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Beth L. Barber, PhD/ Ellen R. Strahlman, MD, MHS, 2 Robert Laibovitz, MD/
Harry A. Guess, MD, PhD, 2 Scott A. Reines, MD, PhD4
Understanding the potential side effects of medications who have glaucoma, because the disease is chronic and
and their impact on health-related quality of life is im- several medications are required in many patients. Cur-
portant to patients. This is particularly true for patients rently, timolol is the most commonly prescribed ocular
hypotensive agent for the treatment of open-angle glau-
Originally received: June 19, 1995. coma. Although timolol is generally well tolerated, sec-
Revision accepted: September 20, 1996. ond-line agents (pilocarpine, epinephrine, and oral car-
1
Department of Outcomes and Performance Assessment, Merck-Medco bonic anhydrase inhibitors) have less desirable tolerability
Managed Care, Montvale, New Jersey.
2
profiles.
Departments· of Epidemiology (ES and HG), and Clinical Neurosci- To compare different treatments for glaucoma by char-
ences (SR), Merck Research Laboratories, West Point, Pennsylvania.
3
acterizing their common side effects and the health-re-
Eye Research Associates, Austin, Texas. lated quality of life of patients receiving treatment, we
4
Department of Clinical Neurosciences, Merck Research Laboratories, developed an evaluative questionnaire for Comparing
West Point, Pennsylvania. Ophthalmic Medications for Tolerability (COMTOL).
Presented at the ARVO Annual Meeting, Ft. Lauderdale, April 1995. The questionnaire is designed to capture the frequency
Supported by Merck Research Laboratories, West Point, P A. and bother of common side effects of topical drugs used
Reprint requests to Beth L. Barber, PhD, Merck-Medco Managed Care, to control intraocular pressure (lOP); the extent to which
Inc., 100 Summit Ave, Montvale, NJ 07645-1753. these side effects and any associated limitations in routine
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Barber et al · COMTOL Validation Study
living activities interfere with the patients' health-related the patients were instructed not to disclose their dosing
quality of life, their compliance with the medication, and frequency to the interviewer.
their satisfaction with the medication. The questionnaire
is intended to be administered by an interviewer. We
Measurements
assessed the measurement characteristics of the question-
naire to ensure that it correctly measures common side Clinical Assessments. Clinical assessments, including vi-
effects and their impact on quality of life, and that it sual acuity, slit-lamp examination, lOP measurements (2
can be used as an evaluative instrument. This assessment hours after the morning medication), and ophthalmoscopy
included measuring internal consistency, test-retest relia- through dilated pupils, were performed at baseline and
bility, reproducibility, construct validity, discriminant va- on study days 8, 13, and 15.
lidity, and responsiveness. This paper describes the ques- COMTOL Questionnaire. The Comparison of Oph-
tionnaire, defines domains and global questions, and pres- thalmic Medications for Tolerability (COMTOL) ques-
ents their measurement characteristics. tionnaire (Appendix A) was interviewer-administered at
baseline and on study days 13 and 15. It consisted of
twelve questions that were based on common side effects
Methods reported by patients in clinical trials of therapy for low-
ering lOP.
Patients Questions 1 and 2 (preference and reason for prefer-
The 70 study participants were men and women, age 18 or ence), are intended to be asked only at the conclusion
older, with open-angle glaucoma or ocular hypertension. of a cross-over trial, and hence were not asked or as-
Patients were excluded from the study if they had pre- sessed in this validation study (which was a parallel
viously received treatment with pilocarpine. Patients were study).
also excluded from the study for ocular conditions includ- Question 3 establishes which side effects (from a list
ing: visual acuity less than 20/80 in both eyes, history or of 15 possible side effects) the patient has experienced.
evidence of acute or chronic angle closure glaucoma, pu- This information is not intended to be analyzed, but
pil unable to dilate sufficiently for an adequate retinal instead to facilitate asking questions 4 and 5, which
examination, history or presence of uveitis, retinal detach- make sense only if the patient has experienced the side
ment, or any other retinal condition for which treatment effect.
with pilocarpine might be inappropriate. Patients were Question 4 refers to each side effect in question 3
also excluded from the study who had any contraindica- that the patient reported having, and asks about the
tion to the use of timolol or pilocarpine ophthalmic solu- frequency with which the patient experienced the side
tion, a history of asthma or chronic obstructive pulmonary effect.
disease (COPD), clinically significant renal disease, or
Question 5 refers to each side effect identified in ques-
severe physical disabilities.
tion 3, and asks about its bothersomeness.
