Download A 12-Week, Randomized, Double-Masked, Multicenter Study of the

A 12-Week, Randomized, Double-Masked,
Multicenter Study of the Fixed Combination
of Latanoprost and Timolol in the Evening
versus the Individual Components
Michael Diestelhorst, MD,1 Lill-Inger Larsson, MD, PhD,2 for the European–Canadian Latanoprost Fixed
Combination Study Group*
Purpose: To compare the efficacy and tolerability of fixed-combination latanoprost and timolol applied in the
evening with the concomitant use of the individual components.
Design: Twelve-week, randomized, double-masked, multicenter study.
Participants: Five hundred seventeen randomized patients with ocular hypertension; open-angle, pigmentary, or exfoliation glaucoma; and baseline (after washout) intraocular pressure (IOP) levels between 23 and 33
mmHg.
Methods: Patients received either the fixed combination of latanoprost and timolol once daily in the evening
and a placebo in the morning and evening or the unfixed combination of latanoprost once daily in the evening
and timolol in the morning and evening. Study visits were at weeks 2, 6, and 12.
Main Outcome Measures: The primary efficacy end point was mean change from baseline to week 12 in
diurnal IOP (mean IOPs of 8 AM, 12 PM, and 4 PM). The fixed combination was considered noninferior to the unfixed
combination if the upper limit of the 95% confidence interval (CI) of the difference was ⬍1.5 mmHg (analysis of
covariance). Adverse events were recorded at each visit.
Results: In all, 502 patients were included in intent-to-treat analyses (fixed combination, n ⫽ 255; unfixed
combination, n ⫽ 247). For the fixed- and unfixed-combination groups, mean baseline diurnal IOP levels were
25.4 mmHg and 25.2 mmHg, respectively, and mean diurnal IOP reductions were 8.7 mmHg and 9.0 mmHg
(between-treatment difference, 0.3 mmHg; 95% CI, ⫺0.1 to 0.7 mmHg; P ⫽ 0.15). Both treatments were well
tolerated.
Conclusions: The fixed combination of latanoprost and timolol administered once daily in the evening is not
inferior to the unfixed combination of latanoprost once daily in the evening and timolol twice daily. The fixed
combination provides an effective and well-tolerated alternative to multiple instillations. Ophthalmology 2006;
113:70 –76 © 2006 by the American Academy of Ophthalmology.
Application of a single topical ocular hypotensive agent is
the preferred initial treatment for patients with glaucoma or
ocular hypertension.1 However, targeted intraocular pressure (IOP) reduction often is not obtained with monotherapy. A study of initial treatment with a ␤-blocking
agent, for example, found that one third of patients required
a change in or an addition to therapy after 1 year, a proportion that increased to half after 2 years.2 When changing the
Originally received: April 29, 2005.
Accepted: June 25, 2005.
Manuscript no. 2005-372.
1
University of Cologne, Cologne, Germany.
2
Pfizer Inc., New York, New York.
The research was supported by Pfizer Inc.
Correspondence to Michael Diestelhorst, MD, Department of Ophthalmology, Univerisitäts-Augenklinik, University of Cologne, Joseph-StelzmannStrasse 9, Cologne 50931, Germany. E-mail: michael.diestelhorst@
medizin.uni-koeln.de.
*See “Appendix” for Study Group membership.
70
© 2006 by the American Academy of Ophthalmology
Published by Elsevier Inc.
