Clinical Therapeutics/Volume 34, Number 2, 2012
Intra-anal Iferanserin 10 mg BID for Hemorrhoid Disease: A
Prospective, Randomized, Double-Blind, Placebo-Controlled
Trial
Alexander Herold, MD1; John Dietrich, PhD2; and Roger Aitchison, ScM2
1
Enddarm-Zentrum Mannheim, Mannheim, Germany; and 2Ventrus Biosciences, Inc., New York, New
York
ABSTRACT
Background: Despite the prevalence of internal
hemorrhoid disease (HD), there are few pharmaco-
logic options. Iferanserin, a selective serotonin recep-
tor antagonist, is being studied for use in the treatment
of HD.
Objective: This Phase IIb study evaluated the effi-
cacy and tolerability of 10-mg twice-daily iferanserin
intra-anal ointment for the cessation of bleeding and
other symptoms associated with internal HD.
Methods: This randomized, double-blind, placebo-
controlled study was conducted at 5 sites in Germany.
Outpatients with Goligher grade I, II, and/or III hem-
orrhoids and bleeding were randomly assigned to re-
ceive iferanserin ointment 10 mg or inactive vehicle
(placebo) BID for 14 days. During treatment, patients
rated the severity of HD symptoms daily on a 10-point
scale using a diary form. At enrollment and study end,
physicians recorded the frequency and intensity of HD
symptoms, adverse events, and results from blood and
urine analyses on clinical-report forms.
Results: Of the 121 patients enrolled in the study,
118 were evaluable for tolerability and 111 for effi-
cacy. The mean age of the tolerability population was
52.7 years, 78.9% were male, and all were white. The
2 groups had similar HD symptoms at baseline, but
overall, patients in the placebo group had numerically
higher grades of HD than did patients in the iferanserin
group. Compared with placebo, iferanserin was asso-
ciated with significantly lower patient-reported sever-
ity ratings of daily bleeding and itching, beginning at
day 1 for bleeding and at day 2 for itching (P 0.05),
but not with reduced ratings for severity of other HD
symptoms, including pain, tenderness, difficulty with
defecation, fullness, throbbing, and gas. In the physi-
cian assessments, iferanserin was associated with sig-
nificantly reduced bleeding frequency by day 14 com-
pared with placebo (P 0.05). Adverse events were
February 2012
mild and infrequent, with no significant differences in
prevalences between the 2 treatment groups and no
clinically significant changes in laboratory values in
any patient.
Conclusion: Compared with placebo, intra-anal if-
eranserin was associated with significantly reduced
patient-reported severity of bleeding and itching and
physician-assessed bleeding frequency in these pa-
tients presenting with grade I, II, and/or III internal
hemorrhoids and bleeding at 5 sites in Germany.
ClinicalTrials.gov identifier: 01483833. (Clin Ther.
2012;34:329 340) 2012 Elsevier HS Journals,
Inc. All rights reserved.
Key words: bleeding, hemorrhoids, iferanserin, se-
rotonin receptor antagonist.
INTRODUCTION
Hemorrhoid disease (HD) is common, although the
precise prevalence has not been reliably estimated. In
the United States in 1990, based on data from the Na-
tional Center for Health Statistics, the estimated prev-
alence of HD among adults was 4.4%, peaking be-
tween the ages of 45 and 65 years.1 This figure,
however, may be an underestimate because some pa-
tients do not seek professional medical care for HD,
preferring self-medication.2 In a general-practice sam-
ple in Great Britain 40 years ago, the estimated preva-
lences of HD were 34.8% among men and 37.2%
among women.3 It is possible that more than half of all
people experience HD at some point in life.4
The etiology of HD is not fully understood. The anal
canal consists of several fibrovascular connective cush-
ions, which together serve as a conformable plug that
Accepted for publication December 15, 2011.
doi:10.1016/j.clinthera.2011.12.012
0149-2918/$ - see front matter
2012 Elsevier HS Journals, Inc. All rights reserved.
329
 Clinical Therapeutics
ensures a watertight closure. The degenerative effects
of aging may weaken or fragment these supporting
tissues, and the repeated effects of straining during def-
ecation and/or of the pressures associated with hard
stool, heavy lifting, and/or pregnancy may lead to their
descent and prolapse.
Prolapsed cushions have impaired venous return,
with blood vessels that become congested, enlarged,
and inflamed.5 It has been suggested that the conges-
