insurance
company. The sponsor of the study has some funds available to pay for care for
injuries resulting directly from being in this study. If you think that you have
suffered a research related injury and that you may be eligible for reimbursement of
some medical care costs, let the study physicians know right away.' j
I

—If the research contract makes an exception for the corporate sponsor not to be

liable for research related injury payment, then please provide documentation
(pertinent section of the contract) to support this. |
Please provide a copy of the revised consent form for review.

Page

I!

-P-kase-note—In^he-Gontwumg-r-eview-for-m^it-stated^hat-an-ame'ndment-^-wouU^^

for review. The IRS has yet to receive this. Please submit (he amendment -when it is ready for
review.

The enrollment of new subjects may continue using previously approved consent document(s),
We cannot confirm the renewal of the referenced study until these conditions arc met, If your
response is not received within ninety days, the study will be filed inactive,

Please send your response to I-IRPP (Mayo Mail Code 820; D-528 Mayo Memorial Building;
420 Delaware St. SE; Minneapolis, MN 55455), The signature of the Principal Investigator is
the only signature required with the response, Only one copy of the response is necessary.
If you have any questions, please contact the IRB office at 612-626-5654.
Sincerely,

Movolny, CIP
trch Compliance Supervisor

)/mq
CC: Scott Crow, Peter Milev, Michael Miller, Richelle Moen, Arm Romine, Marian Thompson

Page 2

,^2-

SC.R-UI^Z-

UNIVERSITY OF MINNESOTA °^Ml b^4 [^ ^1%%^^ b^
uu—-~11

Twin Cities Campus Ambututory Research Center Riverside Prdfessiwol Swid'mg
~6(16'2'4lh~Ave>we Smith —~~
Department of PsychiatnDecember 30,2009 MS/'.s-cAoo/"'"""""'" Smm.W2
lw'mc"'>wwi" MiimMimli-i, AW 55454

Christina Dobrovolny osw: 6I2-627-48W

Institutional'Review Board
University of Minnesota
Mayo Mail Code 820

D528 Mayo Memorial Building KLl'U JAN 0 6 2010
420 Delaware Street S.E.

Minneapolis, Minnesota 55455
RE: "Seroquet XR for the management of Borderline Personality Disorder (BPD)"

HSC#0709IV116844

Dear Christina:
Thank you for your Continuing Review of the referenced study. We are responding to
IRB stipulations as stated in your letter dated 17 DEC 2009, as well as submitting
Protocoi Amendment #2 dated 30 DEC 2009.
Stipulations:
1. Enclosed is the current approved version HI PAA form, version date 24 FEB 2009
& IRB approved on 19 JUN 2009.
2. The research-related injury language has been revised on p. 8 of the revised
consent form dated 30 DEC 2009.
3, In addition, we have changed the signature line on p, 9 of the revised consent
form to read "Signature of Person Obtaining Consent" rather than "Signature of
Investigator."

Protocol Amendment #2, version date 30 DEC 2009
The amendment items are listed & notated in the Protocol Amendment Summary
document dated 30 DEC 2009, The amended protocol includes changes highlighted in
yellow. Please note the green highlights were from protocol Am #1, IRB approved on 02
JUN 2008..
We have enclosed the following documents for your review:
1) Protocol Am #2 version date 30 DEC 2009
2) Protocol Am-#2 Summary 30 DEC 2009
3) Revised consent form version date 30 DEC 2009
4} Current approved version HIPAA form, version date 24 FEB 2009 & IRB
approved on 19 JUN 2009
Thank you and please contact Ann Romine, study coordinator, with any questions at
612.627-4843,
Sincerely,f

S.^MM^l^i
S. Charles Schulz, MD

Principal investigator

Driven to Discover5
Page £

UNIVERSITY OF MINNESOTA

RCT .AN 13 2010

Change In Protocol Request

s^Hu-i/2- -0-jo^t^.y-f^

z/,g/.,,AGEME

'//On.i^^ac^^

-Instr-uc.tJoos;-

^

Usa this form when submitting change requests on 1KB protocols.
t. Submit this form to the Human Research Protection Program:

Campus Mail;

U.S, Mail Address:
Human Research Protection Program

Human Research Protection Program

MMC 820

MMC 820

Minneapolis Campus

420 Delaware St. SE
Minneapolis, MN 55455-0392

Delivor to:
D-528 Mayo Memorial Building
. Minneapolis Campus
8-4:30, M-F

IRB Protocol Information
I RBSludy Number:

0709M16844

Currenl Principal Investigator:
l-'rbnary Title:

S. Charles Schulz
MD, Dept Head

Submission Date

30 DEC 2009

Indn'.ale the type of change/addition and attach all applicable documents:

IZIProlocol Amendment; Version^, Dated 30 UEC 2009
[_J Revised Jnvcstigator Brochure; Ver.siun , Unted
QR.ccruitinentChanges/Advertisemenl.s
DNotice of Closure to Accrual
QChangei's') tn Study Procedures
dOl'her:
1. l^rict'ly summarize (lie uhungc(s). Kor prol.oco! amendments, do not say "See summary of changes provided will)
amendment," Rather, summarize t)u> nature of the significant revisions.
Clarification of procedures including visit windows, study mediuatiun compliance, frequency of 2 side effect
assessments, early discontinuatjon, ynd siratif'ication by genduT.

2, Describe the rationale lor the cttange(s);
To clarify procedures Co ensure consistency of study methods across a)) 3study sites.

3. In your opinion as principal investigator, how will tliese changes affect the ovt'rall risk to subjects in this sfiidy?
These changes will not increase risk to subjects.

4. Do the changes to the study prnmpl changes to the consent form(s)?
<o. D Yes.
H'yes, attach a copy of the revised consent fonn(s) with changes tracked or highlighted as well as a clean copy. Use this space
to t'nrtlu'r describe consent form cliangcs if necessary:

J. PM^^ ^^ &/^ \\^\\f)

Principal Investigator's Signature

Date

The Univcrsily of Minnesota is an equal opportunity cduc'iilor & cmployur.
© 2008 by the Regents of the University of Minnusolii.
Rage 68

1 af2

University of Minnesota

Review Period:

09/25/2009-02/17/2011

Continuing Review of IRB - Pending
Medical Research

Rev; 03/01/200.5

Study Number: 0709IVI16844
Principal Investigator: Sellmann C Schulz
Title(s): Seroquel XR for the Management of Borderline Personality Disorder:
A Randomized Double-Blind Comparison with Placebo
Study Status

Active (Enrolling Subjects)

Funding Source(s)

Funding SourGe: ASTRAZENECA INTL
Funding Type;
Personnel
Schulz, Sellmann (P. I.)
Crow, Scott (Co-lnvestigator)
Cullen, Kathryn (Co-'lnvestigator)
Man, Georges-Jakofci (Staff/Lab)

Heller, Monika (Staff/Lab)
Houri, Alaa (Staff/Lab)
Miller, Michael (Co-lnv^stjgator)
Moen, Richelle (Co-lnvestigator)
Rom ine, Ann (Correspondent)
Vuchetich, John (Co-lnvestigator)

Study Enrollment
Number of Subjects Approved for study:
50

Number of subjects enrolled this review' period:
Male Female Unknown

[I

^4

Total

J2S[

Numtser of subjects enrolled to date:
The University of Minnesota is an equal opportunity educator & employer.
© 2004 by the Regents of the University of Mtnnesota.

Page 1

Male Female Unknown Jot^l E

18 114 |0 f22 } |
Is this a multi-center study?
Yes
Total national accrual to date: 52

Unanticipated Problem Reporting
Since the most recent IRB continuing review approval, have any partJGipants withdrawn from the
research?

Yes
8 early withdrawals and 1 lost to follow-up, 4 early withdrawals were due to adverse events, primarily sedaitlon. 4
due to subject personal circumstances.

Since the most recent IRB continuing review approval, have any partioipants complained about the
research?
No
Have any serious and unantiGipated problems been reported to the IRB?

No

Study Summary
Summarize preliminary information about any results and/or trends:
At our site 22 subjects have been enrolled and have taken at least 1 dose, of study medication. 13 subects have
completed all 11 visits of the study. 9 subjects have not completed the study. The majority of subjects who
completed study to date show a decrease in symptoms from baseline as measured by the assessment scale
scores. 2 other sites are participating jn this trial. Each site has an enrollmentgoalof33subJBetstoobtain a totalof
99 subjects enrolled. Enrollment numbers to date are as follows; University of Iowa: 27 subjects McLean Hospital,

Han/ard University: 3 subjects Enrollment goals may:need to be adjusted per site as we get closer to our enrollment
total.

Have there been any changes in protocol approved by the IRB since last continuing review?
Yes
Achartge in protocol, Amendment #3, dated July 20,2010, was approved perlRB letterdatec) Novembers, 2010.
This amendment adds an optional brain imaging (fMRt) addendum to the main study. The Gonsentform and Brain
Imaging Addendum dated October 20,2010 was also approved. To date no subjects have been enolledthe brain
imaging study,

Since the most recent IRB continuing review approval, have there been any progress reports on the
research?

No

The University of Minnesota is an equal opportunity educator & employer. Page 2
© 2004 by the Regents of the University of Minnesota.

Since the most recent IRB continuing review approval, have there be@n any multi-center trial reports?
No
Since the most nScent 1RB continuing review approval, have there been any other information
relevant to this research discovered, especially information about the risks and benefits associated
with the research?

No
Since the most recent IRB continuing review approval, have subjects experienced any benefits?
Yes
The majority of subjecte who completed study to date show a decrease in symptoms from baseline as measured by
the assessment scale scores.

External Findings
Is there anything in the relevant recent literature that the IRB should know about concerning this
research?

No

Consent/Assent Forms
Have there been any changes to the consent and/or assent form (s) since the last IRB approval?

No
!Have translated consent short forms been used in conjunGtjon'with an interpreter to obtain .consent

for this study?
No

Other Comments

The'University of Minnesota is an equal opportunity educator &'employer- Pages
©2004 by the Regents of the University of Minnesota.

