Multiple-Dose Efficacy Comparison of the Two Topical Carbonic Anhydrase Inhibitors Sezolamide and MK-927 Alain Bron, MD; Erik A. Lippa, MD, PhD; Frans Gunning, MD; Claude B\l=e'\nichou,MD; Pierre Lesure, MD; Daniel Sirbat, MD; Jean Royer, MD; Jacques Flament, MD; Coleen Clineschmidt; Deborah Panebianco, MS; Agnes Buntinx, MS; Fran\l=c;\oiseBrunner-Ferber, PhD; Jean-Luc George, MD; Erik Greve, MD \s=b\ The multiple-dose twice-daily efficacy of the topical carbonic anhydrase inhibitor MK-927, a racemic compound, was compared with that of its pharmacologically more active S-enantiomer in a four-center, double-masked, random-
ized, placebo-controlled, parallel study
of 1.8% sezolamide hydrochloride (MK\x=req-\ 417), 2% MK-927, and placebo, given twice daily to 48 patients with bilateral primary open angle glaucoma or ocular hypertension and morning intraocular pressure greater than 24 mm Hg in both eyes following washout of ocular hypotensive medications. Parallel 10-hour modified diurnal curves were performed before the study and on day 14, with 4-hour curves on days 1 and 4. Both compounds demonstrated significant
\/ -927 was the first topical carbon¬
anhydrase inhibitor to demon¬ strate clinically significant efficacy in lowering intraocular pressure (IOP) of ic
Accepted for publication September 13, 1990. From the Departments of Ophthalmology, University of Besan\l=c;\on(Drs Bron and Royer), University of Nancy-Brabois (Drs Lesure, Sirbat, and George), and University of Strasbourg (Drs
B\l=e'\nichouand Flament), France; Departments of Clinical Research (Dr Lippa and Ms Clineschmidt), Clinical Pharmacology (Drs Buntinx and Brunner-Ferber), and Biostatistics (Ms Panebianco), Merck Sharp & Dohme Research Laboratories, West Point, Pa; and Glaucoma Center, Academic Medical Center, Amsterdam, the Netherlands (Drs Gunning and Greve). Presented in part at the Association for Research in Vision and Ophthalmology Annual Meeting, Sarasota, Fla, May 1, 1989. Reprint requests to Clinical Research, Merck Sharp & Dohme Research Laboratories, West Point, PA 19486 (Dr Lippa).
lowering of intraocular pressure at 8 AM, 12 hours following the evening dose, and through 10 and 6 hours following the 8 AM dose for sezolamide and
MK-927,
respectively. Morning trough (evening) activity as measured by mean percent change in intraocular pressure from prestudy was 9.2% for sezolamide and \m=-\11.1%for MK-927 (\m=-\13.5% and \m=-\9.6%);peak effect occurred 2 hours
after dose administration and was \m=-\19.4%and \m=-\19.2% for sezolamide and MK-927, respectively. From 2 hours after dose administration, sezolamide consistently demonstrated a slightly greater decrease in intraocular pressure than MK-927; however, these differences were
statistically significant. (Arch Ophthalmol. 1991;109:50-53)
not
patients with glaucoma pertension after single-
ocular hy¬ and multipledose administration. It is a thienothiopyran-2-sulfonamide that has shown excellent activity in vitro.1"3 It is a or
See also pp 38 and 46. racemic compound with a single chiral center and thus can be separated into R- and S-enantiomers that are mirror images of one another. The S-enantiomer, sezolamide hydrochloride (previ¬ ously MK-417), is substantially more active than the R-enantiomer.3 The concentration inhibiting human car¬ bonic anhydrase isoenzyme II is 0.54 nmol/L and 44 nmol/L for sezola¬ mide and MK-927, respectively.4 More¬ over, sezolamide is specific for carbon¬ ic anhydrase isoenzyme II (ratio of