Question 6 asks about the extent to which the patient's
Study Design quality of life has been interfered with by these side
This 2-week, randomized, parallel study assessed the effects.
measurement characteristics of a questionnaire designed Question 7, which is asked only at baseline, identifies
to compare the side effects of different topical ophthalmic activities the patient performs on a routine basis.
solutions for lowering lOP, and how these side effects Question 8 refers to each activity identified by the
affected the health-related quality of life of patients who patient in question 7, and asks the extent to which the
received these medications. A three-week saline run-in patient had to limit the activity as a result of using the
period, which included a washout of ocular hypotensive eye drops.
medications, preceded randomization to either timolol
0.5% twice a day or pilocarpine 2% four times a day. Question 9 asks the extent to which the patient's qual-
Patients were examined at pretreatment and on study days ity of life has been interfered with by these activity
8, 13, and 15. The questionnaire was administered by an limitations.
interviewer at baseline (day 1) and on study days 13 and Question 10 asks how often the patient missed one or
15. more doses of test medication.
Because the purpose of the study was to validate a Question 11 asks those patients who reported missing
questionnaire designed to compare topical ophthalmic at least one dose (in question 10) to indicate why they
agents, and because the dosing regimen is a part of that did not take the eye drops.
assessment, treatment regimens were deliberately not Question 12 asks how satisfied the patient has been
masked to the patient or ophthalmologist examiner. How- with the test medication.
ever, in order to obtain the most objective responses possi-
ble, the questionnaire interviewer was masked to the pa- Defining and Scoring Domains and Global Ques·
tient's regimen, the interviews were conducted in a room tions. Question 4 was scored from 0 ("I did not have
with bright lights (to induce miosis in all patients), and the symptom") to 6 ("Always"). Question 5 was scored
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Ophthalmology Volume 104, Number 2, February 1997
SO = standard deviation.
from 0 ("Not at all bothered") to 5 ("Extremely both- is that of commonly reported side effects of lOP therapy
ered"). Questions 6 and 9 were scored 0 ("Not at all") being frequent and bothersome, causing limitations in liv-
to 5 ("Extremely"). Question 8 was scored 0 ("Not at ing activities, and adversely affecting patients' self-per-
all) to 6 ("Extremely"). Question 10 was scored 0 ("I ceived quality of life. We assessed construct validity by
did not miss any doses") to 6 ("Always"). Question 11 correlating side effect and living activity domain scores
was scored 0 ("I did not take the eye drops because of with four patient-perceived global measures: (i) interfer-
side effects that I experienced") or 1 ("I did not take the ence of side effects on overall quality of life, (ii) interfer-
eye drops for some other reason."). Question 12 was ence of activity limitations on overall quality of life, (iii)
scored 0 ("Totally satisfied") to 5 ("Totally dissatis- compliance with therapy, and (iv) satisfaction with ther-
fied"). Thus, with all questions except question 11, the apy. Correlations exceeding twice their estimated stan-
higher score indicated the patients' increased discomfort. dard error were considered to be statistically significant.
Factor analysis using the varimax rotation of the princi- We assessed discriminant validity by evaluating the
pal components procedure' was performed with all items ability of the questionnaire to distinguish between the
in question 4 for each treatment group to establish mean- scores of patients receiving timolol and the scores of pa-
ingful underlying domains. This analysis was repeated tients receiving pilocarpine. For these comparisons, co-
for all items in questions 5 and 8. Redundant items and variance was analyzed, comparing least square mean
"routine" activities that were not performed by more scores at day 15 while controlling for baseline scores.
than half of the patients were eliminated. Domain scores Responsiveness is the extent to which scores change
were calculated as the average of the items in the domain. when subjects improve or deteriorate. Changes (from
Questions 6, 9, 10, 11, and 12 were prespecified global baseline to day 15) in side effect and living activity do-
questions, which were scored as indicated above. main scores in the timolol group were compared (using
Measurement Characteristics. A comprehensive eval- Student's t tests) to changes in side effect and living
uation of the measurement characteristics of an evaluative activity domain scores in the pilocarpine group to deter-
instrument should address internal consistency, test-retest mine whether differences between the two groups could
reliability, reproducibility, construct validity, discrimi- be detected.