C^: 50
UNIVERSITY OF MINNESOTA ^ ^
Twin Cities Campus Depiirtmenl of Psychiatry F2S2/2A West

Memo

1450 Riverside Avenue

Minneapolis, MN 55454
Office: 612-273-9800

To: S. Charles Schulz, M.D.
From:Scott Crow, M.D.

CC: Kathy Mischke and Kyle Rudser, Ph.D.

Date: April 7, 2010
Re: Seroquel XR BPD Study and Safety Meeting

We met for safety monitoring on March 3, 2010 and interviewed progress to date.
The following study issues were reviewed and discussed;

1. There is not sufficient information available on the Harvard site; they have
incomplete information on only one patient and it is unclear whether they are
recruiting or not,
2. No screen failures have been reported. Is this correct? If there are screen

failures that is not problematic, but it would help in evaluating the rate of
recruitment.
3. Retention appears to be really excellent. However, clarification is warranted
in regard to discontinuation of drug and discontinuation of study (i.e,, from
evaluation). In order to allow for an intent to treat analysis at the end of the

study, patients should be continued to be evaluated to the degree they allow
in the event it is decided to discontinue treatment regimen.

4. There appear to be preexisting symptoms at study entry that are being
captured as AE's, These should not be included as adverse events unless
they increase in severity or frequency.
5. If possible, severity ratings for the AE's experienced by the Harvard site
enrollees should be provided.

6. If subjects do not return pill bottles for count it appears that that should be
listed as a protocol deviation.

Last, it was noted that recruitment from across the sites is lagging behind that initially
proposed with current enrollment at less than half of what it is expected to be. If
enrollment stays at the current rate, the study is expected to finish in 5 years rather
than the planned 2 years.

1

Driven to Discover5

Seroquel XR BPD Study
Data and Safety Monitoring Meeting 8/26/09
Attendance: Scott Crow, M.D,, Safety Officer

Kathy Mlschke, Clinical Trial Monitor
Kyle Rudser, Biostatistician
Data regarding study recruitment, progress, and protocol adherence (all with blinded treatment
assignment) were reviewed, for the first 10 patients enrolled in :the study. Several issues for

further clarificatton/reiteration were identified:
1, There should b6 clarification ,in the protocol as to whether 50 mg dose is given for the
first two days or the entire first week.
2. If an individual is discontinued from the study or withdraws from the study, there is some
ambiguity in the protocol as to what happens for follow-up. A 14 day follow-up is
conducted for subjects who complete a regular end of study termination visit and this
should be the same for early termination/discontinuation subjects if possible, including
monitoring for adverse events.
3. All adverse events, serious or not, and expected or not should be reported.
4. There has been some delay in entering of CRF data into the database. The delay
appears to be gradually diminishing over the period of patient follow-up visits but there is
an overall concern. While there is no specification of expected time to data entry, within
two weeks of "visit 10" would seem appropriate for effective safety monitoring. Adverse
events, however, are still to be reported within timelines specified in the protocol.
5. Clarification is needed regarding study rules for visitwindows and classification of
missed visit/scheduling of subsequent visits.
6, Protocol deviations are not being reported. These include missed visits, missed doses,
missing safety endpoints, and general occurrences that deviate from the protocol.
7, There is concern over the lack of data on identified safety endpojnts, Specifically;
prolactin, glucose, cholesterol, triglycerides, and BMI (weight and height), which all need
to be assessed at both baseline and end of study for all patients.

MEMORANDUM
TO: Scott Crow, M.D.

CC: Ann Romine
FROM: Dr. S. Charles Schulz, Head, Department of Psychiatry

RE: Seroquel XR BPD Study - Data and Safety Monitoring Meeting
DATE: October 28, 2009
I am writing this memorandum to initiate a discussion regarding the Data and Safety Monitoring
Meeting of August 2009. Dr. Crow you are the safety officer and I appreciate your having discussed
the meeting with me and look forward to hearing your thoughts about my response to the meeting.

I will go through each of the point below:
1. I agree there should be clarification as to how long the 50 mg dose is given. I know that we
changed the original protocol after the feedback ffom the Titration and Taper McLean IRB.
Attached is the Dosing amendment,
2. I believe it is a good idea to clarify how subjects are managed if they are discontinued or
withdraw from the study. I am not sure it is clear to the Data and Safety Monitoring
Committee that the design of the two week follow up is to be able to transfer people from the
study to the next phase of their care. Also, people with borderline personality disorder have
difficulties with abandonment and we have always designed our studies to not have the last
rating period be the person's last appointment with us. Therefore, the idea of clarifying tha-t
people who are withdrawing from the program or are discontinued should have the follow up
is a good idea. We will request an amendment to clarify the follow-up for those subjects
(P.21).
3. The idea of reporting all adverse effects events is of course appropriate. I need more specific
information about how our sites have been doing on this issue and suggestions for how to
comply with this statement.
4. I can understand concern regarding entering data from the CRF into the database. I am not
sure whether this is related to the suspension of entering subjects or some other reason. I
have discussed with Ann having a teleconference of all sites so we can address this issue.
5. I can understand that it is important to clarify the "windows" and "classification of .missed
visit." We have designed a definition statement and will submit as an amendment.
6, Regarding theissue of protocol "deviation" I would like Dr. Crow's opinion of protocol
deviation and then work to make sure that they are appropriately recorded.

7. I have a question regarding the statement of lack of data on identified safely end-points. I
have seen all of the laboratory studies at each point and am not quite sure what the'DSMB is
requesting. In the meantime I will review laboratory data to examine for any missing values.
I look forward to discussing this with you both sooa so that I can make any needed changes to the
protocol.

PI: Schulz University of Minnesota
HSG#: 0709M16844 Human Research Protection Program
Reviewer: Ognjanovic Institutional Review Board

Meeting Date: 01/26/2011
Full Committee Review—Continuing Review of Approved Research
I

"An 1KB shall conduct cwtiniiing revbw of research covered by this policy at intervals appropriate to the degree of
risk, but not less than once per year, and shall have the authority to obsen'e of have a third party obsen'e the

consent process aiidlhe research." 21CFR56.109 and45CFR46.109
"Continuing review of research must be substantive and meaningful." OHRP Guidaiice 1-15-0.7

Short Title: Seroquel XR for the Management of Borderline Personality Disorder:
A Randomized Double-Blind Comparison with Placebo

Enrollment: ^ Open D Closed D On hold
Treatment: [X] Continues Q Complete [_] 'Not a treatment study
Follow-up: ^Continues D Complete D No follow-up required
Funding: D Federal [X] Industry Sponsored Q Foundation
Departmental Q None

Enrollment Numbers: Approved: 50 Enrolled: 22 Years active: 5
UPIRTSOs (Unanticipated Problem InvQlvlag Risk to Subjects or Others):
Have any UPIRTSOs been reported !m the last year? Q Yes ^ No

Are there concerns to be discussed by the Committee? Q Yes 1^ No
Study Summary: ^Adequate D Deficient
[_] None - too early Q None - data analysis elsewhere

External Findings: ^ DSMB letter D Progress report D Action letter
Consent and Assent Forms; ^ Submitted D Missing d' Waived or not applicable

HIPAA Form$; D Submitted d Missing D Waived or not applicable
Q Closed to enrollment - forms are no longer pertinent

Are all persons listed on consent form also listed in the IRB records? Q Yes ^ No

Inclusion of Children in Research:
If children are included in this research confirm that they should still be included,

D Yes D No ^i NA - children excluded
If children are included, is there new information which affects the regulatory classification

(45CFR46 Subpart D) indicate the change,

(404) Minimal risk
D (405) Greater than minimal risk; but holds pfospeGt of direct benefits IQ subjects.
Q (406) Greater than minimal risk; no prospect of direct benefit to subjects, but likely to
yield generalizable knowledge about the subjects disorder or condition.

University ofMimiesotaIRB
Continuing ReviewFonn
Version October 2010

Substantive Changes: If any of the following are evident from the continuing review report,
describe the changes for Committee discussion,

Q Change in funding
Q Change in conflict of interest

Change hi risk or benefit

D Change in subject population

Change in data management

Minor changes in consent form
D Major changes in consent form

Dr. Crow is reviewing subjects' adverse events

for all three sites to monitor subjects' safety,

Items for Committee Discussion:
this lias been approved by the IRB previously and
- Scott Crow was a member of DSMB and a co-investigator?
is included in 4.4 of protocol.
-Dr Shultz is a member of the Scientific Advisory Board of Astra Zeneca (the sponsor), where they discuss

other uses of the medication Seroquel, and Dr Shultz is the Pl of this study that is trying to investigate if
Seroquel can be used for other purposes than thus far approved. Conflict of interest?

Recommended Stipulations:
- Scott Crow is mentioned in the consent, but is not an investigator on the IRB application,

Recommended Suggestions:

Dr. Crow is a cuiTent Co-PI on the study. He was added after
original review oftlie project,

Recommended Action; Q Approve as Submitted
a Approve with Suggestions
Approve with Stipulations as noted

gguuumi
lllllliilBl.HIII

Response to original reviewer
Response can be reviewed by IRB staff
a Approval Deferred - additional information required

Continuing Review Interval: [X] Annually
[_] Every 6 months
Quarterly
Q Other interval:
I have completed a substantive and meaningful review based on the mformation made available
at this lime.

Print name of reviewer; Simona Ognjanovic Date; 1/26/2011

Signed name of reviewer:
If you choose to submit this form electronically, please send to irb(%umn.edu.
Forms submitted from a utnn.edu account do not need a hard-copy signature.