therapeutic regimens of insufficiently responsive patients, it
has been suggested that an agent with a complementary
mode of action be added if the first-choice monotherapy is
well tolerated.3 In this setting, a combined-drug preparation
is preferable to maximize adherence to therapy and quality
of life.3
The ␤-adrenergic receptor antagonist timolol, which
lowers IOP by reducing the production of aqueous humor,4 – 6 exhibits additive effects when combined with other
ocular hypotensive agents.7–10 The complementary mechanism of action of the prostaglandin F2␣ analog latanoprost,
which acts primarily by increasing outflow,11 makes it a
logical choice for combination with timolol. In fact, the
fixed combination of latanoprost and timolol has been
shown to reduce IOP more effectively than either agent used
alone and has been found to have good tolerability.12–14
We recently published the results of a double-masked,
randomized, crossover study comparing fixed-combination
latanoprost and timolol administered once daily in the
ISSN 0161-6420/06/$–see front matter
doi:10.1016/j.ophtha.2005.06.027
Diestelhorst and Larsson 䡠 Fixed Combination of Latanoprost and Timolol in the Evening
morning versus once-daily evening latanoprost and twicedaily timolol in patients with open-angle glaucoma and
ocular hypertension.15 Both regimens were found to be well
tolerated and effective. The 1.1-mmHg difference in mean
within-patient diurnal IOP levels favoring the unfixed combination may have reflected the fact that latanoprost was
administered in the evening, whereas the fixed combination
was instilled in the morning. Previous studies have shown
better diurnal IOP control with evening dosing of both
latanoprost16,17 and latanoprost and timolol,18 probably reflecting the fact that latanoprost’s maximum effect occurs 8
to 12 hours after dosing.
The purpose of the present study was to assess the
efficacy and tolerability of the fixed combination of latanoprost and timolol administered in the evening versus those
of an evening dose of latanoprost and twice-daily doses
(morning and evening) of timolol.
Materials and Methods
Study Design
This 12-week, randomized, double-masked study was conducted at
53 centers throughout Europe and Canada. The protocol was
reviewed by an institutional review board/independent ethics committee before the study, and the research was conducted in accordance with the ethical standards maintained in the Declaration of
Helsinki. All patients were fully informed and provided written
consent for participation before enrollment.
Patients
See Table 1 for study inclusion and exclusion criteria.
Treatments and Assessments
Potentially eligible patients were assessed at a screening visit 4
weeks to 5 days before study entry. Medical and ocular histories
were recorded; visual acuity (VA) was measured; and visual field
(if not performed within the previous year), lid and slit-lamp
examination, and ophthalmoscopy were performed. Intraocular
pressure was measured using a calibrated Goldmann applanation
tonometer. All ocular measurements were performed in both eyes.
Required washout periods before the baseline visit were 5 days for
cholinergic agonists and carbonic anhydrase inhibitors, 2 weeks
for adrenergic agonists, and 4 weeks for ␤-adrenergic antagonists
and prostaglandin analogs. Patients requiring a 4-week washout
returned after 2 weeks for an IOP safety check. If the IOP was ⬎33
mmHg at the safety visit, the patient was either excluded from the
study or treated with an IOP-lowering medication with a shorter
washout period. If an alternative ocular hypotensive medication
was used, a washout period was required before the baseline visit.
Patients with IOP levels of ⬍33 mmHg at the safety visit could
continue in the study.
Study visits occurred at baseline and weeks 2, 6, and 12. At the
baseline visit, VA measurement and lid and slit-lamp examinations
were repeated, and masked evaluators performed 3 IOP measurements in each eye starting with the right at 8 AM, 12 PM, and 4 PM.
The masked evaluator recorded IOP readings. Statistical analyses
included the mean of these IOP measurements at each time point.
To be eligible for randomization, an 8 AM IOP level between 23
mmHg and 33 mmHg was required. After the 4 PM IOP level was
obtained, eligible patients were assigned consecutively to 1 of the
2 treatment groups 1:1 using randomization codes generated by
Pharmacia Global Pharmaceutical Sciences. Patients assigned to
receive the fixed combination instilled 1 drop (active ingredients:
latanoprost 0.005% and timolol maleate 0.5%) once daily in the
evening and 1 drop of a placebo (vehicle of the fixed combination) in
the morning and evening. Patients in the unfixed-combination group
administered 1 drop of latanoprost 0.005% once daily in the evening
and 1 drop of timolol maleate 0.5% in the morning and evening.