nant validity, and responsiveness. All 95% confidence interval limits for Cronbach's
We measured internal consistency with Cronbach' s alphas, intraclass correlation coefficients, and concor-
alpha. 2 Good internal consistency is defined as an alpha dance correlation coefficients, were calculated using the
coefficient greater than 0.70 and less than 0.95. 3 Reliabil- Jackknife method. 7
ity refers to the extent to which a single observation can
consistently distinguish between members of a popula-
tion. We used the intraclass correlation coefficient (ICC) 4 Results
to quantify reliability. An ICC of 0.75 and above is con-
sidered acceptable for a research instrument. 5 A total of 70 patients from one center was entered into
Reproducibility refers to the extent to which repeated this study. The predominantly white (90%) population
administration to a stable population yields the same re- had an average age of 53 years (range 33 to 82) and
sults. We used the concordance correlation coefficient6 to was 61% female (Table 1). Treatment groups were very
quantify reproducibility. similar with respect to baseline characteristics.
The underlying construct that the symptoms measure Six patients discontinued therapy prior to completing
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Barber et al · COMTOL Validation Study
Table 2. Domains
Domain Items in Domain Scoring
the study due to clinical adverse effects. However, all 70 velop and validate a questionnaire that would be general-
patients responded to the questionnaire at the three time izable for comparison of other topical ophthalmic agents
points. Five of the six patients discontinued therapy while (not simply timolol and pilocarpine). Therefore, because
receiving pilocarpine due to drug-related adverse experi- some topical ophthalmic agents may cause severe accom-
ences that were possibly, probably, or definitely drug-
related. The sixth patient discontinued therapy while re-
ceiving timolol after experiencing headache, insomnia,
Table 3. Internal Consistency
and skin rash that were possibly drug related.
Cronbach's 95% Confidence
Domain Definitions Domain Alpha Interval*
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Ophthalmology Volume 104, Number 2, February 1997
modation problems and less severe vision problems, and a routine activity at baseline. Other items were eliminated
some other drugs may cause brow ache without vision if they were redundant. For instance, the items ''walking
problems, problems with vision, accommodation, and more than I mile," "walking several blocks," and
brow ache were defined as three separate domains provid- ''walking 1 block'' all seem to measure the same patient
ing a total of five frequency-of-side-effects domains (Ta- capability; therefore, because the items ''walking more
ble 2). than 1 mile" and "walking I block" were both selected
Five similar domains were defined for the 15 items by fewer patients than the item ''walking several blocks,''
regarding bothersomeness of side effects (question 5): only the item "walking several blocks" was kept. The
ocular symptoms, taste, vision, accommodation, and brow item ''bathing or dressing yourself' was eliminated be-
ache. Three limitation-of-living-activities domains were cause the average scores for this item at day I5 were the
defined using 7 of the 14 items that comprised question smallest averages of all items (timolol group average =
8 (the other 7 items were eliminated: see Item Reduction, 0.00, pilocarpine group average = 0.40), indicating that
below). In the future, when the COMTOL is administered topical ophthalmic drugs are unlikely to significantly limit
in a clinical trial, patients will be asked at baseline to these activities.
identify from the list of 7 items the activities they perform
on a routine basis. Internal Consistency
The Cronbach' s alphas for all domains with more than
Item Reduction one question had high values (0.73-0.98), supporting the
domain definitions (Table 3). This statistic is not defined
All side effects were retained in the questionnaire, even
for domains consisting of only one question.
if they occurred infrequently in patients receiving timolol
or pilocarpine.