University of Minnesota IRB
Continuing ReviewFonn
Version October 2010

Committee IVIeeting Minutes
January 26, 2011

Agendaltem:1
Continuing Review-MedicaI

pl: Schulz, Sellmann

ReVie^yer; Pgnjanoxic
Reviewer: NoMe

Agenda Item:; None
Agenda Item: None

Protocol Title and HSC^:''Seroquel XR for ^
ARandomizedDouble^lmdConip^i^spni^WPIac^
Item Description:
-N6ne""'.l'-l,\:-^%

|Distussioalof:e(mtroYerted:Issues, Summary:^, f^,;:';;,; :;V;-; ,;^
The IRB committee notes that the Pl's conflict of interest management plan has been reviewed previously by the IRB
Committee. The committee acknowledges current, IRB approved language in the consent form that references the
Pl's role on the Scientific Advisory Board.
The committee also notes that Dr. Scott Crow is a co-investigator and he is monitoring adverse events from all three
participating sites. This does not create a conflict of interest as researchers are required to monitor adverse events.

iRevisions, Clarifications or jStipulatidns:
None

Change iii Risk/Benefit Balance;
None

Committee Must Address:

El 21CFR56.111 &45CFR46.111
(Applicable Criteria Met)

D 45CFR46-Subpart B
(Research Involving Pregnant Women or Fetuses)

D 21CFR50.23 &45CFR.116

D 45CFR46-Subpart C

(Waiver or Alteration of Consent Process)

(Research Involving Prisoners—Indicate Level of Risk, e.g. Minimal or
Greater Than Minimal)

D 21CFR50.27 &45CFR46.117
D 21CFR50 & 45CFR46-Subpart D

(Waiver of Consent Documentation)

(Research Involving Children—Detail Inclusion or Exclusion Justification
and Indicate Level of Risk, e.g. Minimal or Greater Than Minimal,
Describe Consent Requirements as Specified in 21CFR50.55 and

45CFR46.408)

Determinations and Justifications Required by Regulations and Guidelines;
None

IRB Decision: Approve Continuing Renewal

Length of Approval: One Year

Additional Info: None

Vote

Yes:

No: 0

Abstain: 0

Not Present:

Date: 02/07/2011
To: S. Charles, Schulz (scs@umn.edu)
From: irb@umn.edu

Subject: #STUDYNBR# - PI #PILASTNAME# - IRB - APVD Continuing Review
Message: TO : crowx002@umn.edu, scs@umn.edu, vuche002@umn.edu, romi0004@umn.edu,
moenx008@umn.edu, rega0026@umn.edu, mjmiller@umn.edu,

The IRB: Human Subjects Committee renewed its approval of the referenced study
listed below:

Study Number: 0709M16844
Principal Investigator: Sellmann Schulz

Expiration Date: 01/25/2012
Approval Date: 01/26/2011
Title(s): Seroquel XR for the Management of Borderline Personality Disorder: A
Randomized Double-Blind Comparison with Placebo
This e-mail confirmation is your official University of Minnesota HRPP notification of
continuing review approval. You will not receive a hard copy or letter. This secure

electronic notification between password protected authentications has been deemed by
the University of Minnesota to constitute a legal signature.
You may go to the View Completed section of http://eresearch.umn.edu/ to view or
print your continuing review submission.

For grant certification purposes you will need this date and the Assurance of
Compliance number, which is FWA00000312 (Fairview Health Systems Research

FWA00000325, Gillette Childrens Specialty Healthcare FWA00004003). Approval
will expire one year from that date. You will receive a report form two months before

the expiration date.
In the event that you submitted a consent document with the continuing review form, it
has also been reviewed and approved. If you provided a summary of subjects'
experience to include non-UPIRTSO events, these are hereby acknowledged.

As Principal Investigator of this project, you are required by federal regulations to
inform the IRB of any proposed changes in your research that will affect human
subjects. Changes should not be initiated until written IRB approval is received.
Unanticipated problems and adverse events should be reported to the IRB as they
occur. Results of inspections by any external regulatory agency (i.e. PDA) must be
reported immediately to the IRB. Research projects are subject to continuing review.

If you have any questions, please call the IRB office at (612) 626-5654. The IRB
wishes you continuing success with your research.

University of Minnesota

Review Period:

12/03/2010-01/25/2012

Continuing Review of IRB - Pending
Medical Research

Rev: 03/01/200?

Study Number: 0709M16844
Principal Investigator: Sellmann C Schulz
Title(s): Seroquel XR for the Management of Borderline Personality Disorder:
A Randomized Double-Blind Comparison with Placebo
Study Status

Active (Enrolling Subjects)

Funding Source(s)

Funding Source: ASTRAZENECA INTL
Funding Type;
Personnel
Schulz, Sellmann (P. I.)
Crow, Scott (Co-lnvestigator)
Cullen, Kathryn (Co-lnvestigator)
Man, Georges-Jakob (Staff/Lab)

Hourj, Alaa (Staff/Lab)
Miller, Michael (Co-lnvestigator)
Moen, Richelle (Co-lnvestigator)
Romine, Ann (Correspondent)

Roots, Monika (Staff/Lab)

Study Enrollment
Number
of Subjects Approved for study:
50 ~' ~~~J"" ' -''-•----- -- -—.'•

|total enrolled: 34

Number of subjects enrolled this review period:
Male Female Unknown Total

E

I:

3E

14 |

Number of subjects enrolled to date;

Male

rr

Female

K

Unknown
,10

Total

: 14 ~|

The University of Minnesota Is.an equal opportunityaducatorS, employer. ' Page 1
© 2004 by the Regents ofthe University of Minnesota.

Is this a multi-center study?
Yes
Total national accmal to date; 60

Unanticipated Problem Reporting
Since the most recent IRB continuing review apppoval, have g>ny participants withdrawn from the
research?

Yes
There have been 4 early withdrawals, all due to adverse event: sedation,

Since the most recent IRB continuing review approval, have any participants complained about the
research?
No
Have any serious and unanticipated problems been reported to the IRB?

No

Study Summary
Summarize preliminary iriformatlon about any results ancl/or trends;
One of 3 participating sites withdrew from the study early in 2011, McLean Hospital at Harvard University, pl Mary
Zanarinl, The site withdrew due to inability to enroll subjects. The 2 remaining sites,D of MN & D of Iowa, will be
completing the enrollment goal of 99 total subjects.

Have there been any changes in protocol approved by the IRBsince last continuing review?
No
Sincethe most recent IRB continuing review approval, have there been anyi progress reports on the
research?
No
Since the most recent IRB continuing review approval, have there been any multi-center trial reports?
No
Since the most recent IRB continuing review approval, have there been any other information
relevant to this research dificovered, especially information about the risks and benefits associated
with the research?
No

The University of Minnesota is an equal opportunity educator& employer. Page 2
©2004 by the Regents of (he University of Minnesota.

Since the most recent IRB confinuing review approval, have subjects experienced any benefits?
Yes
Some subjects have reported reduction In their symptoms of Borderline Personality Disorder,

External Findings
Is there anything in the relevant recent I itergfure that the IRB should know about concerning'this
research?
No

Consent/Assent/HIPAA Forms
Have there been any changes to the consent and/or assent form (s) since the .last IRB approval?
No
Have translated consent short forms been usecl in conjunction with an interpreter to obtain consent

for this study?
No

Other Comments
We hope to complete enrollment for the study in 1 year^

The'University of Minnesota is:an equal opportunity educator & employer- Page 3
© 2004 by the Regents of the University of Minnesota.

Memo
To: S. Charles Schulz, M.D.
From: Scott Crow, M.D.

CC; Kyle Rudser Ph.D., and Kathy Mischke

Date: 11/8/2011
Re: Seroquel XR BPD Study Safety Monitoring Minutes

Safety monitoring and enrollment dgta were reviewed to date and the following were
noted.

1. Tjme to data entry has dJminjshedi substantially, particularly at the Minnesota
site with the median now approaching 10 days. This is extremely useful for
adequate and timely safety monitoring.
2. It was noted previously that one subject at the Iowa site had weight gain rated
at mild but recorded as an SAE; it had been requested that this be clarified
and likely corrected. This has not yet been done but needs to be done.
3, Baseline safety data are now present for all newly enrolled subjects which also
represents gn important improvement,
4. A substantial number of AEs have a severity rating: of "unknown". In order to
facilitate safety monitoring, severity ratings need to be clarified and gssigned
to these AEs.
5. As noted previously, it appears that screen fails are being tracked and entered
info the data base at the Iowa site but they are not be entered at the
Minnesota site (unless in fgct there are truly no screen fails which seems

unlikely). Ultimately it is of greatest important simply that these be tracked
and entered somewhere as they will undoubtedly be needed for reporting trial
results ultimately. On the other hand they are being entered at the Iowa site
and it would be best to handle this consistently across sites, by the
mechanism of entering them for the Minnesota site as well.

PI: Schulz University of Minnesota
HSC#: 0709M16844 Human Research Protection Program
Reviewer: QuicH Institutional Review Board

Meeting Date: 11/16/2011
Full Committee Review—Continuing Review of Approved Research
I 'I

"An 1KB shall conduct coi-itiiitiiiig review of research mvet'ed by this policy at intervals appropriate to the- degree of
risk, but not less than once per year, and shall have the authority to observe or have a third party obsen'e the
consent process and the research," 21CFR56.109 and 45CFR46,109
"Cantiming review of research must be substantive and meatsingfiil." OHRP Guidance 1-15-07

I • ••

Short Title: Seroquel XR for the Management of Borderline Personality Disorder
Enrollment: [X] Open d Closed Q On hold
Treatment: [X] Continues Q! Complete Q "Not a treatment study
Follow-up: [3 Continues 0 Complete Q No follow-up required
Funding: D Federal |^1 Industry Sponsored d Foundation
m Departmental Q Noile
Enrollment Numbers: Approved: 50 Enrolled: 34 Years active: 4
UPIRTSOs (Unanticipated Problem Involving Risk to Subjects or Others);
Have any UPIRTSOs been reported In the last year? Q Yes CX] No
Are there concerns to be discussed by the Committee? Q Yes [^ No
Study Summary; :[X] Adequate D Deficient
Q TSIone - too early Q None - data analysis elsewhere

External Findings: ^ DgMB letter Q Progress report D Action letter
Consent and Assent Forms: [X]; Submitted D Missing Q Waived or not applicable
HIPAA Forms: ^ Submitted D Missing Q Waived or not applicable,
D Closed to enrollment - forms are w longer pertinent

Are all persons listed on consent form also listed in the mB records? [^ Yes Q No

Inclusion of Child fen in Research:
If children are included in this research confirm that they should still be included.