At baseline and week 6, each patient received a kit containing
study drugs packaged in 2.5-ml bottles. Each kit held 3 cartons: 1
contained the morning medication bottle (labeled 8 AM), and 2
contained the evening medication bottles (labeled 8 PM bottle A
and 8 PM bottle B). Patients were instructed to administer 1 drop of
study drug to the affected eye(s) every morning from the bottle
labeled 8 AM and 1 drop every evening from each of the 2 bottles
Table 1. Study Criteria
Inclusion Criteria
Exclusion Criteria
● Age ⱖ 18 yrs
● Unilateral or bilateral ocular hypertension or primary
open-angle, pigmentary, or exfoliative glaucoma
● Naive to IOP-lowering medication
● Closed or barely open anterior chamber angle, history of acute angle-closure glaucoma,
ocular surgery on the globe of the eye, or history of any ocular filtering surgical
intervention (unfiltered eye could be enrolled)
● Argon laser trabeculoplasty, selective laser trabeculoplasty in the study eye(s), or
ocular inflammation in either eye during the 3 mos before screening
● Insufficient response to current IOP-lowering
monotherapy or dual therapy at screening (opinion
of investigator)
● Baseline mean 8 AM IOP in study eye(s) between 23
mmHg and 33 mmHg after washout of previous
therapy
● Best-corrected visual acuity ⱖ 20/200
● Able to adhere to the treatment/visit plan
● Known hypersensitivity to benzalkonium chloride or any other component in either
study drug solution
● Any abnormal ocular conditions or symptoms that would prevent study eligibility
(opinion of investigator), conditions in which treatment with ␤-blocking therapies
was contraindicated, an ocular infection in either eye within 3 weeks before screening,
or use of an investigational medication within the month preceding screening
● Use of a systemic medication known to affect IOP levels unless patient and
medication dosage had been stable for 3 mos before screening and unless the dosage
was not expected to change during the study period
● Woman of childbearing potential who was not using adequate contraceptive methods
or was pregnant or nursing
IOP ⫽ intraocular pressure.
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Ophthalmology Volume 113, Number 1, January 2006
labeled 8 PM. The evening regimen was to be administered with a
5-minute interval between drops from bottle A and bottle B. The
first dose of study medication was instilled the evening of the
baseline visit, and patients were instructed not to instill study
medication on the morning of their next study visit. Each patient’s
IOP level was measured by a masked observer at any time during
the week 2 visit and at 8 AM, 12 PM, and 4 PM during the week 6
and week 12 visits. As at baseline, masked evaluators performed 3
IOP measurements in each eye starting with the right at each
measurement time. It was requested that the same examiner measure IOP using the same calibrated tonometer at each time point
and at each visit for a given patient. At weeks 6 and 12, patients
instilled the 8 AM dose of study medication after IOP measurement.
Visual acuity measurement and lid and slit-lamp examinations
were repeated at weeks 6 and 12, and ophthalmoscopy was performed at week 12.
Throughout the study, all adverse events were recorded and
monitored by investigators. The intensity of each adverse event
was graded using defined criteria, and events were classified as
serious or nonserious. Patients with serious adverse events, adverse events related to study medication, or ocular adverse events
at the week 12 visit had an additional follow-up visit 2 weeks later.
Variables and Analyses
Only data for study eyes, which met all inclusion and no exclusion
criteria, were included in the efficacy analyses. If both eyes qualified as study eyes, the average IOP of the 2 eyes was used in the
analyses. The primary efficacy variable was the mean change
between baseline and week 12 in mean diurnal IOP. The mean
diurnal IOP of a patient at any visit was calculated as the mean
value of the IOPs recorded at 8 AM, 12 PM, and 4 PM. If data for any
time point were missing, the mean diurnal IOP was calculated as
the mean of the nonmissing IOP measurements. Between-group
differences were analyzed using an analysis of covariance model
with baseline IOP as a covariate and treatment and center as
factors. The treatment difference (fixed combination ⫺ unfixed
combination) and a 95% confidence interval (CI) for the difference
were calculated, and the fixed combination was considered noninferior to the unfixed combination if the upper limit of the 95% CI
of the difference was ⬍1.5 mmHg. This noninferiority design was
chosen to determine whether the fixed combination was no less
effective (either more or similarly effective) than the unfixed
combination. Treatment differences for secondary efficacy variables, such as mean change in diurnal IOP at week 6 and percent
change from baseline in diurnal IOP at weeks 6 and 12, were tested
using an analysis of covariance model with baseline, treatment,
and center in the model. Differences in proportions of patients with
prespecified percentages of mean diurnal IOP reductions from baseline to week 12 and achieving prespecified diurnal IOP levels were
tested using center-stratified Cochran–Mantel–Haenszel tests. Intentto-treat (ITT) efficacy analyses included all patients who received
study medication, had a baseline IOP measurement, and had at
least 1 valid week 6 or week 12 IOP measurement. The lastobservation-carried-forward method was used to impute missing
data. The per protocol population included all patients in ITT
analyses who completed the 12-week study with no major protocol
deviations.