Items on "routine activities" (e.g., "vigorous activi- Reliability and Reproducibility
ties'' and ''climbing more than one flight of stairs'') were The intraclass correlation coefficients (0.75 to 0.94) and
eliminated if less than half the patients chose the item as the concordance correlation coefficients (0.74 to 0.93) for
338
Barber et al · COMTOL Validation Study
the 13 domains and 4 global questions indicate good-to- and 12, although tables are not presented. Global question
excellent reliability and reproducibility (Table 4). 10 (missing one or more doses) did not correlate signifi-
cantly with any domain for timolol. However, for pilocar-
Construct Validity pine, this global did correlate with two of the bother-
sameness domains (vision and accommodation), and with
Correlations between global questions 6 and 9 and domain all three limitation-with-living-activities domains (driv-
scores were strong and in the expected direction, with the ing, reading, and moderate activities). Global question 12
exception of the bothersomeness-of-taste domain (Tables (satisfaction with medication) correlated strongly with all
5 and 6). domains (except taste) for pilocarpine, and correlated
We also correlated domains with global questions 10 moderately with four domains (frequency and bother-
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Ophthalmology Volume 104, Number 2, February 1997
Bothersomeness of
Ocular symptoms 0.23 0.87 0.0014*
Taste side effects 0.09 0.20 0.1319
Vision difficulties 0.26 2.00 0.0001 *
Accommodation difficulties 0.21 1.85 0.0001 *
Brow ache 0.11 1.69 0.0001 *
Limitations on
Driving 0.15 1.68 0.0001 *
Reading 0.16 1.63 0.0001 *
Moderate activities 0.01 0.49 0.0275*
Global
6. QOL interfered with by side
effects? 0.21 1.65 0.0001 *
9. QOL interfered with by
activity limitations? 0.14 1.37 0.0001 *
10. How often did you miss one
or more doses? 0.45 1.43 0.0106*
11. Why did you not take the
eye drops? side effects/other 1.77 1.50 0.1996
12. How satisfied have you been
with the test medication? 1.17 2.92 0.0001 *
Discriminant Validity
Discussion
The questionnaire clearly discriminated between the pilo-
carpine and timolol groups with respect to: frequency and We assessed the measurement characteristics of the
bothersomeness of ocular symptoms, vision difficulties, COMTOL questionnaire that was designed to distinguish
accommodation difficulties, brow ache; limitations on
between different topical ophthalmic medications on the
driving, reading, and moderate activities; interference-
basis of tolerability. Within the questionnaire, using factor
with-quality-of-life (both questions 6 and 9); frequency
analysis, clinical judgment, and item importance, we de-
of missed doses (question 10); and satisfaction with medi-
fined:
cation (question 12) (Table 7). The questionnaire did not
discriminate between pilocarpine and timolol groups with • Five frequency-of-side-effects domains (ocular
respect to frequency and bothersomeness of taste side symptoms, taste, accommodation, vision, and brow
effects, or between the two groups with respect to why ache);
eye drops were missed (question 11). For this reason, • Five bothersomeness-of-side-effects domains (ocu-
question 11 was eliminated from the final validated COM- lar symptoms, taste, accommodation, vision, and
TOL questionnaire. brow ache); and
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Barber et al · COMTOL Validation Study
Table 8. Responsiveness: Comparing Changes in Scores in the Timolol Group with Changes in Scores in
the Pilocarpine Group
Timolol Group Pilocarpine Group
Change from Baseline Change from Baseline
Baseline Baseline
Mean Mean p
Domain N Mean N Change SD N Mean N Change SD Value
Frequency of
Ocular symptoms 35 0.22 35 0.41 0.72 35 0.25 35 1.36 1.32 0.0004*
Taste side effects 35 0.01 35 0.10 0.53 35 0.10 35 0.34 0.93 0.1830
Vision difficulties 35 0.16 35 0.38 1.20 35 0.20 35 3.04 2.19 0.0001 *
Accommodation difficulties 35 0.19 35 0.26 1.44 35 0.03 35 3.07 2.54 0.0001 *
Brow ache 35 0.06 35 0.14 0.65 35 0.20 35 2.40 2.72 0.0001 *
Bothersomeness of
Ocular symptoms 35 0.13 35 0.11 0.46 35 0.09 35 0.78 1.05 0.0001 *
Taste side effects 35 0.01 35 0.00 0.12 35 0.09 35 0.19 0.57 0.0636
Vision difficulties 35 0.10 35 0.17 0.78 35 0.06 35 1.93 1.64 0.0001 *
Accommodation difficulties 35 0.20 35 0.00 1.06 35 0.01 35 1.84 1.85 0.0001 *
Brow ache 35 0.11 35 0.00 0.54 35 0.09 35 1.60 1.88 0.0001 *
Limitations on
Driving 34 0.00 34 0.15 0.62 34 0.00 34 1.68 1.81 0.0001 *
Reading 34 0.06 34 0.12 0.72 35 0.00 34 1.61 1.77 0.0001 *
Moderate activities 35 0.00 35 0.01 0.06 33 0.00 33 0.49 1.26 0.0275*
Global
6. QOL interfered with by
side effects? 35 0.20 34 0.00 0.95 35 0.09 35 1.57 1.82 0.0001 *