D Yes D No IEI NA - children excluded
If children are Included, is there new inforrnation which affects the regulatory classification

(45CFR46 Subpart D) indicate the cihange.

D (404) Minimal risk
D (405) Greater than minimal risk; but holds prospect of direct benefits to subjects,
D (406) Greater than minimal risk; no prospect of direct benefit to subjects, but likely to
yield generaUzable kncnyledge about the subject's disorder QI' conditioti,

University ofMumesotaIRB
Conttnumg Review Form

Version October 2010

Substantive Changes: If any of the following are evident from the eontinuing review report,
describe the changes for Committee diseussioti.
0 Change iti risk or benefit

Change in funding

0 Change In subject population

Change in coiiflict of interest
Change in data management

Q Min6r changes in consent form
Major changes in consent form

Items for Committee Discussion:
Pl reports that the Harvard site dropped out, leaving only UofM and l&wa,

Recommended Stipulations:
1. For continuing review, it i$ reported that 34 subjects have been enrolled, but the D8MB report notes that
screen failures have not been registered in the study database. Confirm whether the sum of 34 enroliees
includes screen failures.
2. Update the out-of-study contact address.

Recommended Suggestions:
1. Considering that D of M has enrolled 57% of subjects, the national goal is 99 subjects, and the local
allowance is 50 subjects, it may be necessary to increase the local allowance,
2. On page 2 of the consent form, update the number of study sites from "3" to "2".
Recommended Action: Q Approve as Submitted
Approve with Suggestions

Approve with Stipulations as noted
1 Response to original reviewer

^Response can be reviewed by IRE staff
Q Approval Deferred - additional information required

Continuing Review Interval: Kl Annually
D Every 6 months
Quarterly
a Other interval:
/ have completed a substarnive and mecinmgful review based on the information made. availcible
at this time.

Print name of reviewer: Donald C, QilicH Date: 11/16/2011

Signed name of reviewer:
If you choose to submit this form eleptronically, please send to irhfTOtim.edu.
Forms submitted from a unin.edu account do n&t need a hard-copy signature.

University of Minnesota IRB
Gontiliumg Review Form

Version October 2010

Committee Meeting Minutes
November 16, 2011

Agenda Item;
Continuing Review-IVIedical

Kt: Schulz, Sellmann

IR.evievyer^ Quick
IRevieyrer; 3None

Agenda Itemi None
Agenda Item ^ None

Protocol Title and^HSC^S^'Seroi^
A^Randomized;Double-Blma'Gomp:ayis^
Item Description:
Wone^11.-71®

Discussion of Cohtrovertedlssues Summary;
There were no controverted issues.

tRevisions^:Clarifl(^tibris:o)c^Stipulations;;:;^;j;^:';l:":^^^^^^^^ ':;l'll:'^?/''?'^:li^'^"'':lll:;l':^

It appears as though this study has enrolled a total of 34 subjects. Is this correct? The DSMB report notes
that screen failures have not been registered in the study database. Confirm whether the sum of 34 enrollees includes
screen failures.

[Change in Risk/Bemefit Balance;
None

Committee Must Address:

El 21CFR56.111 & 45CFR46.111
(Applicable Criteria Met)

D45CFR46-SubpartB
(Research Involving Pregnant Women or Fetuses)

D 21CFR50.23 & 45CFR.U6

D 45CFR46-Subpart C

(Waiver or Alteration of Consent Process)

(Research Involving Prisoners—Indicate Level of Risk, e.g. Minimal or
Greater Than Minimal)

D 21CFR50.27 & 45CFR46.117
D 21CFR50 & 45CFR46-Subpart D

(Waiver of Consent Documentation)

(Research Involving Children—Detail Inclusion or Exclusion Justification
and Indicate Level of Risk, e.g. Minimal or Greater Thau Minimal,
Describe Consent Requirements as Specified in 21CFRS0.55 and

45CFR46.408)

Determinations and Justifications Required by Regulations and Guidelines:
None

IRB Decision:
Approve Continuing Review with Stipulations

Length of Approval: One Year

Additional Info: None
Vote Yes: B

No: 0

Abstain: 0

Members Not Present for Vote Due to Conflict of Interest: Crow

Not Present:

11/21/2011
Selltnann C Schulz

Psychi&try, Dept of8393A
F282/2AWest-B
2450 Riverside Ave
Minneapolis, MN 55454

RE: "S^roquel XR for the Management of Borderline Personality Disorder: A Randomized
Double-Blind Comparison with Plaeebo"

IRB Code Number: 0709M16844

Dear Dr. Schulz,

At the meeting on November 1$, 2011, the Institutional Review Board (IRB) reviewed and
renewed approval for the referenced study. The IRB stipulated the following:
• K appears as though this study has enrolled a total' of 34 subjects. Is this correct? The
DSMB report notes that screen failures have not been registered in the study database.
Confirm whetlier the sum of 34 enrollees includes screen failures.
Please provide a response for IRB review.
If your response is not received within ninety days, the study will be filed inactive.

Please send your response to HRPP (Mayo Mail Code 820; D-528 Mayo Memorial Bmlding;
420 Delaware St. SE; Minneapolis, MN 55455), The signature of the Principal Investigator is
the only signature required with the response, Only one copy of the response is necessary.
If you have any questions, please contact the IRB office at 612-626-5654.
Sincerely,

Felicia. Mroczkowski, CIP
Research Compliance Supemsor

FM/mq
CC; Scott Crow, Kathryn Cullen, Michael Miller, Richelle Moen, Ann Romine

University of Minnesota

Review Period;

Continuing Review of IRB - Pending

10/21/2011-11/14/2012
Rev; 03/01/2005

Medical Research

Study Number: 0709M16844
Principal Investigator: S Charles Schulz
Title(s): Seroquel XR for the Management of Borderline Personality Disorder:
A Randomized Double-Blind Comparison with Placebo
Study Status

Active (Enrolling Subjects)

Funding Source(s)

Funding Source: ASTRAZENECA INTL
Funding Type:
Personnel
Schulz, S Charles (P. I.)

Carlson, William (Staff/Lab)
Crow, Scott (Co-lnvestigator)
Cullen, Kathryn (Co-lnvestigator)
Davis, Aubrey (Staff/Lab)

Fryza. Brandon (Staff/Lab)
Han,

Georges-Jakob

Heller,

Monika

(Staff/Lab)

(Staff/Lab)

Houri, Alaa (Correspondent)
Miller, Michael (Co-lnvestigator)
Moen, Richelle (Co-lnvestigator)
Romine, Ann (Correspondent)

Stepka, Megan (Staff/Lab)
Watroba, Lexa (Staff/Lab)

Investigational Drug(s)
The University of Minnesota is an equal opportunity educators employer- page 1
© 2004 by the Regents of the University of Minnesota.

|

|

IND Number: 45,456
IND Holder: AstraZeneca Pharmaceuticals LP (Sponsor)

Study Enrollment
Number of Subjects Approved for study:
50
Number of subjects enrolled this reporting period:
Male Female Unknown Total
R~
^13
~J£

K

Number of subjects enrolled to date:
Male
f20-

Female
T35~

Unknown

10 C

Total
55_

]

\

I

Is this a multi-center study?
Yes
Total national accrual to date: 85

Unanticipated Problem Reporting
Since the most recent IRB continuing review approval, have any participants withdrawn from the
research?

Yes
4 early withdrawals since last continuing review. 2 were due to adverse events, 1 was due to inefficacy, and 1 was
due to subject moving away. 3 screen failures since last Gontinuing review.

Since the most recent IRB continuing review approvali have any participants complained about the
research?
No
Have any serious and unanticipated problems been reported to the IRB?
Yes
13 JUL 2012 - UPIRTSO report date 06 AUG 2012- Submission acknowledged by IRB No changes to consent
form or study were needed.

Study Summary
Summarize preliminary infonnation about any results and/or trends:
We are nearing the end of ow enrollment for this study. Our total enrollment for both all 3 sites will be
approximately 90 subjects (this total does not include screen failures). All subjects will have completed study by the
end of 2012 or early 2013.

Have there been any changes in protocol approved by the IRB since last continuing review?

The University of Minnesota is an equal opportunity educator & employer- Page 2
© 2004 by the Regents of the University of Minnesota.

Yes
MRI addendum and MRI healthy controls were added to the main study. Consents documents will be uploaded
here.

Since the most recent IRB continuing review approval, have there been any progress reports on the
research?

No
Since the most recent IRB continuing review approval, have there been any multi-center trial reports?
No
Since the most recent IRB continuing review approval, have there been any other information
relevant to this research discovered, especially information about the risks and benefits associated
with the research?
No
Since the most recent IRB continuing review approval, have subjects experienced any benefits?
Yes
Some subjects have reported a decrease in their symptoms of Borderline Personality Disorder.

External Findings
Is there anything in the relevant recent literature that the IRB should know about conGerning this
research?

No

Consent/Assent/HIPAA Forms
Have there been any changes to the consent and/or assent form(s) since the last IRB approval?
Yes
The main study consent was updated and approved by the IRB on Aug 9,2012.

Have translated consent short forms been used in conjunction with an interpreter to obtain consent
for this study?
No

Other Comments

The University of Minnesota is an equal opportunity educator & employer- page 3
© 2004 by the Regents of the University of Minnesota.