tion is caused and maintained by 5-hydroxytryptamine
(5-HT) (serotonin) release, which by acting on 5-HT2a
receptors in the vasculature promotes efferent venous
constriction, platelet aggregation, and a cascade effect
producing thrombus formation.6,7 As hemorrhoids
worsen, trapped blood forms piles (protruding skin
folds filled with static and thrombosed blood) above
the pectinate line (internal hemorrhoids) and then be-
low it (external hemorrhoids).
Bleeding often painless and bright red in coloris
one of the most frequent complaints of HD (the Greek
root of hemorrhoid means blood flow). Bleeding oc-
curs as a result of erosion or trauma of the mucosal
lining or inflammation damaging the underlying blood
vessels. Bleeding has been reported to be the HD symp-
tom that primarily motivates patients to seek a physi-
cians consultation.8,9 Other common HD symptoms
are itching and pain10; 5-HT release may lead to those
symptoms.11,12
Iferanserin is a selective 5-HT receptor antagonist
with an affinity for 5-HT2a receptors. It has been hy-
pothesized that an intra-anal ointment application of
iferanserin might modify the vascular effects occurring
in HD and thereby reduce or eliminate the most fre-
quently occurring symptoms of HD. The goal of the
present study was to evaluate the efficacy and tolera-
bility of twice-daily iferanserin intra-anal ointment
versus inactive vehicle (placebo) in the cessation of
bleeding and other symptoms associated with HD.
PATIENTS AND METHODS
This Phase IIb, 14-day, prospective, randomized, dou-
ble-blind, placebo-controlled trial of the effects of in-
tra-anal iferanserin was conducted at 5 investigative
sites in Germany between September 2001 and August
2002. The trial protocol was approved by the ethics
committee of the Chamber of Physicians of Baden-
Wrttemberg (Stuttgart, Germany). All patients pro-
vided written informed consent before screening.
330
Inclusion and Exclusion Criteria
Consecutive ambulatory outpatients aged 18
years with a diagnosis of grade I, II, or III hemorrhoids,
based on the Goligher classification,13 and who had at
least 1 bleeding episode at least every other day during
the 2 weeks before screening, were eligible for enroll-
ment in the study. The Goligher classification assigns a
grade to internal hemorrhoids based on the degree of
prolapse; such grades are considered useful for helping
to guide therapeutic options.14 In grade I hemorrhoids,
tissue protrudes into the lumen of the anal canal but
does not prolapse; in grade II hemorrhoids, tissue pro-
lapses but reduces spontaneously; in grade III hemor-
rhoids, tissue prolapses and requires manual reduc-
tion; and in grade IV hemorrhoids, tissue prolapses but
cannot be manually reduced.2 Patients with grade IV
hemorrhoids; any large bowel and/or anal canal dis-
ease; diabetes mellitus; severe hepatic, renal, and/or
cardiovascular disease; any infectious disease; any di-
agnosis of cancer; and/or pregnancy were excluded.
Study Design
At screening, a complete physical examination and
laboratory evaluation were conducted. Randomiza-
tion at a ratio of 1:1 was achieved by means of opaque
sealed envelopes containing assignment to the iferan-
serin or placebo group.15 The envelopes were shuffled
to produce a random sequence, and each envelope was
bundled with an identical package of iferanserin or
placebo. The envelopes and packages were dispensed
to patients as they qualified for the study. Each pack-
age carried a peel label with a coded identification
number; for each patient, the investigator affixed the
label from the package onto the clinical-report form
provided specifically for the study. Investigators and
patients were blinded to treatment group assignments
and to the contents of the packages.
The ointments were supplied to patients in single-
dose, disposable tubes, with each patient receiving 30
separate single-dose units. Patients were instructed to
apply the ointment intra-anally BID for 14 days by
cleaning the area around the application site, squeezing
the contents of the tube directly into the anal canal
until emptied, and spreading any remaining ointment
around the anus outside of the canal. There were no
additional instructions provided to patients regarding
the ointment after application. On day 15, after 14
days of treatment, patients were required to return to
the investigative sites for another physical and labora-
Volume 34 Number 2