Safety analyses included randomized patients receiving at least
1 dose of study medication (safety population). The Medical
Dictionary for Regulatory Activities coding system was used to
classify adverse events, and frequencies of ocular and systemic
adverse events were tabulated.
The sample size was calculated using a t test with a 1-sided
significance level of 0.025 and 80% power. To test an equivalence
limit of 1.5 mmHg, it was determined before the study that a
72
Table 2. Demographic Data (Intent-to-Treat Population)
Treatment Group
Demographic Characteristic
Gender [n (%)]*
Male
Female
Age (yrs)
Mean
SD
Range
Ethnic origin [n (%)]
White
Black
Other
Study eye(s) [n (%)]
Right
Left
Both
Treated eye(s) [n (%)]
Right
Left
Both
Diagnosis of study eye(s) [n (%)]
Primary open-angle glaucoma
Ocular hypertension
Exfoliative glaucoma
Pigmentary glaucoma
Mixed†
Visual field—any glaucomatous damage
in study eye(s) [n (%)]
Yes
Color of treated eye [n (%)]
Homogeneously brown
Homogeneously blue, gray, or green
Blue–brown or gray–brown
Green–brown
Yellow–brown
Fixed
Combination
(n ⫽ 255)
Unfixed
Combination
(n ⫽ 247)
129 (50.6)
126 (49.4)
99 (40.1)
148 (59.9)
65
10.9
33–94
65
11.2
22–89
251 (98.4)
3 (1.2)
1 (0.4)
242 (98.0)
3 (1.2)
2 (0.8)
27 (10.6)
26 (10.2)
202 (79.2)
33 (13.4)
24 (9.7)
190 (76.9)
8 (3.1)
4 (1.6)
243 (95.3)
7 (2.8)
3 (1.2)
237 (96.0)
163 (63.9)
70 (27.5)
12 (4.7)
5 (2.0)
5 (2.0)
163 (66.0)
60 (24.3)
10 (4.0)
4 (1.6)
10 (4.0)
122 (47.8)
121 (49.0)
107 (42.0)
87 (34.1)
32 (12.5)
22 (8.6)
7 (2.7)
100 (40.5)
99 (40.1)
21 (8.5)
18 (7.3)
9 (3.6)
SD ⫽ standard deviation.
*P ⫽ 0.018 for difference between groups.
†
Different diagnosis in right eye and left eye.
sample of 194 evaluable patients per treatment group was required
assuming a difference of 0.5 mmHg in mean IOP reduction and a
common standard deviation (SD) of 3.5 mmHg. A minimum of
430 patients was planned to allow for patient withdrawals, and 588
were actually enrolled. Overenrollment reflected the fact that patients were entered into a 4-week washout period before randomization. Towards the end of recruitment, investigators started to
increase the number of patients entered to fulfill enrollment goals.
When sufficient patients were randomized, there were still many
undergoing the 4-week washout. Although notices to stop enrollment were sent to investigators, it was felt appropriate that these
patients should be allowed to continue into the study, having been
taken off their standard medication for the purposes of the trial.