PI: Schulz University of Minnesota
HSC#: 0709M16844 Humaa Research Protection Program
Reviewer: Quick Institutional Review Board

Meeting Date: 10/31/12

Full Committee Review—Continuing Review of Approved Research
I

"An 1KB shall conduct continuing review of research covered by this policy at Intervals cippropriateto the degree of
risk, but not less than once per year, and shall have the authority to observe or have a third party observe the
consmt process and the research." 21CFR56.109and45CFR46.109
"Coittinuing review of research must be substantive and meaningful." OHRF Guidance 1-15-07

Short Title: Seroquel XR for the Management of Borderline Personality Disorder

Enrollment; [X] Open Q Closed D On hold
Treatment: ^ Continues Q Complete Q Not a treatment study
Follow-up: 13 Continues Q; Complete Q No follow-up required
Funding: C] Federal ^|: Sponsored Q Foundation D Departmental
Enrollment Numbers: Approved; 50 Enrolled; 55 Years active; 6
UPIRTSOs (Unanticipated Problem Involving Risk to Subjects or Others):
Have any UPIRTSOs been reported in the last year? ^ Yes D No
Are there concerns to be discussed by the Committee? |_| Yes D>3 No

Study Summary: Q Adequate d Deficient
[X] None - too early Q Notte - data analysis elsewhere
t

External Findings; QDSMB letter D Progress report D Action letter
Consent and Assent Forms: ^ Submitted Q Missing Q'Waived or not applicable
HIPAA FOrmS: D Submitted ^ Missing D Waived or not applicable
0 Closed to enrollment - forms are no longer pertinent
Are all persons listed on consent form also listed on the IRB roster? [^ Yes D No

Inclusion of Children in Research:
If children are included in this research confirm that they should still be included.
Yes D No |EI NA - children excluded
If children are included this iiiGlusion must meet one of the following criteria for risk/benefit
assessment according to federal regulation (2ICFR56 and 45CFR46 Subp^rt D),

(404) Minimal risk
(405) Greater than minimal risk; but holds prospect of direct benefits to subjects,
Q (406) Greater than minimal risk; no prospect of direct benefit to subjects, but likely to
yield generalizable knowledge about the subject's disorder or condition,

University of Minnesota IRB
Continuing Review Form

Version 10/27/09

Substantive Changes: If any ofthe following are evident from the continuing review,
describe the changes for Committee discussion,

Change inrisk or benefit Q Change in funding
Change in. subject population |_j Change in conflict of interest
D Minor changes in consent form Q Change In data management
Major changes in consent form

Items for Committee Discussion:
MRI was added in the last year. Cfintrol subjects were added in the last year.

Recommended Stipulations:
1. Our records indicate that 50 subjects were approved for the study but 55 have been enrolled. Explain
how over-enrollrnent occurred and measures taKen to prevent recurrence, inform the IRB how many
subjects are required and provide justification,
2. Submit a 5-yr renewal.

3. Update the out-of-study contact address in the.main consent form for patients.
4. Submit a current HIPAA form.
Recommended Suggestions:

Recommended Action: Q Approve as Submitted
Q Approve with Suggestions
Approve with Stipulations as noted
Response to original reviewer

[><] Response can be reviewed by IRB staff
Q Approval Deferred - additional information required

Continuing Review Interval: ^ Annually
Q Every 6 months
D: Quarterly
0 Other interval;
I have cowpleied a substantive and meaningful review based on the mforwation made gvailable
at this time.

Print name of reviewer; Donald 0. Quick Date; 10/31/2012

Signed name of reviewer:'

If you choose to; sub mit fhis fonn electroniGally, please send to ^rj^utrtntedu.
Forms submitted from a umn.edu account do not need a hard-copy signature.

University of Minnesota IRB
Continuing Review Form

Version 10/27/09

Committee Meeting Minutes
October 31,2012

Agendaltem:
Continuing Review-JVIedical

PI: Schulz, S Charles

Reviewer; ^ Quick
Reviewer: None

Agenda Item: None
A^encla^tem: None

Protocol Title and HSC^:"Seroqu^^
ARandpmizedDduIlle^utdComparteonwithPlhacebo''^
Item Description:
Time for 5 year renewal.

iDiscussidn of Contt-overted Issues Sumimary:
There were no controverted issues.

]RevisionS).Clarifl<:ations:or;StipuIationsi:-'ll.,.;:;,/l::.\^ ;'';:-'y:'l:;AT^':1^

:?')

• The Fairview Research Helpline office moved off-campus as of May 7, 2011. The telephone number is
unchanged; however, please correct the address in the Contacts and Questions section of all consent forms. This
section should read: "If you have any questions or concerns regarding the study and would like to talk to someone
other than the researcher(s), you are encouraged to contact the Fairview Research Helpline at telephone number 612672-7692 or toll free at 866-508-6961. You may also contact this office in writing or in person at Fairview Research
Administration, 2433 Energy Park Drive, St. Paul, MN 55108."
• In response to evolving federal guidelines and increased scrutiny by regulators, the IRB must in some cases
reconsider studies originally reviewed over 5 years ago. To ensure that the IRB has accurate information,
investigators are required to provide a five year renewal form for these studies. Since the original application of this
study dates from September 2007, you are asked to complete a five year renewal form. The most current form can be
downloaded from our web site at: http://www.research.umn.edu/irb/forms.html. Provide the five year renewal form

within 90 days.
• Please submit a current HIPAA form.

I Change in RisK/BeneGt Balance;
None

Committee Must Address:

13 21CFR56.111 & 45CPR46.111
(Applicable Criteria Met)

D45CFR46-SubpartB
(Research Involving Pregnant Women or Fetuses)

D 21CFR50.23 &45CFR.116

D 45CFR46-Subpart C

(Waiver or Alteration of Consent Process)

(Research Involving Prisoners—Indicate Level of Risk, e.g. Minimal or
Greater Than Minimal)

D 21CFR50.27 &45CFR46.117
(Waiver of Consent Documentation)

D 21CFR50 &45CFR46-SubpartD
(Research Involving Children—Detail Inclusion or Exclusion Justification
and Indicate Level of Risk, e.g. Minimal or Greater Than Minimal,
Describe Consent Requirements as Specified in 21CFR50.55 and

45CFR46.408)

Determinations and Justifications Required by Regulations and Guidelines:
None.

Committee Meeting Minutes
October 31,2012
IRB Decision:

Length of Approval: One Year

Approve Continuing Review with Stipulations
Additional Info: None
Vote Yes: |

No: 0

Abstain: 0

Members Not Present for Vote Due to Conflict of Interest: None

Not Present:

November 5,2012

S Charles Schulz
Psychiatry, Dept of

F282/2AWest-B

8393A
2450 Riverside Ave
Minneapolis, MN 55454
RE: "Seroquel XRfor tile Management of Borderline Personality Disotder; A Raiidomized
Double^Blind Comparison with Placebo"
IRB Code Number: 0709M16844
Dear Dr. Schulz,

At the meeting on October 31,2012 the Institutional Review Board (IRB) reviewed and renewed
approval for the referenced study. The'IRB stipulated the following;
• Tile Fairview Research Helpline office moved off-campus as of May 7,2011. The telephone
number is unchanged; however, please correct the address in tile Contacts and Questions section
of all consent forms, This section should read; "If5?ou have any questions or concerns regarding

the study and Would like to talk to someone other than the researcher(s), you are encouraged to
contact the Fairview Research Helpline at telephone nuinber 612-672-7692 or toll free at866508-6961. You may also contact fliis office in writing or m person at Fain'iew Research

AdmMstmiion, 243 3 Energy Park Drive, St. Paid, MN 55108"
• In response to evolving federal guidelines and increased scrutiny by regulators, the IRB must in
some cages reconsider studies originally reviewed over 5 years ago. To ensure that the IRB has
accurate information, investigators are required to provide a five year renewal •fonn for these
studies. Since the original application of this study dEites from September 20,07, you ate asked to
complete a- five year renewal form. The most cuft'ent form catt be downloaded firotti our web site
at; http://www.research.umn.edu/irb/fom-is.htm]. Provide the five year renewal form within 90
days.
• Please submit a current HIPAA form.
Please provide a response and revised consent form for IRB review.

If your response is not received within ninety days, the study will be filed inactive.
Please send your electronic response to HRPP (irb@umn.edu). The signature of the Principal
Investigator is the only signature required with the response. Only one copy of the response is necessary.
If you have any questions, please contact the IRB office at 612-626-5654.
Sincerely,

^6f^

Felicia

Mroczkowski,

Research Compliance Supervisor

FM/ac
CC: Scott Crow, Kafhryu Cullen, Alaa Houri, Michael Miller, Richelle Moen, Ann. Roltiine

CIP

|

UNIVERSITY OF MINNESOTA RECD NOV 2 Q 2012
Twin Cities Campus Ambulatory Re&ewch Center F2S2/2A West
Department of PsycMM,y wowvw^e^wte^
Mhmeapolis, MN 55454
Medical School

Office: 612-626-5001

November 20, 2012

Felicia Mroczkowski
Institutional Review Board
University of Minnesota
Mayo Mail Code 820
D528 Mayo Memorial Building
420 Delaware Street S.E.
Minneapolis, Minnesota 55455

RE: "Seroquel XR for the management of Borderline Personality Disorder (BPD)"

HSC#0709M16844

Dear Felicia;
Thank you for your Continuing Review of the referenced study. We are responding to
IRB stipulations as stated in your letter dated November 5, 2012.
1) The consent form has been updated to include the correct address in, the GontQOts
and Questions section on page 9.

2) We have completed the IRB Five Year Renewal Form,
3) We are submitting the current HtPAA form, version date 24 FEB 2009. No changes
have been made to the HIPAA form,
The following documents are enclosed;
1. Consent form version date 20 NOV 2012
2. IRB Five Year Renewal Form

3. HIPAA form version date 24 FEB 2009

Thank you and please contact Ann Romine, study coordinator, with any questions at
612-626-6812.
Sincerely,

i^UMA^
S. Charles Schulz, MD

principal Investigator

UNIVERSITY OF MINNESOTA

Route this form to;

Five Year Renewal

Rev; 10/1/09

See instructions below.