tory evaluation. Patients were also instructed to keep
all used and unused single-dose tubes and to return
them to the investigative sites on day 15. The tubes
were counted to monitor treatment compliance.
Each laboratory analysis consisted of both a blood
analysis and a urinalysis, with the following laboratory
tests performed before and after the study: hemoglo-
bin, platelets, leucocytes, creatinine, urea, sodium, po-
tassium, aspartate aminotransferase, and alanine ami-
notransferase for the blood analysis; and pH, protein,
glucose, ketone, urobilinogen, bilirubin, blood, nitrite,
and pregnancy for the urinalysis. In performing these
tests, the 5 investigative sites were allowed to use rou-
tine local laboratories.
During the 14-day treatment period of the study,
patients were asked to refrain from self-administering
any intra-anal medication (eg, suppositories), taking
oral laxatives, and taking any of the following medica-
tions, which might have influenced the effects of the
study treatment: analgesics, anti-inflammatories, anti-
depressants, hemostatics, local anesthetics, and anx-
iolytics. Medications that were not expected to influ-
ence the effects of the study treatment could be used
only after consideration of their potential interactions
with iferanserin by the principal investigator (A.H.).
Each patient was instructed to complete a symptom
diary form at baseline and at the end of each day of
treatment for 14 days. At enrollment, patients received
copies of the diary form sufficient for the duration of
the study. This form listed 8 HD symptoms: (1) bleed-
ing; (2) itching; (3) pain; (4) tenderness; (5) fullness; (6)
throbbing; (7) difficulty of defecation; and (8) gas. Pa-
tients were required to rate each symptom on a 10-
point scale, with 1 indicating the absence of a symptom
and 10 indicating extreme aggravation of a symptom.
The diary form also prompted for any other symptoms
and for a description of those symptoms. Patients were
advised to contact the principal investigator of the
study immediately if they experienced any untoward
medical occurrence whatsoever, whether or not it
might be associated with treatment.
During physician examinations at baseline and at
the end of treatment, the investigators quantified on
provided clinical-report forms the frequency and inten-
sity of HD symptoms using the following interval
scales: bleeding frequency (0 never to 4 every day);
bleeding intensity (0 never to 4 staining under-
wear); soiling frequency (0 never to 3 always);
pruritus frequency (0 never to 3 permanent); pain
February 2012
A. Herold et al.
frequency (0 never to 2 constant); prolapsed status
(0 never to 2 permanent); and flatulence (0
never to 3 always). Intra-anal pressure was deter-
mined using manometry, the sizes of hemorrhoids were
measured, and laboratory values were obtained. At 45
days after the completion of treatment, patients were
contacted by telephone by their respective physicians
offices to determine health status.
Protocol compliance of the study centers was mon-
itored by Antares GmbH (Stuhr, Germany), which car-
ried out weekly visits to the study centers and exam-
ined records to ensure appropriate data collection.
Treatment Drug
Iferanserin was formulated as a 0.5% ointment for
intra-anal application from single-dose anal-applicator
tubes. The anal-applicator tubes containing the iferan-
serin ointment and the placebo ointment were identi-
cal. These tubes were designed to deliver 2 g of iferan-
serin ointment (containing 10 mg of iferanserin per
dose) or 2 g of placebo ointment. Each tube had a
1-inch tip designed to ensure application at the proxi-
mal end of the anal canal. With the intended use, pa-
tients in the iferanserin group thus received 10 mg of
iferanserin per single dose and 20 mg of iferanserin
daily, on a twice-daily dosing schedule. The anal-ap-
plicator tubes were provided complete with the iferan-
serin and placebo ointments by the study sponsor.
The investigative sites and patients were instructed
to keep the applicator tubes refrigerated. The lot of
0.5% ointment formulation of iferanserin had an ex-
piration date that extended 2 years beyond the initia-
tion of the study.
End Points and Statistical Analysis
The primary efficacy end points of the study were
patient-assessed severity scores for bleeding on days
7 and 14. Secondary efficacy end points were pa-
tient-assessed severity scores for itching, pain, and
other HD symptoms on days 7 and 14, and physician
assessments of the frequency and severity of HD
symptoms on day 14.
The primary tolerability end points were the occur-
rence during the study of any serious adverse events
and clinically significant changes from baseline in lab-
oratory values obtained during physical examination.
An adverse event was defined as any noxious, unin-
tended, or untoward medical occurrence during the
course of the study. A serious adverse event was de-
331
 Clinical Therapeutics
fined as an adverse event that resulted in death, was
considered life-threatening, required hospitalization,
or resulted in persistent or significant disability.
Data from patients who completed the full 14 days
of diaries were included in the statistical efficacy anal-
ysis. The sample size was calculated to detect a mean
change of 1.5 in diary values with an 80% statistical
power at a 0.05 level of significance. Allowing for a
dropout rate of 9%, the target sample size was 140
patients (70 per treatment group).
A 2-sample t test was used for the primary efficacy
analysis of the difference between the iferanserin and pla-
cebo groups in patient-reported severity of bleeding on
days 7 and 14. A Bonferroni adjustment for multiple
comparisons was applied to control the overall error
Figure 1. Study design and patient disposition in the prospective, randomized, double-blind, placebo-controlled
trial of intra-anal iferanserin 10 mg BID versus inactive vehicle (placebo) for treatment of patients with
hemorrhoid disease and bleeding.
332
rate.16 Significance was defined as a 2-tailed P value 0.05,
and statistical analysis was conducted using JMP version 9
(SAS Institute Inc., Cary, North Carolina).
Post Hoc Analysis
After the study, a post hoc analysis was conducted
to compare the number of patients in each group who
achieved cessation of bleeding or other individual HD
symptoms by day 7 and did not experience symptom
return for the remainder of the treatment period
(through day 14). A Cochran-Mantel-Haenszel statis-
tic was used to compare the percentages of patients
who achieved cessation of symptoms after stratifica-
tion by hemorrhoid grade at baseline.17,18
Volume 34 Number 2
 A. Herold et al.