Results
Of the 588 patients enrolled between March 27 and December 5,
2003, 517 were randomized (fixed combination, n ⫽ 263; unfixed
combination, n ⫽ 254). Eight patients randomized to receive the
fixed combination and 7 to be treated with the unfixed combination
Diestelhorst and Larsson 䡠 Fixed Combination of Latanoprost and Timolol in the Evening
Table 3. Intraocular Pressure (IOP) and IOP Reduction from Baseline to Week 12 (Intent-to-Treat Population)
Baseline IOP (mmHg)
(Mean ⴞ SD)
Diurnal
8 AM
12 PM
4 PM
IOP Change from Baseline to
Week 12 (mmHg)
(Least Square Mean ⴞ SE)
Fixed
Combination
(n ⫽ 255)
Unfixed
Combination
(n ⫽ 247)
Fixed
Combination
(n ⫽ 255)
Unfixed
Combination
(n ⫽ 247)
Difference
(95% CI)
P Value
25.4⫾2.3
26.0⫾2.3
25.4⫾2.7
24.7⫾2.9
25.2⫾2.4
26.0⫾2.3
25.3⫾2.9
24.5⫾2.9
⫺8.7⫾0.2
⫺9.1⫾0.2
⫺8.7⫾0.2
⫺8.2⫾0.2
⫺9.0⫾0.2
⫺9.5⫾0.2
⫺9.1⫾0.2
⫺8.3⫾0.2
0.3 (⫺0.1–0.7)
0.4 (⫺0.1–0.8)
0.4 (⫺0.0–0.9)
0.1 (⫺0.4–0.5)
0.15
0.12
0.06
0.78
CI ⫽ confidence interval; SD ⫽ standard deviation; SE ⫽ standard error.
were excluded from ITT analyses because they either did not
receive study medication or did not have required measurements;
thus, the ITT population included 255 and 247 patients, respectively. An additional 28 patients in the fixed-combination group
and 18 in the unfixed-combination group were excluded from the
per protocol population primarily due to major protocol violations.
One patient randomized to fixed combination did not receive study
medication and was excluded from analyses of tolerability.
Treatment groups were well matched with regard to age, ethnic
origin, and baseline ocular characteristics (Table 2). The gender
distributions differed significantly (P ⫽ 0.02), but when gender
was added to the analysis of covariance model for the primary
analysis, the conclusion regarding noninferiority was not affected.
The most common IOP-reducing medications at screening were
␤-blockers (fixed combination, n ⫽ 109; unfixed combination, n ⫽
107) and prostaglandins (fixed combination, n ⫽ 114; unfixed
combination, n ⫽ 102).
Efficacy
In the ITT population, mean baseline diurnal IOP levels were
approximately 25 mmHg in both treatment groups (Table 3). The
reduction in mean diurnal IOP from baseline to week 12 was 8.7
mmHg in the fixed-combination group and 9.0 mmHg in the
unfixed-combination group. The between-group difference was 0.3
mmHg, and the upper bound of the 95% CI was ⬍1.5 mmHg,
indicating noninferiority of the fixed combination (P ⫽ 0.15).
At week 12, the fixed combination was noninferior at each
measurement time (Table 3), and mean diurnal IOP levels were
similar (fixed combination, 16.7 mmHg; unfixed combination,
16.4 mmHg; P ⫽ 0.15). At week 6, the mean diurnal IOP reduction from baseline was noninferior in the fixed-combination group
(fixed combination [mean ⫾ SD], 8.7⫾0.1; unfixed combination,
8.9⫾0.1; difference [95% CI]: 0.2 [⫺0.2 to 0.6]; P ⫽ 0.36). Percent
reductions in mean diurnal IOP levels were similar at week 12 (fixed
combination, 34.0⫾0.6%; unfixed combination, 35.1⫾0.6%; P ⫽
0.18) and week 6 (fixed combination, 34.3⫾0.6%; unfixed combination, 34.9⫾0.6%; P ⫽ 0.42). No statistically significant difference
was observed with regard to numbers of patients reaching prespecified percentages of mean diurnal IOP reduction at the end of
treatment (Fig 1). Numbers achieving specific mean diurnal IOP
levels at week 12 also were similar (Fig 2), except for the percentage reaching ⱕ15 mmHg, where borderline statistical significance was noted (P ⫽ 0.05) in favor of the unfixed combination.
The results of the per protocol analyses confirmed those in the ITT
population, except that the difference in percentages of patients reaching ⱕ15 mmHg was not statistically significant (P ⫽ 0.19).
Safety
Both treatments were well tolerated, but the fixed combination demonstrated a better tolerability profile with regard to percentages of
patients reporting at least 1 adverse event and reporting an ocular
adverse event (Table 4). The majority of adverse events were mild
Figure 1. Patients reaching prespecified percentages of mean diurnal intraocular pressure (IOP) reduction at week 12 (intent-to-treat population).