Instructions:
Use this form whensubmftting for five-year renewal on IRB profocpls,
), Submit this form to the Research Subjects' Proteaions Programs Office:
U.S. Mail Address:
Human Research Protection Program

MMC 820

420 Delaware St. SE
Minneapolis, MN 554S5-0392

Campus Mail:

Human R6seareh Protection Program

MMC 820

'Minneapolis Campus

Deliver to;
D-528 Mayo Memorial Building
Minneapolis Campus
8-4:30, M-F

IRB Protocol Information
IRB Study Number:
Current Principal Investigator;
Primary Title:

0709M16844
S, Charles Schulz, MD
Seroquel XR for the Management of Borderline Personality Disorder (BPD)

1. State the original hypothesis or research question in a few short sentences:

The hypothesis of this proposal is that Seroquel XR will be statistically superior to placebo in
this controlled teial. A double-blind, placebo-controlled randomized trial is proposed to test

the efficacy and safety of Seroquel XR, A fixed dose strategy will be employed - 150 mg/d
and 300 mg/d.
2. Summarize any major changes to this study in the past five years. For instance, describe any new findings, any significant
changes in the protocol or project design, indicate any changes in study personnel;

1) The Brain Imaging Addendum was approved by the IRB on November 5,3010.
2) MeLewi Hospital withdrew participation in the study as of March 201 1, Their reason for
withdrawal was inability to meet enrollment goal. As the original enrollment goal was 33 per
site for a total of 99 subjects, the 2 remaining sites (University of Minnesota and University
of Iowa) incorporated McLean's enrollment to aim for a goal of 49 and 50 subjects per each
site,

3) The Brain Imaging Healthy Control Addendum was approved by the IRB on August 9,
2012,

2a. State if any of these changes increased risk to the subject population in your opinion:

These changes have not increased risk to the subject population,

3. Summarize the scientific progress indicating what you have learned. If there has been no substantial progress, then
provide an explanation:

Some subjects have reported a .reduction in their symptoms of Borderline Personality
Disorder.

4. List the publications developed With this research:

None yet as we are finishing up subject visits.

The University of Minnesota is an equal opportunity educator & empjoyer.
© 2008 by thfc Regents of the University of Minnesota.

1 of 3

5. If children are included in this study, is there a plan in place to re-consent minor subjects as they reach the age of

majority?

Qi Yes D No KlNA
6, Has the funding source for this research changed? If yes, then how?

D Yes E3 No D'NA

The University of Minnesota is an equal opportunity educator & employer.
i§> 200S|by the Regents of the University of Minnesota.

2 of 3

7. If there are multiple study title associated with this work, state if there are any that are no longer active:

N/A
8, How many subjects have you enrolled to date?

We have enrolled 52 subjects at our site. This includes 3 screen failures for a total of 49
randomized subjects.
9, Are you requesting additional subjects at this time?

No
10. If you are currently enrolling subjects, or plan to enroll in the future, then please provide a copy bf(he consent forms
with all informqtion up to date.

We have completed enrollment as of November 2012 and are seeing the final subjects in the
study,

Th? University of Minnesota is an equgl opportunity educator & employer,
• © 20p8 by the Regents of the University of Minnesota.

3 Of 3

UNIVERSITY OF MINNESOTA
7'iciH Citifs Cmilpus

Hunitin Kesiwrcll I'rnteetwn t'rngram
Office iiftlit.' Viye I'lvshlmiljnr Reseuivh

D52fi Mnyi) Menmrhll tiulMinf;
420 Oelawan Snvrt S.E.

MMC 820

MiiiMtiiwlis, MH 5545S
Office: ht2-6U-5654
/•at- ftl!-fi36-6061
E-nmil; irh@unm.filn or ihv^umn.t'iln
Weluiiu': htlii://wseurch.wmu'tlit/.wh)ccl!i/

November 29, 2012
S Charles Schulz
Psychiatry, Dept of
F282/2AWest-B

8393A
2450 Riverside Ave
Minneapolis, MN 55454
RE; "Seroquel XR for the Management of Borderline Personality Disorder: A Rafidomized Double-Blind
Comparison witii Placebo

IRB Code Number: 0709M16844
Dear Dr. Schulz,

The Institutional Review Board (IRB) received your response to its stipulations for renewal. Since this
information satisfies the conditions set by the IRB, approval for the recent renewal is confirmed in our files.
The consent form dated November 20, 2012 is also approved.
For youi" records and for grant certification purposes, the approval date for the referenced project is October
31, 2012 and the Assurance of Compliance number is FWA00000312 (Fairview Health Systems Research

FWA00000325, Gillette Children's Specialty Healthcare FWA00004003). Approval for the project will
expire one year from that date. You will receive a report form two months before the expiration date.
As Principal Investigator of this project, you are required by federal regulations to inform the IRB of any
proposed changes in yoyr research that will affect human subjects. Changes should not be initiated until
written IRB approval is received. Unanticipated problems and adverse events should be reported to the IRB
as they occur. Results of inspections by any external regulatory agency (i.e. PDA) must be reported
immediately to the 1KB. Research projects are subject to continuing review,
If you have any questions, please call the EU3 office at 612-626-5654.
The IRB wishes you continued success with your research.
Sincerely,

FeliciaMroczkowski, CIP
Research Compliance Supervisor

FM7ac
CC; Kathiyri Cullen, AlaaHouri, Michael Miller, Riclielle Moen, Ann Ronune

Driven to Discover5

University of Minnesota

Continuing Review of IRB - Pending

Review Period;
09/07/2012-10/30/2013
Rev: 03/01/2005

Medical Research

Study Number: 0709IVI16844
Principal Investigator: S Charles Schulz
Title(s): Seroquel XR for the Management of Borderline Personality Disorder:
A Randomized Double-Blind Comparison with Placebo
Study Status
Complete

Funding Source(s)

Funding Source: ASTRAZENECA INTL
Funding Type:

Personnel
Schulz, S Charles (P. I.)

Carlson, William (Staff/Lab)
Cullen, Kathryn (Co-lnvestigator)
Davis, Aubrey (Staff/Lab)
Fryza, Brandon (Staff/Lab)
Han, Georges-Jakob (Staff/Lab)
Heller, Monika (Staff/Lab)
Houri, Alaa (Correspondent)

LaRiviere, Lori (Staff/Lab)
Miller, Michael (Co-lnvestigator)
Moen, Richelle (Co-lnvestigator)
Romine, Ann (Correspondent)

Stepka, Megan (Staff/Lab)
Watroba, Lexa (Staff/Lab)

Investigational Drug(s)
The University of Minnesota is an equal opportunity educator & employer. Page'
©2004 by the Regents of the University of Minnesota.

IND Number: 45,456
IND Holder: AstraZeneca Phannaceuticals LP (Sponsor)

Study Enrollment
Number of Subjects Approved for study:
80
Number of subjects enrolled this reporting period:
Male Female Unknown Total

T

n

3°:

13 I

Number of subjects enrolled to date:
Male

22

Female
y36~

Unknown

3°:

Total

|58 |

Is this a multi-center study?
Yes
Total national accrual to date: 95

Unanticipated Problem Reporting
Since the most recent IRB continuing review approval, have any participants withdrawn from the
research?
Yes
One subject withdrew early due to leaving the country.

Since the most recent IRB continuing review approval, have any participants complained about the
research?

No
Have any serious and unanticipated problems been reported to the IRB?
No

Study Summary
Summarize information about any results and/or trends:
A total of 79% of the subjects receiving quetiapine XR were rated as ???responders??? compared to 62% of those
who received placebo. Treatment-emergent adverse events included sedation, change In appetite, and dry mouth.
The overall completion rate for the 8-week double-blind treatment phase was 63% (55% for quetiapine XR 150 mg,
58% forquetiapine XR 300 mg, and 79% for placebo).

Have there been any changes in protocol approved by the IRB since last continuing review?
No

The University of Minnesota is an equal opportunity educator & employer. Page 2
©2004 by the Regents of the University of Minnesota.

Describe any new information (i.e, lessons learned, things to do differently) discovered during the
course of this research study pertinent to protecting subjects:
Nothing to report.

On what date was this study completed or discontinued?

03/12/2013

External Findings
Is there anything in the relevant recent literature that the IRB should know about concerning this
research?

No

Consent/Assent/HIPAA Forms
Have there been any changes to the consent and/or assent form(s) since the last IRB approval?
No
Have translated consent short forms been used in conjunction with an interpreter to obtain consent
for this study?
No

Other Comments
The last subject completed at University of Minnesota on Feb 6, 2013. The last subject completed at University of
Iowa on March 11 , 2013. Data analysis has been completed at the University of Iowa. The manuscript draft has
been completed by Dr. Black in August 2013. Clinicaltrials.gov has been updated with results in August 2013.

The University of Minnesota is an equal opportunity educator & employer. Page 3
© 2004 by the Regents of the University of Minnesota.

University of Minnesota Mail - Fwd: IRB# 0709M16844 sfaidy closure letter lTttps://n3ail.google.com/imil/u/l/?ui=2&ik=dd3dle7c9e&view=pt&searc...

A

Almarie Coleman <colem258@umn.edu>

Fwd: IRB# 0709M16844 study closure letter

1 message
Andrew Alien <alle0302@umn.edu> Wed, Feb 12, 2014 at 4:30 PM
To: Almarie Coleman <colem258@umn.edu>, Felicia Mroczkowski <kensl001@umn.edu>
Hey Almarie,
This sponsor needs an actual letter for study close out to receive payment. Can you write one for them? I am not

sure how you and Felicia handle this when the Pl closes the study during CONREN in the past, but I thought you two
may be the best to handle this request.
Andrew
Forwarded message
From: <romi0004@umn.edu>

Date: Wed, Feb 12, 2014 at 4:27 PM
Subject: IRB# 0709M 16844 study closure letter
To: Andrew R Alien <alle0302@umn.edu>
Cc: Harvey Gross <gross042@umn.edu>

Hi Andrew,
Harvey is unable to receive our final study payment from AstrZeneca as they are awaiting the IRB study closure
letter for study IRB# 0709M16844. The IRB acknowledged study closure in response to our final continuing review,
but AZ said this was not sufficient for their records.
Could we have a study closure letter sent to us? Electronic version is fine.