Downloaded From: http://archopht.jamanetwork.com/ by a Oakland University User on 06/08/2015
approximately 1400:1, based on ratio of K,s), the isoenzyme of carbonic anhy¬ drase, which is present in the ciliary
processes.5
The ability of MK-927 to effectively lower IOP has been demonstrated in normotensive rabbits as well as in rab¬ bit and monkey models of ocular hy¬ pertension.6"" In contrast with several previously developed topical carbonic anhydrase inhibitors for which good activity in animal models did not carry over to substantial activity in hu¬ mans,91" MK-927 at 2% has been shown to be active in normal subjects and has demonstrated significant efficacy in patients after single- and multiple-dose administration (peak decrease from predose of 25% to 33% at 4 to 6 hours after dose administration11 "; peak de¬ crease from baseline diurnal curve of approximately 20% at 2 hours after dose administration15). Moreover, MK-927 has demonstrated acceptable ocular tolerability together with an absence of significant systemic bio¬ chemical effects."1 The ophthalmic formulations of both MK-927 and sezolamide are isotonic, buffered at pH 5.2, and pre¬ served with benzalkonium chloride. Maximum available concentrations are 2% for MK-927 and 1.8% for sezola¬ mide. MK-927 and sezolamide have been shown to have similar tolerability profiles in normal subjects.1' Singledose sezolamide was shown to be more potent than MK-927 in patients with glaucoma or ocular hypertension; how¬ ever, the difference in activities was not
large.18
This
study was undertaken to assess
Mean Intraocular Pressure
Mean (SD) Intraocular
Time, h
Prestudy
Pressure,
Day
Day 1
mm
Hg Day
4
0·_27.1 1_27.3 ± 2_26.2 ± 4_25.9 ± 6_24.6 ± 8_25.5 ± 10_26.3 ±
2.9_26.2 4.2_24.7 4.8t_24.7 3.5_22.9 ± 4.7 _21.9 ± 4.2 _22.3 4.2_21.2 ± 4.2 _20.9 ± 3.8 _21.1 4.6_20.4 ± 3.6 _20.8 ± 3.7 _20.7 3.5_._^__._j__20.0 3.6_._^_._^_21.4
0·_29.0 1_29.1 2_27.9 4_26.5
4.6_29.4 4.9_26.9 4.0_24.1 3.2_22.9
±
±
± ± ±
±
14
Hydrochloride
1.8% Sezolamide ±
4.4___._22.6
± ± ± ± ± ±
±
4.4 3.6 3.6 3.5 4.5 4.6 4.5
2.0% MK-927
6
25.0 ±2.0
10
25.2 ±2.7
± ±
± ±
5.2_26.9 5.5t_23.6 4.8 _20.9 3.7 _21.4
...
5.2 5.9 ± 4.5 ± 3.4 20.8 ± 3.5 22.1 ± 3:ß 22.8 ± 3.7
5.6t_25.8 5.5 _23.6 2.8 _22.4 2.6 _22.4
±
± ± ±
...
± ±
Placebo 26.6 ± 3.7
28.6 ± 3.6
26.1 ±
2.6t
26.0 ±
3.7
26.3 ± 3.3
27.2 ± 2.8
6_23.6
±
8_24.1
±
10
25.8 ± 3.2t
25.9 ± 4.4
2.6_._^_._^_22.9 3.8__LJ_L^J_22.6
*
± 4.4
± 3.7
24.4 ± 3.8
25.6 ±3.9
Immediately predose on days 1, 4, and 14. tDecrease and percent decrease from prestudy significantly different from ß ßß and percent decrease from prestudy significantly different from ...
...
zero zero
ications of at least 72 hours for parasympathomimetic solutions, at least 8 days for sympathomimetic solutions, and at least 14 days for ß-blockers or any other agents. Exclusion criteria included concomitant systemic or dermatologie medication known to affect IOP, any concurrent ocular thera¬ py other than the study drug, a history of intraocular surgery, best corrected Snellen visual acuity at a distance equal to or worse than 2/10 in both eyes, and recent signs of ocular infection or inflammation.