73
Ophthalmology Volume 113, Number 1, January 2006
Figure 2. Patients achieving prespecified mean diurnal intraocular pressure (IOP) levels at week 12 (intent-to-treat population). *P ⫽ 0.05.
to moderate in intensity, and most patients recovered completely.
Eye disorders were the most frequently reported adverse events
and occurred more frequently in the unfixed-combination group
(fixed combination, 27/262 [10.3%]; unfixed combination, 43/254
[16.9%]). With the exception of ocular hyperemia (fixed combination, 6/262 [2.3%]; unfixed combination, 18/254 [7.1%]) and
eye irritation (fixed combination, 6/262 [2.3%]; unfixed combination, 11/254 [4.3%]), no other individual ocular adverse event was
reported in ⱖ3% of patients in either treatment group. The majority of ocular adverse events were related to hyperemia (Medical
Dictionary for Regulatory Activities preferred terms hyperemia,
ocular hyperemia, and red eye), which was reported in 8 of 262
(3.1%) patients receiving the fixed combination and in 22 of 254
(8.7%) of those treated with the unfixed combination. Few discontinuations due to adverse events occurred in either treatment group
(Table 4). Five serious adverse events occurred in the fixedcombination group, and 2 in the unfixed-combination group; 1 was
considered possibly related to study medication (toxic keratoconjunctivitis in a patient receiving the fixed combination). One patient died of a myocardial infarction. No systemic adverse event
was considered related to study medication.
Discussion
The results of this 12-week study provide evidence that the
fixed combination applied in the evening is noninferior to
the unfixed combination of latanoprost applied in the
evening and timolol twice daily. The mean between-group
difference in mean diurnal IOP reduction from baseline was
0.3 mmHg, demonstrating noninferiority of the fixed combination. Although the noninferiority criterion for the
present study was 1.5 mmHg, the upper bound of the 95%
CI was ⬍1.0 mmHg, allowing us to conclude noninferiority
at that level of difference as well. These findings support the
impression that the 1.1-mmHg difference favoring the unfixed combination found in our previous study15 (which had
a noninferiority criterion of 1.0 mmHg) was related, at least
in part, to the fact that the fixed combination was instilled
in the morning, whereas latanoprost was instilled in the
evening as part of the unfixed combination.
Previous studies have documented the effectiveness of
once-daily fixed-combination latanoprost and timolol in
comparison with other 2-drug regimens. For example,
fixed-combination latanoprost and timolol has been shown
to be more effective than either the twice-daily administration of fixed-combination dorzolamide and timolol19 or the
unfixed combination of brimonidine and timolol both dosed
twice daily.20,21 Fixed-combination latanoprost and timolol
also has been shown to provide diurnal IOP reductions
statistically similar to those of the unfixed combination of
brimonidine twice daily and latanoprost once daily.22 In
contrast, concomitant travoprost once daily in the evening
and twice-daily brinzolamide were reported to lower IOP
levels more effectively than the once-daily morning administration of fixed-combination latanoprost and timolol23;
however, the evening versus morning dosing schedules of
travoprost and the fixed combination, respectively, may
Table 4. Treatment-Emergent Adverse Events (Safety Population)
Fixed Combination
(n ⴝ 262)
Unfixed Combination
(n ⴝ 254)
Patients with
n (%)
No. of Events
n (%)
No. of Events
P Value
At least 1 adverse event
Ocular adverse events
Systemic adverse events
Adverse events related to study medication
Discontinuation due to an adverse event
44 (16.8)
31 (11.8)
16 (6.1)
21 (8.0)
6 (2.3)
58
39
19
25
6
62 (24.4)
51 (20.1)
17 (6.7)
33 (13.0)
7 (2.8)
91
70
21
45
12
0.04
0.01
0.86
0.08
0.80
74
Diestelhorst and Larsson 䡠 Fixed Combination of Latanoprost and Timolol in the Evening
have contributed to this finding. It is notable that in all of
these comparisons the fixed combination of latanoprost and
timolol was instilled once daily, whereas comparator regimens required 2, 3, or 4 instillations per day. More complex
medication regimens have been associated with poorer compliance in patients with glaucoma or ocular hypertension.24,25
As in previous studies,12–14 both the fixed and unfixed
combinations of latanoprost and timolol were found to be
well tolerated. The fixed combination had a somewhat better tolerability profile, though, possibly because only a
single dose of medication was instilled each day, compared
with 3 doses for patients in the unfixed-combination group.