Table I. Baseline demographic and clinical characteristics in this trial of intra-anal iferanserin 10 mg BID versus
inactive vehicle (placebo) for the treatment of patients with hemorrhoid disease and bleeding (tolera-
bility population).*

Characteristic Iferanserin (n 59) Placebo (n 59)

Age, y
Mean (SD) 50.7 (12.33) 54.6 (12.56)
Range 1877 3079
Sex, no. (%)
Male 45 (76.3) 48 (81.4)
Female 14 (23.7) 11 (18.6)
Body mass index, kg/m2
Mean (SD) 26.3 (4.04) 25.6 (3.90)
Range 18.642.1 9.235.0
Blood pressure, mm Hg
Systolic
Mean (SD) 131.8 (13.55) 137.2 (15.42)
Range 100175 110190
Diastolic
Mean (SD) 82.6 (6.42) 85.9 (9.10)
Range 70100 75115
Laboratory values
Serum creatinine, mg/dL
Mean (SD) 0.88 (0.19) 0.92 (0.19)
Range 0.561.58 0.531.50
Serum AST, U/L
Mean (SD) 12.18 (3.36) 15.61 (18.11)
Range 6.022.0 1.4121.0
Serum ALT, U/L
Mean (SD) 16.82 (8.66) 16.67 (8.11)
Range 5.047.0 6.046.0
Previous diagnosis of hemorrhoids, no. (%) 41 (69.5) 42 (71.2)

Goligher grades at baseline
Grade I 4/58 (6.9) 0
Grade II 37/58 (63.8) 31 (52.5)
Grade III 17/58 (29.3) 28 (47.5)

AST aspartate aminotransferase; ALT alanine aminotransferase.

*All of the patients were white.

Patients diagnosed at least 30 days before date of informed consent.

Grade I bleeding with no prolapse; grade II prolapse that spontaneously returns to within the anal canal; grade III
prolapse that requires manual reduction. The overall difference in Goligher HD grades between the 2 treatment groups was
statistically significant (P 0.027).