Study Design This was a four-center, double-masked, randomized, placebo-controlled, parallel study. Treatment regimens consisted of 1.8% sezolamide, 2.0% MK-927, or placebo (common vehicle) administered to each eye at 8 AM and 8 PM for 14 days. Between 2 and 10 days prior to drug administration, a
...
...
hypertension with IOP simulta¬ neously greater than or equal to 24 mm Hg in both eyes at 8, 9, or 10 AM on the prestudy diurnal curve day following a washout period for ocular hypotensive med¬ ocular
(Worse Eye)
(P < .05). (P < .01).
prestudy 10-hour diurnal IOP curve was performed following the appropriate wash¬ out period (8, 9, 10 AM, noon, and 2, 4, and 6 PM). On study days 1 and 4, IOP was measured immediately before and 1, 2, and 4 hours after dose administration. On study day 14, IOP was measured immediately
before and 1, 2, 4, 6, 8, and 10 hours after dose administration, paralleling the pre¬ study diurnal curve times. A 2-week washout period for topical ß-blockers was chosen to limit patient time without medication to approximately 1 month. Potential small residual effects in some patients are well controlled for by the placebo group. Within each center, all mea¬ surements of IOP for a given patient were performed by the same person, applanation tonometry followed instillation of a fluorescein-benoxinate solution, and the same Golclmann applanation tonometer was used. Patients were closely monitored through¬ out the study with repeated evaluation of symptoms, visual acuity, and external and anterior segment signs. Both prestudy and poststudy examinations included dilated ophthalmoscopy and visual field exam¬ ination.
Statistical Methods
Fig 1. —The 1.8% sezolamide hydrochloride treatment group: mean percent change in intraocu¬ lar pressure (IOP) readings (worse eye) from prestudy at the same time. Circles represent day 1 ; squares, day 4; and asterisks, day 14. Hour 0 corresponds to 8 AM; SD range, 7.1% to 13.9%. and compare the relative efficacy of the maximum concentrations of 1.8% sezolamide and 2% MK-927 when given twice daily for a 2-week period. PATIENTS AND METHODS Patient Selection and Entry This study was approved by the appropri¬ ate ethical review board at each of the
participating hospitals and each patient gave his or her informed consent prior to entry into the study. Patients were men or postmenopausal or sterilized women 35 to
80 years of age. Each underwent a medical and ophthalmologic screening examination 2 to 14 days prior to entry into the study. Admission criteria included a history and examination consistent with a diagnosis of bilateral primary open angle glaucoma or
Downloaded From: http://archopht.jamanetwork.com/ by a Oakland University User on 06/08/2015
The primary variables tested were change and percent change in IOP from prestudy values at the same time. Prestudy within-treatment group changes were tested using the matched-pairs t test. Tests for significant differences between treatment groups were based on a linear model. The analysis of variance model used included terms for treatment, iris color,
prior ocular hypotensive therapy, investi¬ gator, and all two-way interactions. All tests were two-sided with type I error set
equal to 0.05. were analyzed both with respect to "average eye" (mean of right and left eye) and "worse eye." Worse eye was de¬ at
Results
fined as follows: (1) the eye with the greater IOP at 8 AM on the prestudy diurnal curve day; (2) if IOP was equal in both eyes at
five
categories
was
as
follows: blue
(n 20); green (n 3); hazel
or light golden brown (n=10); brown (n 12); =
=
=
and dark brown (n 3). The only significant difference be¬ tween treatment groups with regard to the above variables was for that of sex, with significantly more men in the sezolamide treatment group than in the MK-927 and placebo groups (12 in the sezolamide group vs seven in the MK-927 group and nine in the placebo group). However, men and women =
not anticipated to experience substantially different degrees of effi¬ cacy. There were 16 patients in each of were
the three treatment groups.