Thx!
ann

Ann Romine,RN
Study Coordinator

Psychiatry
ph612.626.6812
fax612.626.5103

Mailing Address:
University of Minnesota

Department of Psychiatry
2450 Riverside Ave S
F212/2AWest
Minneapolis, MN 55454

Sincerely,

1

of

2

2/13/2014

10:53

AM

|

Appendix D

CONSENT FORM

TITLE:

Seroquel XR for the Management of Borderline Personality
Disorder (BPD)

PROTOCOL NO.:

IRUSQUET0454

INVESTIGATOR:

S. Charles Schulz, MD

SITE:

University of Minnesota Medical School, Dept of Psychiatry

TELEPHONE:

612.273.9820

INTRODUCTION
You have been asked to take part in a clinical research study at the University of
Minnesota Medical School, Department of Psychiatry. This consent form describes the
purpose, procedures, possible benefits and risks of the study. Before agreeing to
participate in this research study, it is important that you read and understand this form.
You are encouraged to discuss any questions that you may have about this study with
the study staff and study doctors. If you participate, you will receive a copy of this form
to keep.
This study is being conducted by the following researchers in the Department of
Psychiatry at the University of Minnesota Medical School: S. Charles Schulz, MD;
Richelle Moen-Moore, PhD; Michael J. Miller, PsyD; Scott Crow, MD, and Ann Romine,
RN. This study is receiving support funding from AstraZeneca Pharmaceuticals LP.
BACKGROUND AND PURPOSE OF THE STUDY
You are being asked to take part in this research study of the investigational drug
quetiapine fumarate extended-release (SEROQUEL XR™). You are being invited to
participate in this research study because you have identified traits of borderline
personality disorder (BPD).
Quetiapine fumarate extended-release (SEROQUEL XR™) is approved by the United
States Food and Drug Administration (FDA) for the treatment of schizophrenia, mania,
and bipolar depression. It is not approved for the treatment of borderline personality
disorder; however other atypical antipsychotic medications, including Seroquel
immediate-release, have been tested with positive results being seen as evidenced by
reduction in BPD symptoms. The purpose of this study is to determine the safety and
effectiveness of quetiapine fumarate extended-release (SEROQUEL XR™) in the
treatment of borderline personality disorder (BPD) compared to placebo (inactive
substance).
IRB# 0709M16844
Version: 15 JUN 2012

Page 1 of 9

Study IRUSQUET0454
IRB Approval: 09 AUG 2012

NUMBER OF SUBJECTS / LENGTH OF PARTICIPATION
An estimated 99 subjects will take part in this study from 3 study sites.
Your total study participation will last up to 12 weeks (depending on washout period)
and include up to 10 study visits. Study visits will take between thirty minutes and 2
hours, depending on which procedures are necessary for that visit.
During the study, you may be asked to return for an unscheduled visit any time your
condition warrants medical attention or a dose adjustment is required at no cost to you.
STUDY PROCEDURES
If you decide to participate in this study you will come in for 10 study visits. The
assessment visits will take place at the Ambulatory Research Center (ARC), University
of Minnesota Medical Center, Fairview -Riverside Campus, in the Riverside
Professional Building, 606 24th Avenue South, suite 602, Minneapolis, MN 55454.
Screening Visit (Visit 1)
The following tests and procedures will be performed to determine eligibility at Visit 1:

Review of your medical, psychiatric and medication history.

A physical examination including an eye examination and measurement of your
vital signs (heart rate and blood pressure), height, and weight.

Electrocardiogram (ECG – which measures the electrical activity of your heart)

Collection of a fasting (no food or drink for 8 hours, except water) blood sample
(15 milliliters or approximately one tablespoon) for routine laboratory tests.

If you have diabetes mellitus type 1, a fasting glycosylated hemoglobin (HbA1c)
will be obtained. Your (HbA1c) will need to be less than 8.6% to participate in the
study.

Collection of a urine sample for drug screen for illegal drugs. Results of the drug
screen must be negative for you to participate in this study.

Collection of a urine sample for pregnancy testing for potential child-bearing
female subjects. Results of the pregnancy test must be negative for you to
participate in this study. The urine pregnancy test will be repeated again at visit 6.

Mental health history and assessment interview.
You may be asked to stop taking certain medications for depression, mood and anxiety
for 14 to 28 days. This is called a washout period where the effects of these
medications leave your body.
If you possibly could become pregnant during the study, you must talk to the study
doctor about the method of birth control that you will use to avoid getting pregnant
during the study and for 30 days after your study participation is completed.

Baseline Visit (Visit 2)
IRB# 0709M16844
Version: 15 JUN 2012

Page 2 of 9

Study IRUSQUET0454
IRB Approval: 09 AUG 2012

The mental health history and assessment interview will determine whether you have
traits of Borderline Personality Disorder (BPD). A minimum of 5 out of 9 BPD traits are
required to meet eligibility for participation in the study. If you are eligible to participate
in the study you will then come in for the second visit which is the Baseline Visit. At this
visit you will receive the study medication with instructions and begin taking the study
medication.
Study Medication
Your medication will either be quetiapine fumarate extended-release (Seroquel XR) or
placebo (sugar pill). Neither you nor the study team will know whether you are taking
Seroquel XR or placebo. Whether you receive Seroquel XR or placebo will be
determined by chance, like the flip of a coin. You will be assigned to 1 of 3 groups in
the study. Of the 3 groups, 2 groups will receive Seroquel XR (active medication), and 1
group will receive placebo (inactive medication). This means you will have a 2 out of
3 chance of getting Seroquel XR, and a 1 out of 3 chance of receiving placebo.
The 3 groups to which you will be assigned to are 1) Seroquel XR 150 mg per day, 2)
Seroquel XR 300 mg per day, or 3) placebo. You will take by mouth the number of
tablets instructed by your study doctor and will be instructed to take the assigned tablets
at approximately the same time each day.
It is important that you take the study medication as directed. The study tablets must be
taken every day. Any extra study medication tablets and the container, even if it is
empty, must be returned to the research coordinator. The study medication should be
taken only by you and should not be taken by anyone else.
The study coordinator will call you the day after your baseline visit to ask you how you
are feeling after your initial dose of study medication and to address any questions or
concerns you may have.
Study Treatment Period (Visits 3-10)
After the Baseline Visit you will return to the study clinic weekly for the next 8 weeks
(visits 3-10). At each visit you will complete questionnaires about your behavior and
mood and the study team will monitor your symptoms and any side effects you may
have. Each of these study visits will last approximately 30 minutes to 1 hour.
At visit 6 you will have a urine pregnancy test (females) and weight. The final visit (visit
10) will include vital signs, weight, blood and urine tests (drug screen and pregnancy
test for potential child-bearing female subjects), ECG, and side effect assessments. You
will complete a final set of questionnaires regarding your behavior and mood at this visit.
At the final visit we will also discuss your dosing titration off of the study medication and
options for your post-study follow-up care. Follow-up visits will be scheduled with one of
the study doctors accordingly.
RISKS, DISCOMFORTS AND INCONVENIENCES
There is a risk that the symptoms of your illness will not respond to the study
medication. Your condition may worsen during the wash-out phase if you need to titrate
off your existing medications before starting the study medication. You may experience
increasing symptoms such as unstable mood, sleep disturbance, and the possibility of
IRB# 0709M16844
Version: 15 JUN 2012