February 2012 333

 Clinical Therapeutics

The baseline characteristics for the 2 groups of tol-

Table II. Baseline physician-assessed symptoms of erability-evaluated patients appear in Table I. All of
hemorrhoid disease in this trial of intra- the patients were white and, with few exceptions, be-
anal iferanserin 10 mg BID versus inactive tween 40 and 79 years of age (mean age, 52.7 years).
vehicle (placebo) for the treatment of pa- With the exception of hemorrhoid grade, the 2 treat-
tients with hemorrhoid disease and bleed- ment groups did not differ significantly in baseline
ing (efficacy population). Data are number
characteristics, HD symptoms, and laboratory values.
(%) of patients.
The majority of the patients (70.3%) reported that
Hemorrhoid Disease Iferanserin Placebo they had previously received a diagnosis of HD. Pa-
Symptom (n 56) (n 55) tients who received placebo had higher grades of HD
as defined by the Goligher classification; none had
Bleeding 56 (100) 55 (100) grade I hemorrhoids versus 4/58 iferanserin-treated
Itching 32 (57.1) 28 (50.9) patients (6.9%), and 28 (47.5%) had grade III hem-
Pain 18 (32.1) 22 (40.0) orrhoids versus 17/58 iferanserin-treated patients
Tenderness 27 (48.2) 24 (43.6) (29.3%). Most of the patients (57.6%) overall had
Difficulty with 22 (39.3) 17 (30.9) grade II hemorrhoids. The overall difference in Goli-
defecation gher HD grades between the 2 treatment groups was
Fullness* 15 (26.8) 29 (52.7) statistically significant (P 0.027). Baseline HD symp-
Throbbing 6 (10.7) 6 (10.9) toms reported by the efficacy-evaluable patients in
Gas 7 (12.5) 5 (9.1) each treatment group are presented in Table II. The
symptom profiles of the 2 groups were not significantly
*P 0.007.
different with respect to bleeding, itching, and pain,
but the placebo group had a greater prevalence of the
symptom fullness (52.7% vs 26.8% in the iferan-
RESULTS serin group, P 0.007).
Although the study protocol prohibited the use of
A total of 121 patients were enrolled in the study
topical anesthetics, after the study 2 patients in each
(Figure 1). Of these, 10 were lost to evaluation. There
treatment group reported that they had used such med-
were 3 patients for whom the respective randomized
ications during the 14-day treatment period of the trial.
treatment group could not be identified after treatment Despite the protocol violation, these patients were not
because the randomization code labels identifying their excluded from analysis because of their equal distribu-
treatment were not affixed to their clinical report tion (2 in each treatment group).
forms when these were returned for analysis. Based
on the 1:1 nature of the original randomization, it
Patient-Reported Outcomes
was possible to calculate that 1 of these 3 patients
Compared with placebo, intra-anal iferanserin was
had been assigned to the iferanserin group and 2 to
associated with significantly reduced mean patient-re-
the placebo group, but without the labels it was not
ported severity scores for daily bleeding and daily itch-
possible to identify the treatment group assignments
ing on days 7 and 14 (bleeding, P 0.0001 and P
of any of these patients. After exclusion of their data
0.0075, respectively; itching, P 0.0008 and P
from the analysis, there were 118 patients evaluable 0.0207) (Table III). Intra-anal iferanserin was not as-
for tolerability. During the course of the study, 3 of sociated with significantly reduced mean patient-re-
these 118 patients were lost to follow-up, 1 in the ported severity scores for daily pain compared with
iferanserin group and 2 in the placebo group. After placebo on days 7 and 14. These primary efficacy re-
the study, an additional 4 patients were withdrawn sults on days 7 and 14 did not change when the Bon-
from the efficacy evaluation, 2 from each treatment ferroni adjustment for multiple comparisons was ap-
group, because they did not complete their full 15- plied. When corrected for hemorrhoid grade at study
day sets of patient diaries. There were thus 111 pa- entry, the level of statistical significance for the differ-
tients evaluable for efficacy, 56 in the iferanserin ence between iferanserin and placebo on days 7 and 14
group and 55 in the placebo group. was not meaningfully changed. The adjusted signifi-

334 Volume 34 Number 2

 A. Herold et al.

Table III. Patient-reported effects on days 7 and 14 of intra-anal iferanserin 10 mg BID versus inactive vehicle
(placebo) for the treatment of patients with hemorrhoid disease and bleeding.

Score,* Mean (SD) P

Between
Symptom/ Treatments, on Between Treatments,
Day Iferanserin (n 56) Placebo (n 55) Given Day From Baseline

Bleeding
Baseline 5.4 (2.1) 6.1 (2.4) NS
7 1.6 (1.1) 3.5 (2.7) 0.0001 0.0003
14 1.7 (1.5) 3.1 (3.0) 0.0075 0.0442
Itching
Baseline 3.7 (2.0) 3.6 (2.1) NS
7 1.4 (0.7) 2.5 (1.6) 0.0008 0.0002
14 1.3 (1.3) 2.1 (1.5) 0.0207 0.0024
Pain
Baseline 3.9 (2.1) 4.3 (2.6) NS
7 1.9 (1.3) 3.2 (2.9) NS NS
14 1.8 (1.7) 2.7 (2.3) NS NS

*Scale: 1 the absence of the symptom to 10 extreme aggravation of the symptom.

Logarithm-transformed for analysis.

cance levels in the analysis of patient-reported severity
of daily bleeding were: baseline, not significant; day 7,
P 0.001; and day 14, P 0.0058. The adjusted
significance levels in the analysis of patient-reported
severity of daily itching were: baseline, not significant;
day 7, P 0.0004; and day 14, P 0.0120.
When the iferanserin and placebo groups were com-
pared with respect to changes from baseline in mean
patient-reported severity scores on days 7 and 14, the
mean changes with intra-anal iferanserin were signifi-
cantly greater than that with placebo for both the daily
bleeding scores (P 0.0003 on day 7; P 0.0442 on
day 14) and daily itching scores (P 0.0002 on day 7;
P 0.0024 on day 14) (Table III). The differences
between the iferanserin and placebo groups in terms of
changes from baseline in daily pain scores were not
significant.
The response to intra-anal iferanserin for the treat-
ment of patient-reported severity of daily bleeding,
itching, and pain occurred rapidly. The difference be-
tween intra-anal iferanserin and placebo in terms of
change from baseline in patient-reported severity of
daily bleeding was significant at P 0.05 from day 1
(Figure 2). The difference between intra-anal iferan-
serin and placebo in terms of change from baseline in
patient-reported severity of daily itching was signifi-
cant at P 0.05 from day 2. Once evident, the signif-
icant difference between intra-anal iferanserin and pla-
cebo in patient-reported severity of daily bleeding and
itching was maintained throughout the study. The re-
sponse to intra-anal iferanserin in terms of change
from baseline in patient-reported severity of daily pain
was significantly greater than the response to placebo
on days 3 and 4 of the study (both, P 0.05), but the
difference was not maintained at the level of statistical
significance after day 4.
Physician-Assessed Outcomes
On physical examination at the end of treatment,
physician-assessed frequency of bleeding was signifi-
cantly improved with intra-anal iferanserin (P 0.05),
but the differences compared with placebo were not
significant for the categories of bleeding intensity, soil-
ing frequency, pruritus, pain frequency, prolapse fre-
quency, and flatulence. There were no significant
changes from baseline to study end with either intra-