Intraocular Pressure
Fig 2.—The 2% MK-927 treatment group: mean percent change in intraocular pressures (IOP) (worse eye) from prestudy at the same time. Circles indicate day 1 ; squares, day 4; and asterisks, day 14. Hour 0 corresponds to 8 AM; SD range, 6.6% to 15.3%.
Fig 3. —Mean percent change in intraocular pressure (IOP) (worse eye) from prestudy to day 14 at the same time for all three treatment groups. Closed circles represent 1.8% sezolamide hydrochloride group; squares, 2% MK-927 group; and open circles, placebo group.
prestudy, then the worse eye was that with the greater IOP at 8 AM on day 1, immediately before dose administration; and (3) if IOPs in both eyes were equal at 8 AM on both the prestudy day and on day 1, then the worse eye was defined to be the right eye. Results for the worse eye and the average eye analyses were similar and therefore only the results for the worse eye are given below. The analysis was based on 48 patients 8 AM
who
completed the study per protocol. RESULTS
Forty-eight patients entered and completed the study per protocol (six to 18 patients per center). There
and 20 women. The mean 58.9 years (range, 34 to 74 years). Fourteen of the patients had secondary nonocular diagnoses, the most prevalent being diabetes mellitus (n 5) and hypertension (n 5). Elev¬ en patients had received no prior ther¬ apy, 24 had received only a ß-blocker, and 13 had received a ß-blocker and one or more additional agents (10 re¬ ceived a parasympathomimetic agent; one, an oral carbonic anhydrase inhibi¬ tor; one, guanethidine and epinephrine; and one, a parasympathomimetic, guanethidine, and epinephrine). The distribution by iris color into one of were
age
=
28
men
was
=
Downloaded From: http://archopht.jamanetwork.com/ by a Oakland University User on 06/08/2015
The Table presents the mean IOP data and SDs for each treatment group.
Although prestudy morning
IOPs were generally greater for the MK-927 treatment group, this differ¬ ence was not significant. Figures 1 and 2 graphically depict the data for the 1.8% sezolamide and 2% MK-927 treat¬ ment groups with respect to percent change in IOP from prestudy; Fig 3 compares activity between the three groups on day 14. In the Table and the figures, hour 0 represents 8 AM; hour 1, 9 AM; etc. For both 1.8% sezolamide and 2% MK-927, the percent decrease in IOP from prestudy was significantly differ¬ ent from zero at all postdose times on days 1, 4, and 14 (P
ized, placebo-controlled, parallel study
of 1.8% sezolamide hydrochloride (MK\x=req-\ 417), 2% MK-927, and placebo, given twice daily to 48 patients with bilateral primary open angle glaucoma or ocular hypertension and morning intraocular pressure greater than 24 mm Hg in both eyes following washout of ocular hypotensive medications. Parallel 10-hour modified diurnal curves were performed before the study and on day 14, with 4-hour curves on days 1 and 4. Both compounds demonstrated significant
\/ -927 was the first topical carbon¬
anhydrase inhibitor to demon¬ strate clinically significant efficacy in lowering intraocular pressure (IOP) of ic
Accepted for publication September 13, 1990. From the Departments of Ophthalmology, University of Besan\l=c;\on(Drs Bron and Royer), University of Nancy-Brabois (Drs Lesure, Sirbat, and George), and University of Strasbourg (Drs
B\l=e'\nichouand Flament), France; Departments of Clinical Research (Dr Lippa and Ms Clineschmidt), Clinical Pharmacology (Drs Buntinx and Brunner-Ferber), and Biostatistics (Ms Panebianco), Merck Sharp & Dohme Research Laboratories, West Point, Pa; and Glaucoma Center, Academic Medical Center, Amsterdam, the Netherlands (Drs Gunning and Greve). Presented in part at the Association for Research in Vision and Ophthalmology Annual Meeting, Sarasota, Fla, May 1, 1989. Reprint requests to Clinical Research, Merck Sharp & Dohme Research Laboratories, West Point, PA 19486 (Dr Lippa).