Page 3 of 9

Study IRUSQUET0454
IRB Approval: 09 AUG 2012

suicidal feelings. Your symptoms could be severe and could require hospitalization and
have consequences for your family, job, or your finances.
Your condition may worsen if the study drug has no effect on you. Also, as this is a
study in which some patients will receive placebo (inactive substance), you may not
improve if you are assigned to this part of the study. Throughout the study, your study
team will closely monitor for the possibility of worsening symptoms at each clinic visit
and will intervene appropriately. Telephone follow-up and additional visits may be used
to evaluate your health and to check for increased symptoms. You are asked to contact
your study doctor as soon as possible if these symptoms cause you any concern. If this
happens, your study doctor will discuss with you whether you should continue in the
study and other alternative treatments available for your condition.
If you or your doctor chooses to end your participation in the study, you will be given
medication titration instructions by the study doctor to taper off your study medication.
Acute withdrawal symptoms such as nausea, vomiting, and insomnia have very rarely
been described after abrupt cessation of antipsychotic drugs including Seroquel.
However, gradual withdrawal is advisable.
The study medication may cause some side effects. You may experience none, some
or all of those listed below.
A common side effect for this type of drug, including the study medication, when
beginning treatment is sleepiness. This may affect mental and physical abilities required
to operate an automobile or machinery. You should exercise special caution when
driving or using machinery since the study medication may cause drowsiness, lack of
coordination or slowed reaction time.
You may experience lightheadedness, feeling faint or fainting when standing up,
particularly if you wake up during the night during the first week of treatment. This is
most common when you begin taking Seroquel XR or increase the dose of Seroquel XR
and will usually pass with time. You should exercise caution if you wake up during the
night (for example, to go to the bathroom) during the first week of treatment. Stand up
slowly and carefully to avoid falling in case you do feel faint. If you awaken during the
night and feel dizzy upon sitting up or standing, lie or sit back down and wait until you
can get up without feeling faint.
Other relatively common symptoms are rapid heart beat, dry mouth, constipation,
indigestion, feeling weak, swelling of arms and legs, weight gain, fainting and stuffy
nose.
In some cases there may be a change in the amount of white blood (cells in your blood
to help fight infections) or an increase in a type of white blood cells, “eosinophilia”,
which is sometimes seen in allergic reactions. If you experience symptoms such as
fever and/or sore throat and sores on the tongue or inside of the mouth please contact
your study doctor. If the symptoms are severe, you should go to the Emergency Room.
Some patients have shown an increase in the amount of liver enzymes (indicating
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possible liver injury or damage). If your blood tests indicate increased liver enzymes, the
study doctor will discuss the results and recommendations with you.
More uncommon side effects are allergic reactions and fits (seizures).
Rare side effects that have been reported are fever, very marked drowsiness, muscle
stiffness, marked increase in blood pressure or heart beat, reduced consciousness and
priapism (long-lasting and painful erection).
There is a rare, but potentially serious, side effect associated with this class of drugs,
including the study medication called neuroleptic malignant syndrome (NMS), a
potentially life-threatening disorder that includes symptoms such as fever, tight muscles,
changes in blood pressure and heart rate, confused thinking, and an increase in the
amount of “creatine phosphokinase”, a substance in the muscles.
This class of drugs may also cause a movement disorder called tardive dyskinesia (TD).
Symptoms of this disorder are that certain muscle groups (e.g. the tongue and lip
muscles) will move even if the person does not want them to move. In most cases the
symptoms stop when the medication is withdrawn, but in some cases they are
permanent.
In recent studies in bipolar depression, extrapyramidal symptoms that can be muscle
tightness, restless feelings, tremor, stiff walking, or lack of coordination were more
common in patients treated with Seroquel than in patients with no treatment.
Seroquel was recently approved in the U.S. by the FDA (October 2006) for the
treatment of depressive episodes associated with bipolar disorder. All medications
used to treat depression (i.e. antidepressants including quetiapine) received a warning
from the FDA regarding the risk of suicidal thoughts and actions in some children and
teenagers, as well as adults. You should watch for warning signs, especially when
beginning therapy or changing dose, which include thoughts about dying, attempts to
commit suicide, new or worsening depression, new or worsening anxiety, feeling very
agitated or restless, panic attacks, difficulty sleeping, new or worsening irritability, acting
aggressive, being angry, or violent, acting on dangerous impulses, or an extreme
increase in activity and talking.
Extended-release Seroquel, regular Seroquel, and the non-active tablets (placebo)
contain lactose, which may cause discomfort if you are lactose intolerant.
There have been reports of hyperglycaemia (high blood sugar) and diabetes in patients
treated with Seroquel and other drugs like it. Also, increases in fatty substances such
as triglycerides or cholesterol may occur. Further, people taking Seroquel can have
increase in weight and waist size. These side effects, taken together, are now known
as the “metabolic syndrome.” In general, these symptoms and laboratory tests go away
when the medications are stopped, but may last for some period. You will be tested for
changes in glucose, triglycerides, and cholesterol at the beginning and at the end of the
study.
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You may experience an allergic reaction to Seroquel XR. Symptoms of an allergic
reaction include rash, hives, or difficulty breathing in extreme circumstances. If you
experience an allergic reaction, you should contact your study doctor. If the symptoms
are severe, you should go to the Emergency Room.
Studies with Seroquel and other drugs of this type have shown an increased risk of
death in elderly patients with dementia and behavioral disturbances.
There may be risks involved in taking this medication that have not been identified in the
studies done so far, but every precaution will be taken and you are encouraged to report
anything that is troubling you. Your study doctor and the study staff will monitor your
condition closely.
With your cooperation regarding the instructions given by your study doctor, frequent
examinations and laboratory tests, the risk of unwanted side effects may be minimized.
We ask you to report any health problems during the study to your study doctor.
There are some types of medications that are not allowed to be taken with study
medication, including but not limited to, medications in the same class as Seroquel,
medications for depression, medications for mood, and some medications for anxiety
and sleep. Your study doctor will discuss these limitations on using medications with
you. Your study doctor will also provide you with a list of over-the-counter medications
and herbal drugs that cannot be taken during the course of the study.
During the washout and if you receive placebo your condition will not be treated with
active medication and may become worse, stay the same or improve.
There is a risk that the symptoms of your illness will not respond to the study
medication. Your condition may worsen if the study medication has no effect on you. If
this happens, your study doctor will discuss with you whether you should continue in the
study and other alternative treatments available for your condition.
Possible side effects from blood drawing include faintness, inflammation of the vein,
pain, bruising, or bleeding at the site of puncture. There is also a slight possibility of
infection.
Fasting for 8 hours could cause dizziness, headache, stomach discomfort or fainting.
WOMEN OF CHILDBEARING POTENTIAL
Taking the study medication may involve unknown risks to a pregnant woman, an
unborn child, or breastfeeding infant. Therefore, if you are pregnant, planning to
become pregnant during the research study period or are breastfeeding a child, you
cannot participate in this study.
If you are a woman of childbearing potential:

You confirm to the best of your knowledge that you are not pregnant and you do
not intend to become pregnant during this study.

You must avoid becoming pregnant by using one of the following methods of
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birth control during this study: double-barrier method (condoms or diaphragm with
spermicide), oral contraceptive (birth control pills), implant (Norplant®), dermal
contraception (patch), long-term injectable contraceptive (Depo-Provera®),
intrauterine device (IUD) or tubal ligation.
If you are female, a urine pregnancy test will be done at Visit 1, Visit 6, and Visit 10 to
confirm that you are not pregnant. Results of the pregnancy test must be negative for
you to participate in this study.
If at any time during this study you think you might be pregnant, or later learn that you
were pregnant during the study, you must contact the study doctor immediately for
further instructions.
If you become pregnant during the study, you will be withdrawn from the study. All
costs for care related to your pregnancy, childbirth, and post-partum/newborn care will
be your responsibility. The sponsor will request access to your records concerning your
pregnancy, childbirth and postpartum care as well as your infant’s medical records.
UNFORESEEN RISKS
Since the study drug is investigational for this indication, there may be other risks that
are unknown at present, including possibly life-threatening reactions.
NEW INFORMATION
You will be given any new information about the study medication that becomes known
during the course of this study that might reasonably affect your willingness to continue
to take part in the study.
POSSIBLE BENEFITS
Although Seroquel XR is being tested as a treatment for BPD, there is no guarantee
that you will receive any medical benefit. Study drug and study procedures will be
provided at no cost. You may receive information about your health from the physical
examinations, laboratory tests, and psychological evaluations done in this study. Your
participation will provide information about the study medication and BPD that may
benefit others in the future.
ALTERNATIVE TREATMENT
You do not have to take part in this study to be treated for your illness or condition.
Other treatments and therapies for your condition are available, including
psychotherapy or medication therapy. Although there are currently no medications
approved by the Food and Drug Administration (FDA) for the treatment of Borderline
Personality Disorder, Seroquel XR is available by prescription off-study. The study
doctor can discuss with you the important benefits and risks of these treatments and
therapies.

CONFIDENTIALITY
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To help protect your privacy, the researchers have obtained a Certificate of
Confidentiality from the National Institutes of Health. With this certificate, the
researchers cannot be forced to disclose the information that may identify you, even by
a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative,
or other proceedings. The researchers will use the Certificate to resist any demands for
information that would identify you, except as explained below. The Certificate cannot
be used to resist a demand for information from personnel of the United States
Government that is used for auditing or evaluation of federally funded projects or for
information that must be disclosed in order to meet the requirements of the Federal
Food and Drug Administration (FDA).
You should understand that a Certificate of Confidentiality does not prevent you or a
member of your family from voluntarily releasing information about yourself and your
involvement in the research. If an insurer, employer or other person obtains your written
consent to receive research information, then the researcher may not use the Certificate
to withhold that information.
The Certificate of Confidentiality does not prevent the researchers from disclosing
voluntarily, without your consent, information that would identify you as a participant of
the research project to prevent serious harm to you or someone else. This may occur
under the following circumstances such as the present danger of child abuse, suicide,
and/or homicide.
The Certificate of Confidentially does not represent an endorsement of the study by the
Department of Health and Human Services or National Institutes of Health.
Records of your participation in this study will be held confidential except as disclosure
required by law or as described in this informed consent document under the section
PROTECTED HEALTH INFORMATION (PHI). The study doctor, the sponsor or
persons working on behalf of the sponsor, and under certain circumstances, the United
States Food and Drug Administration (FDA) and the Institutional Review Board (IRB)
will be able to inspect and copy confidential study-related records, which identify you by
name. Therefore, absolute confidentiality cannot be guaranteed. If the results of this
study are published or presented at meetings, you will not be identified.
COMPENSATION FOR PARTICIPATION
You will be compensated $30.00 for each visit in the form of a check that will be mailed
to your home 2-3 weeks after your last study visit. Study drug and study procedures will
be provided at no cost. We will also provide free parking and have transportation
options available to you as needed.
RESEARCH RELATED INJURY
In the event that this research activity results in an injury, treatment will be available, including
first aid, emergency treatment, and follow-up care as needed. Care for such injuries will be
billed in the ordinary manner, to you or your insurance company. The sponsor of the study has
some funds available to pay for care for injuries resulting directly from being in this study. If you
think that you have suffered a research related injury and that you may be eligible for
reimbursement of some medical care costs, let the study physicians know right away.
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PROTECTED HEALTH INFORMATION (PHI)
Your PHI created or received for the purposes of this study is protected under the
federal regulation known as HIPAA. Refer to the attached HIPAA authorization for
details concerning the use of this information.
VOLUNTARY NATURE OF THE STUDY
Participation in this study is voluntary. Your decision whether or not to participate in this
study will not affect your current or future relations with the University of Minnesota or
University of Minnesota Medical Center, Fairview. If you decide to participate, you are
free to withdraw at any time without affecting those relationships.
Your participation in the study may also be stopped by the study doctors if health risk or
protocol violation is determined. If you stop being part of the study, the study doctor will
talk to you about any medical issues regarding the stopping of your participation, as well
as follow-up care options.
CONTACTS AND QUESTIONS
You may ask any questions you have now, or if you have questions later, you are
encouraged to contact the researchers at the following phone numbers: Dr. S. Charles
Schulz at (612) 273-9820 or the study coordinator Ann Romine at (612) 627-4843.
If you have any questions or concerns regarding the study and would like to talk to
someone other than the researcher(s), you are encouraged to contact the Fairview
Research Helpline at telephone number 612-672-7692 or toll free at 866-508-6961.
You may also contact this office in writing or in person at University of Minnesota
Medical Center, Fairview Riverside Campus, 2200 Riverside Avenue, Minneapolis, MN
55454.
You will be given a copy of this form to keep for your records.
STATEMENT OF CONSENT
I have read the information above and my questions have been answered to my
satisfaction. I understand I may withdraw from the study at any time without affecting
any future relations with the University of Minnesota Medical Center, Fairview. I
consent to participate in the study.

Participant’s Name (Print): ________________________________________________

______________________________________________________________________
Signature of Participant
Date

______________________________________________________________________
Signature of Person Obtaining Consent
Date
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