February 2012 335

Clinical Therapeutics
Figure 2. Mean patient-reported severity of daily
(A) bleeding, (B) itching, and (C) pain
scores in this trial of intra-anal iferan-
serin 10 mg BID versus inactive vehicle
(placebo) for the treatment of patients
with hemorrhoid disease and bleeding.
336
anal iferanserin or placebo in intra-anal pressure mea-
sured at rest and during squeeze. The mean reduction
in hemorrhoid size with intra-anal iferanserin com-
pared with placebo was indeterminate, as the differ-
ence did not reach statistical significance (31.71% re-
duction with iferanserin vs 25.44% reduction with
placebo; P 0.24).
Tolerability
There were no serious adverse events reported dur-
ing the trial, and there were no serious adverse events
reported on 45-day telephone follow-up. A total of 19
patients reported 39 adverse events in the study (Table
IV). There were no significant differences between the
2 treatment groups in the prevalences of adverse
events. All cases of adverse events were considered
mild, and none of the patients required any medical
treatment for any adverse event. Of the 21 adverse
events reported in iferanserin-treated patients, 9 were
gastrointestinal; of the 18 adverse events reported in
the placebo group, 11 were gastrointestinal. Between
baseline and the end of the study, there were no signif-
icant changes in blood or urine values in any of the
patients in either treatment group.
Post Hoc Findings
The findings from the post hoc analysis of the main-
tenance of the treatment effects on patient-reported
daily bleeding, itching, and pain are reported in Table
V. Daily bleeding ceased at day 7 and did not return by
day 14 in 57.1% (32/56) of iferanserin-treated patients
versus 20.0% (11/55) of the placebo group (P
0.0001). Daily itching ceased at day 7 and did not
return by day 14 in 59.4% (19/32) of iferanserin-
treated patients versus 32.1% (9/28) of the placebo
group (P 0.034). Daily pain ceased at day 7 and did
not return by day 14 in 50.0% (9/18) of iferanserin-
treated patients versus 18.1% (4/22) of the placebo
group (P 0.032). When corrected for hemorrhoid
grade by the Cochran-Mantel-Haenszel statistic, the
level of statistical significance for the difference be-
tween iferanserin and placebo in terms of maintenance
of treatment effects from day 7 through day 14 did not
meaningfully change. The corrected significance levels
in the analysis of maintenance of treatment effects
from day 7 through day 14 were: cessation of bleeding,
P 0.0005; cessation of itching, P 0.028; and ces-
sation of pain, P 0.043.
Volume 34 Number 2
 A. Herold et al.

Table IV. Tolerability of 14-day treatment with intra-anal iferanserin 10 mg BID versus inactive vehicle (placebo)
for the treatment of patients with hemorrhoid disease and bleeding.* Data are number (%) of patients.

System Organ Class Iferanserin (n 59) Placebo (n 59)

Any adverse event 11 (18.6) 8 (13.6)