lowering of intraocular pressure at 8 AM, 12 hours following the evening dose, and through 10 and 6 hours following the 8 AM dose for sezolamide and
MK-927,
respectively. Morning trough (evening) activity as measured by mean percent change in intraocular pressure from prestudy was 9.2% for sezolamide and \m=-\11.1%for MK-927 (\m=-\13.5% and \m=-\9.6%);peak effect occurred 2 hours
after dose administration and was \m=-\19.4%and \m=-\19.2% for sezolamide and MK-927, respectively. From 2 hours after dose administration, sezolamide consistently demonstrated a slightly greater decrease in intraocular pressure than MK-927; however, these differences were
statistically significant. (Arch Ophthalmol. 1991;109:50-53)
not
patients with glaucoma pertension after single-
ocular hy¬ and multipledose administration. It is a thienothiopyran-2-sulfonamide that has shown excellent activity in vitro.1"3 It is a or
See also pp 38 and 46. racemic compound with a single chiral center and thus can be separated into R- and S-enantiomers that are mirror images of one another. The S-enantiomer, sezolamide hydrochloride (previ¬ ously MK-417), is substantially more active than the R-enantiomer.3 The concentration inhibiting human car¬ bonic anhydrase isoenzyme II is 0.54 nmol/L and 44 nmol/L for sezola¬ mide and MK-927, respectively.4 More¬ over, sezolamide is specific for carbon¬ ic anhydrase isoenzyme II (ratio of
Downloaded From: http://archopht.jamanetwork.com/ by a Oakland University User on 06/08/2015
approximately 1400:1, based on ratio of K,s), the isoenzyme of carbonic anhy¬ drase, which is present in the ciliary
processes.5
The ability of MK-927 to effectively lower IOP has been demonstrated in normotensive rabbits as well as in rab¬ bit and monkey models of ocular hy¬ pertension.6"" In contrast with several previously developed topical carbonic anhydrase inhibitors for which good activity in animal models did not carry over to substantial activity in hu¬ mans,91" MK-927 at 2% has been shown to be active in normal subjects and has demonstrated significant efficacy in patients after single- and multiple-dose administration (peak decrease from predose of 25% to 33% at 4 to 6 hours after dose administration11 "; peak de¬ crease from baseline diurnal curve of approximately 20% at 2 hours after dose administration15). Moreover, MK-927 has demonstrated acceptable ocular tolerability together with an absence of significant systemic bio¬ chemical effects."1 The ophthalmic formulations of both MK-927 and sezolamide are isotonic, buffered at pH 5.2, and pre¬ served with benzalkonium chloride. Maximum available concentrations are 2% for MK-927 and 1.8% for sezola¬ mide. MK-927 and sezolamide have been shown to have similar tolerability profiles in normal subjects.1' Singledose sezolamide was shown to be more potent than MK-927 in patients with glaucoma or ocular hypertension; how¬ ever, the difference in activities was not
large.18
This
study was undertaken to assess
Mean Intraocular Pressure
Mean (SD) Intraocular
Time, h
Prestudy
Pressure,
Day
Day 1
mm
Hg Day
4
0·_27.1 1_27.3 ± 2_26.2 ± 4_25.9 ± 6_24.6 ± 8_25.5 ± 10_26.3 ±
2.9_26.2 4.2_24.7 4.8t_24.7 3.5_22.9 ± 4.7 _21.9 ± 4.2 _22.3 4.2_21.2 ± 4.2 _20.9 ± 3.8 _21.1 4.6_20.4 ± 3.6 _20.8 ± 3.7 _20.7 3.5_._^__._j__20.0 3.6_._^_._^_21.4
0·_29.0 1_29.1 2_27.9 4_26.5
4.6_29.4 4.9_26.9 4.0_24.1 3.2_22.9
±
±
± ± ±
±
14
Hydrochloride
1.8% Sezolamide ±
4.4___._22.6
± ± ± ± ± ±
±
4.4 3.6 3.6 3.5 4.5 4.6 4.5
2.0% MK-927
6
25.0 ±2.0
10
25.2 ±2.7
± ±
± ±
5.2_26.9 5.5t_23.6 4.8 _20.9 3.7 _21.4
...