9. QOL interfered with by
activity limitations? 35 0.03 35 0.11 0.72 35 0.03 35 1.34 1.64 0.0001 *
10. How often did you miss
one or more doses? 35 0.23 35 0.20 1.16 35 0.31 35 1.14 1.90 0.0144*
12. How satisfied have you
been with the test
medication? 35 0.97 35 0.26 1.54 35 0.57 35 2.29 1.84 0.0001 *
• Three limitations-of-living-activities domains (limi- that the most frequent systemic adverse experience among
tations with driving, reading, and moderate activi- patients treated with timolol was dizziness at 1%. In a
ties). study of 489 patients, Wilson et al 9 discovered that the
As well, we retained four of the five prespecified global most frequent systemic adverse experience of patients
questions: 6, 9, 10, and 12. This validation study has treated with timolol was cardiovascular at 1.4%, followed
shown that 11 ofthe 13 domains (all but the frequency-of- by headaches at 1.2%, and dizziness at 0.6%. Clearly in
taste and bothersomeness-of-taste domains) and 4 global the population included in the present trial, which ex-
questions (6, 9, 10, and 12) of the COMTOL question- cluded patients with contraindications to timolol or other
naire have good-to-excellent internal consistency, relia- ,8-blockers, systemic side effects would occur at a very
bility, reproducibility, construct validity, discriminant va- low rate.
lidity, and responsiveness. Therefore, the COMTOL ques- Although these systemic side effects are not directly
tionnaire has met validation criteria and is suitable for queried in the questionnaire, any interference which such
use in clinical trials comparing topical ophthalmic medi- systemic effects may have on living activities such as
cations. reading, driving, or walking several blocks would be cap-
The list of side effects in questions 4 and 5 was con- tured by the questionnaire. Including patients taking a ,8-
'structed from common side effects of topical therapies for blocker (timolol) to help identify activities that might
lowering lOP, as reported by patients in clinical trials. be adversely affected by medication provides additional
For a topical medication, these consist primarily of ocular evidence that the questionnaire addresses adverse effects
and other local effects, and effects on visual function. of ,8-blockers on living activities. The tolerability ques-
Because systemic side effects of ,8-blockers occur infre- tionnaire is intended to supplement, but not to replace,
quently in patients who do not have contraindications, 8 •9 the reporting of spontaneously occurring adverse events
we did not include systemic side effects in questions 4 which is a part of any clinical trial. Using both together
and 5. In a study of 2,217 patients, Katz et al 8 discovered may permit a more comprehensive assessment of the
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Ophthalmology Volume 104, Number 2, February 1997
safety and tolerability profiles of the ophthalmic agents that attempts to discriminate between treatments based
being evaluated in the trial. on tolerability of common side effects. Before comparing
Although some side effects listed in questions 4 and how common side effects of different medications affect
5 did not occur frequently in this study with timolol patients, the treatments must have been adequately stud-
and pilocarpine, they may be common local or visual ied so that the most common side effects of the different
side effects of other topical ophthalmic medications. medications are known, documented, and included in the
Therefore, we did not eliminate any side effects so that list of side effects that are examined by the questionnaire.
the questionnaire could be used in comparative studies We believe that the COMTOL includes the most com-
of other topical ophthalmic medications used to treat mon ocular and other local side effects, and effects on
lOP. visual function, of topical ophthalmic agents for treating
Specifically, although there were very few reports of lOP, and provides a method for assessing how such medi-
bitter or unusual taste, we kept the frequency-of-taste and cations affect common living activities. Of course, tolera-
the bothersomeness-of-taste domains because we know bility is highly patient-specific and results established in
that bitter or unusual taste is a side effect of dorzolamide clinical trials cannot be assumed to apply to patients with
(a new topical CAl agent). However, this study could not other medical conditions that were excluded from the
adequately evaluate the measurement characteristics of trials and that may affect medication tolerability.
these two domains.
During the validation process, global question 11 (why References
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