Eye disorders 0 1 (1.7)
Eye pruritus 0 1 (1.7)
Gastrointestinal disorders 6 (10.2) 5 (8.5)
Abdominal discomfort 3 (5.1) 1 (1.7)
Constipation 1 (1.7) 2 (3.4)
Diarrhea 1 (1.7) 1 (1.7)
Fecal incontinence 1 (1.7) 1 (1.7)
Flatulence 1 (1.7) 1 (1.7)
Abdominal pain 1 (1.7) 0
Defecation urgency 1 (1.7) 0
Upper abdominal pain 0 2 (3.4)
Anal pruritus 0 1 (1.7)
Anorectal discomfort 0 1 (1.7)
Painful defecation 0 1 (1.7)
General disorders and administration site conditions 2 (3.4) 1 (1.7)
Chest pain 1 (1.7) 0
Pyrexia 1 (1.7) 0
Fatigue 0 1 (1.7)
Feeling abnormal 0 1 (1.7)
Infections and infestations 2 (3.4) 0
Cystitis 1 (1.7) 0
Nasopharyngitis 1 (1.7) 0
Injury, poisoning, and procedural complications 1 (1.7) 0
Eye injury 1 (1.7) 0
Metabolism and nutrition disorders 1 (1.7) 0
Decreased appetite 1 (1.7) 0
Musculoskeletal and connective tissue disorders 0 1 (1.7)
Pain in extremity 0 1 (1.7)
Nervous system disorders 1 (1.7) 1 (1.7)
Headache 1 (1.7) 1 (1.7)
Renal and urinary disorders 1 (1.7) 0
Urinary incontinence 1 (1.7) 0
Reproductive system and breast disorders 1 (1.7) 0
Metrorrhagia 1 (1.7) 0
Skin and subcutaneous tissue disorders 3 (5.1) 1 (1.7)
Pruritus 3 (5.1) 1 (1.7)

*No significant between-group differences were found. If a patient had 1 episode of a particular adverse event, the patient
was counted only once for the event. If a patient had 1 adverse event in a system organ class, the patient is counted only once
for that system organ class.

DISCUSSION HD and bleeding, intra-anal iferanserin was associated

In this 14-day, prospective, multicenter, randomized, with significant reductions in patient-reported severity
double-blind, placebo-controlled trial in patients with of daily bleeding and itching and physician-assessed

February 2012 337

 Clinical Therapeutics
Table V. Patient-reported maintenance effects from days 7 to 14 of intra-anal iferanserin 10 mg BID versus
inactive vehicle (placebo) for the treatment of patients with hemorrhoid disease and bleeding. Data are
number (%) of patients.
Symptom Iferanserin
Bleeding 32/56 (57.1)
Itching 19/32 (59.4)
Pain 9/18 (50.0)
bleeding frequency compared with placebo. The effects
of intra-anal iferanserin on patient-reported severity of
daily bleeding, itching, and pain occurred rapidly,
achieving statistical significance compared with pla-
cebo by days 1, 2, and 3, respectively. The prevalences
of adverse events did not differ significantly between
the 2 treatment groups; they were predominantly gas-
trointestinal, and they were mild and infrequent.
On post hoc analysis, daily bleeding was reported to
have been resolved with the use of intra-anal iferan-
serin in 57.1% of patients by day 7; daily itching, in
59.4% of patients; and daily pain, in 50.0% of pa-
tients; for these patients, the effect was maintained
through day 14. For all 3 HD symptoms assessed (daily
bleeding, itching, and pain), treatment with intra-anal
iferanserin was associated with significant differences
in this elimination-without-return end point compared
with placebo.
The present exploratory study of intra-anal iferan-
serin had several limitations. The level of enrollment
was lower (121 vs 140) than was originally calculated
for the purposes of statistical analysis. Because the in-
clusion criteria specified only bleeding prior to entry,
considerably fewer efficacy-evaluable patients with
itching (n 60) and pain (n 40) were enrolled. It is
possible that a treatment effect of intra-anal iferanserin
on HD symptoms other than daily bleeding, itching, or
pain might have been observed if the enrollment had
been greater. The magnitudes of the treatment effects
of intra-anal iferanserin on daily bleeding and itching
compared with those of placebo do not seem to have
been affected by the lower enrollment. At the time of
randomization by the envelope method, there was no
intentional stratification according to Goligher hemor-
rhoid grades or HD symptoms; by chance, a greater
proportion of the placebo group had higher grades of
hemorrhoids. However, Goligher grades reflect the de-
gree of prolapse only; the Goligher system does not
338
Placebo P
11/55 (20.0) 0.0001
9/28 (32.1) 0.034
4/22 (18.1) 0.032
reflect the severity or frequency of HD symptoms.19
When corrected for hemorrhoid grade at study entry,
the levels of statistical significance of the differences
between the iferanserin and placebo groups in patient-
reported severity of daily bleeding and daily itching on
days 7 and 14 did not meaningfully change. There was
a protocol violation in the inclusion of data from 4
patients (2 in each treatment group) in the evaluation
who revealed after the study that they had used topical
analgesics for pain during the 14-day treatment period
of the trial. The inclusion of the data from these pa-
tients may have lessened the validity of the findings on
pain.
A significant number of patients with HD seek med-
ical help for symptoms. In the United States, for exam-
ple, the annual rate of office visits for hemorrhoids has
been calculated as 12 in 1000 patients.20 Lifestyle
modificationssuch as improving anal hygiene, in-
creasing fluid intake, taking sitz baths, and avoiding
straining can be helpful in ameliorating HD symp-
toms, but evidence of efficacy is lacking. The 1 lifestyle
modification that has been reported as efficacious is the
use of fiber supplements for grades I and II hemor-
rhoids. In a meta-analysis of data from 7 trials that
compared the use of fiber and a nonfiber control, fiber
was associated with moderately improved overall HD
symptoms and HD bleeding.21
There are many over-the-counter topical prepara-
tions for hemorrhoids. The topical preparations typi-
cally contain a combination of local anesthetics, corti-
costeroids, astringents, and aseptics and are usually
formulated as an ointment, which provides a protec-
tive coating on the hemorrhoid surface. However,
there are no data from published randomized con-
trolled studies to support their efficacy. Long-term use
of over-the-counter preparationsparticularly of cor-
ticosteroidsis routinely discouraged because it might
Volume 34 Number 2
 A. Herold et al.