5.2 5.9 ± 4.5 ± 3.4 20.8 ± 3.5 22.1 ± 3:ß 22.8 ± 3.7
5.6t_25.8 5.5 _23.6 2.8 _22.4 2.6 _22.4
±
± ± ±
...
± ±
Placebo 26.6 ± 3.7
28.6 ± 3.6
26.1 ±
2.6t
26.0 ±
3.7
26.3 ± 3.3
27.2 ± 2.8
6_23.6
±
8_24.1
±
10
25.8 ± 3.2t
25.9 ± 4.4
2.6_._^_._^_22.9 3.8__LJ_L^J_22.6
*
± 4.4
± 3.7
24.4 ± 3.8
25.6 ±3.9
Immediately predose on days 1, 4, and 14. tDecrease and percent decrease from prestudy significantly different from ß ßß and percent decrease from prestudy significantly different from ...
...
zero zero
ications of at least 72 hours for parasympathomimetic solutions, at least 8 days for sympathomimetic solutions, and at least 14 days for ß-blockers or any other agents. Exclusion criteria included concomitant systemic or dermatologie medication known to affect IOP, any concurrent ocular thera¬ py other than the study drug, a history of intraocular surgery, best corrected Snellen visual acuity at a distance equal to or worse than 2/10 in both eyes, and recent signs of ocular infection or inflammation.
Study Design This was a four-center, double-masked, randomized, placebo-controlled, parallel study. Treatment regimens consisted of 1.8% sezolamide, 2.0% MK-927, or placebo (common vehicle) administered to each eye at 8 AM and 8 PM for 14 days. Between 2 and 10 days prior to drug administration, a
...
...
hypertension with IOP simulta¬ neously greater than or equal to 24 mm Hg in both eyes at 8, 9, or 10 AM on the prestudy diurnal curve day following a washout period for ocular hypotensive med¬ ocular
(Worse Eye)
(P < .05). (P < .01).
prestudy 10-hour diurnal IOP curve was performed following the appropriate wash¬ out period (8, 9, 10 AM, noon, and 2, 4, and 6 PM). On study days 1 and 4, IOP was measured immediately before and 1, 2, and 4 hours after dose administration. On study day 14, IOP was measured immediately
before and 1, 2, 4, 6, 8, and 10 hours after dose administration, paralleling the pre¬ study diurnal curve times. A 2-week washout period for topical ß-blockers was chosen to limit patient time without medication to approximately 1 month. Potential small residual effects in some patients are well controlled for by the placebo group. Within each center, all mea¬ surements of IOP for a given patient were performed by the same person, applanation tonometry followed instillation of a fluorescein-benoxinate solution, and the same Golclmann applanation tonometer was used. Patients were closely monitored through¬ out the study with repeated evaluation of symptoms, visual acuity, and external and anterior segment signs. Both prestudy and poststudy examinations included dilated ophthalmoscopy and visual field exam¬ ination.