Although no systemic adverse event was related to study
medication, long-term adverse events could be reduced with
once-daily dosing of timolol.
It is worth noting that the final number of randomized
patients was higher than planned due to an unexpectedly
high recruitment rate near the end of enrollment and an
unexpectedly low attrition rate during screening. The larger
sample provided additional power to detect differences between groups if they existed.
The research was limited by its relatively short timeframe. Twelve weeks is sufficient to observe changes in IOP
levels and to document the presence or absence of many
potential adverse events. However, follow-up periods of
several years are required to assess differences between
therapies with regard to changes in VA or cup-to-disc ratio,
the occurrence of long-term side effects, and patient compliance and persistency with treatment.
In summary, the fixed combination of latanoprost and
timolol applied in the evening is noninferior to the unfixed
combination of latanoprost applied in the evening and timolol twice daily. Compared with published data of the fixed
combination applied in the morning, our study implies an
additional IOP-lowering effect of latanoprost when applied
in the evening. The fixed combination provides a once-daily
alternative to the 3 instillations needed with the individual
components, which may interfere with patient compliance.
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Appendix: Members of the
European–Canadian Latanoprost Fixed
Combination Study Group
Canada
Iqbal Ahmed, MD, Mississauga; Pierre Blondeau, MD,
Sherbrooke; Shawn Cohen, MD, Montreal; Robert G.
Douglas, MD, Burnaby; Oscar P. Kasner, MD, Montreal;
Thomas Klein, MD, Brampton; Frederic Lord, MD, Montreal; Donald Nixon, MD, Barrie; Kevin Parkinson, MD,
Coquitlam; Paul Rafuse, MD, Halifax; Aaron Wolfe Rifkind, MD, Hamilton; David Paul Tingey, MD, London;
David B. Yan, MD, Mississauga.
Germany
Andreas Bayer, MD, Weilheim; Hartmut Benning, MD,
Mainz; Thomas Christ, MD, Schorndorf; Michael Diestelhorst, MD, Köln; Joachin Floren, MD, Gladbach; Anselm
Grundler, MD, Erlangen; Thomas Hamacher, MD, Starnberg; Cornelia Herschel, MD, Köln; Konstantin Papakostas,
MD, Gummersbach; Klaus Rosbach, MD, Mainz; MariaLuise Scherzer, MD, Regenstauf.
76
Greece
Konstandinos Georgakopoulos, MD, Rio Patra; Stavros Giannikakis, MD, Athens; Konstandinos Karabatsas, MD,
Larissa; Emmanouil Vaikousis, MD, Piraeus.
Italy
Maria Teresa Dorigo, MD, Padova; Enrico Gandolfo, MD,
Brescia; Leonardo Mastropasqua, MD, Chieti; Ugo
Menchini, MD, Firenze; Nicola Orzalesi, MD, Milano.
The Netherlands
Catharina E. De Graaf-Kret, MD, Rijswijk; H. Ferdinand A.
Duijm, MD, Zwolle; Jan-Peter Flipse, MD, Bergen op
Zoom; Antoinette G. J. E. Niessen, MD, Schiedamse Vest;
Erik J. G. M. van Oosterhout, MD, Eindhoven; Henricus
G. N. Veraart, MD, Tilburg; Herman A. Wessels, MD,
Roosendaal.
Spain
Alfonso Arias, MD, Madrid; Elena Arrondo, MD, Barcelona; Jose Isidro Belda, MD, Alicante; Julio De La Camara,
MD, Barcelona; Soledad Jimenez, MD, Cádiz; Mercedes
Lasso, MD, Vizcaya; Francisco Munoz Negrete, MD, Madrid; Aureli Rilo, MD, Barcelona; Ana Isabel Vazquez, MD,
Málaga; Jaume Vila, MD, Manacor (Palma de Mallorca).
Sweden
Albert Alm, MD, Uppsala; Adnan Chatila, MD, Orebro;
Enping Chen, MD, Stockholm; Mazhar Ghawji, MD,
Skövde.