permanently damage or cause ulceration of the peri- ment. The prevalences of adverse events did not dif-
anal skin.22 fer significantly between the 2 treatment groups;
Invasive procedures for the treatment of HDfrom they were predominantly gastrointestinal, and they
outpatient treatments such as rubber band ligation, were mild and infrequent.
injectable sclerotherapy, and infrared coagulation, to
surgical procedures including open and closed hemor-
ACKNOWLEDGMENTS
rhoidectomy have been reported as effective for HD
This research was funded by Sam Amer, Inc., Monte-
symptoms, but each procedure may lead to complica-
cito, California, and Ventrus Biosciences, Inc., New
tions, including bleeding, pain, recurrence, and sep-
York, New York.
sis.2225 Invasive procedures are usually suitable only
The authors thank the following investigators, who
for grades III and IV hemorrhoids. These procedures
participated in the study: Jens-Uwe Bock, MD, Prax-
also escalate the cost burden of HD to health care
isklinik, Kiel, Germany; Baji Marla, MD, Proktologis-
systems.
che Praxis, Essen, Germany; Gregor Dornschneider,
In some countries in Europe and Asia, oral fla-
MD, Proktologische Praxis, Heidelberg, Germany;
vonoids are used for the treatment of HD symptoms,
Bernhard Strittmatter, MD, Praxisklinik 2000,
the most popular formulation being a combination of
Freiburg, Germany; and Jens Kirsch, MD, Enddarm-
hesperidin with diosim.22 Flavonoids are believed to be
Zentrum Mannheim, Mannheim, Germany.
vasotonic, with properties that increase venous tone,
Dr. Herold was the studys principal investigator,
lymphatic draining, and capillary permeability, with
and he and the other study investigators (Drs. Bock,
an anti-inflammatory effect. The exact mechanism of
Marla, Dornschneider, Strittmatter, and Kirsch) re-
action of flavonoids remains imperfectly understood.19
ceived honoraria from Sam Amer, Inc. for participa-
In a meta-analysis of data from 14 randomized con-
tion in the study. Dr. Dietrich and Mr. Aitchison have
trolled studies of flavonoids, limitations in method-
received consultants fees from Ventrus Biosciences,
ological study and potential publication bias led to
Inc. Dr. Herold was involved with the conception and
doubts about the benefits of these agents in treating
design of the study. Dr. Dietrich drafted the manu-
HD symptoms.26
script. Dr. Dietrich and Mr. Aitchison provided statis-
In this current investigative context, intra-anal
tical analysis. Analysis, interpretation, and critical re-
iferanserin merits further exploration. Intra-anal ifer-
visions were undertaken by all of the authors. The
anserin for the treatment of HD symptoms is now un-
overall responsibility for the manuscript belonged to
dergoing evaluation in a 600-patient, randomized,
Dr. Herold. The study sponsors were actively involved
double-blind, placebo-controlled trial (ClinicalTrials.
in the study design, ensurance of the accuracy of the
gov identifier: 01355874), in which the primary end
data collection and analysis, and interpretation of
point is the cessation of bleeding by day 7 that persists
data. Editorial support for the manuscript was pro-
through day 14.
vided by representatives of Galen Press, Inc. and was
paid for by the study sponsors.
CONCLUSIONS
In these patients with HD and bleeding, treatment
CONFLICTS OF INTEREST
with intra-anal iferanserin was associated with a sig-
The authors have indicated that they have no other
nificant reduction relative to placebo in patient-re-
conflicts of interest with regard to the content of this
ported severity of daily bleeding from day 1 to study
article.
end (day 14) and in patient-reported severity of daily
itching from day 2 to study end. Iferanserin use was
not associated with significant improvements in the
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Volume 34 Number 2
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