Statistical Methods
Fig 1. —The 1.8% sezolamide hydrochloride treatment group: mean percent change in intraocu¬ lar pressure (IOP) readings (worse eye) from prestudy at the same time. Circles represent day 1 ; squares, day 4; and asterisks, day 14. Hour 0 corresponds to 8 AM; SD range, 7.1% to 13.9%. and compare the relative efficacy of the maximum concentrations of 1.8% sezolamide and 2% MK-927 when given twice daily for a 2-week period. PATIENTS AND METHODS Patient Selection and Entry This study was approved by the appropri¬ ate ethical review board at each of the
participating hospitals and each patient gave his or her informed consent prior to entry into the study. Patients were men or postmenopausal or sterilized women 35 to
80 years of age. Each underwent a medical and ophthalmologic screening examination 2 to 14 days prior to entry into the study. Admission criteria included a history and examination consistent with a diagnosis of bilateral primary open angle glaucoma or
Downloaded From: http://archopht.jamanetwork.com/ by a Oakland University User on 06/08/2015
The primary variables tested were change and percent change in IOP from prestudy values at the same time. Prestudy within-treatment group changes were tested using the matched-pairs t test. Tests for significant differences between treatment groups were based on a linear model. The analysis of variance model used included terms for treatment, iris color,
prior ocular hypotensive therapy, investi¬ gator, and all two-way interactions. All tests were two-sided with type I error set
equal to 0.05. were analyzed both with respect to "average eye" (mean of right and left eye) and "worse eye." Worse eye was de¬ at
Results
fined as follows: (1) the eye with the greater IOP at 8 AM on the prestudy diurnal curve day; (2) if IOP was equal in both eyes at
five
categories
was
as
follows: blue
(n 20); green (n 3); hazel
or light golden brown (n=10); brown (n 12); =
=
=
and dark brown (n 3). The only significant difference be¬ tween treatment groups with regard to the above variables was for that of sex, with significantly more men in the sezolamide treatment group than in the MK-927 and placebo groups (12 in the sezolamide group vs seven in the MK-927 group and nine in the placebo group). However, men and women =
not anticipated to experience substantially different degrees of effi¬ cacy. There were 16 patients in each of were
the three treatment groups.
Intraocular Pressure
Fig 2.—The 2% MK-927 treatment group: mean percent change in intraocular pressures (IOP) (worse eye) from prestudy at the same time. Circles indicate day 1 ; squares, day 4; and asterisks, day 14. Hour 0 corresponds to 8 AM; SD range, 6.6% to 15.3%.
Fig 3. —Mean percent change in intraocular pressure (IOP) (worse eye) from prestudy to day 14 at the same time for all three treatment groups. Closed circles represent 1.8% sezolamide hydrochloride group; squares, 2% MK-927 group; and open circles, placebo group.
prestudy, then the worse eye was that with the greater IOP at 8 AM on day 1, immediately before dose administration; and (3) if IOPs in both eyes were equal at 8 AM on both the prestudy day and on day 1, then the worse eye was defined to be the right eye. Results for the worse eye and the average eye analyses were similar and therefore only the results for the worse eye are given below. The analysis was based on 48 patients 8 AM
who
completed the study per protocol. RESULTS
Forty-eight patients entered and completed the study per protocol (six to 18 patients per center). There
and 20 women. The mean 58.9 years (range, 34 to 74 years). Fourteen of the patients had secondary nonocular diagnoses, the most prevalent being diabetes mellitus (n 5) and hypertension (n 5). Elev¬ en patients had received no prior ther¬ apy, 24 had received only a ß-blocker, and 13 had received a ß-blocker and one or more additional agents (10 re¬ ceived a parasympathomimetic agent; one, an oral carbonic anhydrase inhibi¬ tor; one, guanethidine and epinephrine; and one, a parasympathomimetic, guanethidine, and epinephrine). The distribution by iris color into one of were
age
=
28
men
was
=
Downloaded From: http://archopht.jamanetwork.com/ by a Oakland University User on 06/08/2015
The Table presents the mean IOP data and SDs for each treatment group.
Although prestudy morning
IOPs were generally greater for the MK-927 treatment group, this differ¬ ence was not significant. Figures 1 and 2 graphically depict the data for the 1.8% sezolamide and 2% MK-927 treat¬ ment groups with respect to percent change in IOP from prestudy; Fig 3 compares activity between the three groups on day 14. In the Table and the figures, hour 0 represents 8 AM; hour 1, 9 AM; etc. For both 1.8% sezolamide and 2% MK-927, the percent decrease in IOP from prestudy was significantly differ¬ ent from zero at all postdose times on days 1, 4, and 14 (P
