SURVEY OF OPHTHALMOLOGY VOLUME 41 • SUPPLEMENT 1 * NOVEMBER 1996

Clinical Experience with Brimonidine 0.2% and Tlmolol 0.5% in Glaucoma and Ocular Hypertension

JOEL S. SCHUMAN, MD

New England Eye Center, New Englmut Medical Co#er Hospitals, Tufts University School of Medicine, Boston, Massachusetts, USA

Abstract. The ocular hypotensive efficacy and safety of brimonidine tartrate 0.2%, a highly selective alpha2-adrenergic agonist, was compared with that of timolol 0.5%, a nonselective beta-blocker in two multicenter, randomized, double-masked studies. Combined data from a 12-month completed study and 6-month interim data from an ongoing study are reported. Efficacy and safety were evaluated at baseline, weeks 1 and 2, and months 1, 2, 3, 6, 9, and 12. Intraocular pressure (IOP) was measured at peak (2 hours after the morning dose) and trough (12 hours after the evening dose). Patients (n = 926) instilled either brimonidine tartrate 0.2% or timolol maleate 0.5% twice daily. At peak, the mean decreases from baseline IOP ranged from 5.9 _+ 3.2 mm Hg to 7.6 -+ 3.6 mm Hg for brimonidine and 6.0 +- 3.4 mm Hg to 6.6 _+ 3.6 mm Hg for timolol (p < 0.001 within groups compared with baseline). No significant between-group differences were seen at peak except for weeks 1 and 2 and month 3 (p _< 0.04), when brimonidine had lower mean IOR At trough the mean decreases from baseline ranged from 3.7 -- 4.0 mm Hg to 5.0 -+ 3.0 mm Hg for brimonidine and 5.9 - 3.4 to 6.6 _+ 3.0 for timolol. A significant between- group difference was seen at trough at all visits (< 0.001), when timolol had a lower mean IOP. Brimonidine and timolol showed sustained efficacy. Both drugs were well-tolerated. The brimonidine group had more ocular allergy, oral dryness and conjunctival follicles. The timolol group had more burning and stinging. In the brimonidine group, 38/513 (7.4%) discontinued treatment due to ocular allergy. The timolol group had significantly lower mean heart rate compared to baseline. The effect on blood pressure was minimal for both drugs. Briinonidine showed efficacy similar to timolol and a relatively low rate of ocular allergy. Brimonidine 0.2% administered twice daily is an effective and safe ocular hypotensive agent that maintains IOP-lowering in chronic use. (Surv Ophthalmol 41 [Suppl 1]: $27-$37, 1996)

Key words, alpha2-adrenergic agonist • brimonidine • glaucoma ° ocular hypertension • timolol

Br imonid ine tartrate 0.2% (ALPHAGAN TM, A1- lergan, Inc., I rvine, CA, USA) is a p o t e n t and highly selective alpha2-adrenergic agonist 3'6 that low- ers intraocular pressure (IOP) by decreasing aque- ous product ion and increasing uveoscleral outflow? 4 Alpha2-adrenoreceptor agonists are a class of com- pounds known to reduce IOP, but their widespread use has been limited by side effects such as sedation and hypotension (clonidine) 1° and ocular allergy and tachyphylaxis (apraclonidine). 16"2°'23'~5 Brimonidine differs f rom these earl ier c o m p o u n d s in that it has s ignif icantly h ighe r affinity for the a lpha 2- adrenoceptor.2a'3'13

Brimonidine has been shown to effectively lower IOP in normotens ive , g l aucomatous and ocular hypertensive eyes. A dose-ranging study with 168 pa t ien ts with g l a u c o m a or ocular h y p e r t e n s i o n showed tha t b r i m o n i d i n e 0.2% d e c r e a s e d IOP wi thout significant systemic side effects, s A dos- ing-frequency study in 101 patients showed that twice-daily adminis t ra t ion of the d rug had IOP-

lowering effects similar to that achieved with three times daily administration, and was without signifi- cant ocular or systemic side effects. 21,24a An exercise- induced tachycardia study with 24 healthy volunteers who received one drop of br imonidine 0.2% before exercise stress testing showed no adverse effects on cardiovascular or puhnonary parameters, is

The first reports of the long- term efficacy and safety of the drug indicated that br imonidine 0.2% had IOP-lowering comparable to timolol, no loss of potency over time, and an allergy rate much lower than that repor ted for apraclonidine. 2'° The present repor t combines the data f rom the first, c o m p l e t e d , 1 2 - m o n t h s tudy (Study 1) wi th 6 months of interim data from an ongoing long-term study (Study 2).

Mater ia l s and M e t h o d s

STUDY DESIGN

Two multi-center, double-masked randomized ,

$27

© 1996. Survey of Ophthalmology. (7 Kent Street, Brookline, MA 02146. Tel: 617-566-2138. Fax: 617-566-4019)

$28 Surv Ophthalmol 41 (Suppl 1) November 1996

parallel-group, active-controlled comparison clinical trials were conducted. Protocols for both studies were similar, allowing for pooled analysis. One study was completed at 12 months (Study 1) and the other (Study 2) is ongoing. Patients instilled either brimonidine 0.2% or timolol maleate 0.5% twice daily for the study duration. Examinations were performed at baseline, weeks 1 and 2, and months 1, 2, 3, 6, 9 and 12.

PATIENT SELECTION

Adult patients who had primary open-angle glau- coma or ocular hypertension in both eyes and who were receiving no more than two ocular hypotensive agents were recruited for the studies. The washout period was 4 days for pilocarpine or carbonic anhy- drase inhibitors, 2 weeks for topical alpha-adrenergic agonist agents, and 4 weeks for topical beta-adrener- gic blocking agents. Patients were required to have post-washout IOP <_23 mm Hg and <35 mm Hg and best-corrected visual acuity of 20/100 or better in each eye. The study was approved by the institutional re- view board of each participating institution and writ- ten informed consent was obtained from each patient.

The systemic exclusion criteria included uncon- trolled systemic disease, pregnancy, lactation or childbearing potential, contraindications to alpha- adrenoceptor agonist or beta-adrenoceptor antago- nist therapy, abnormally low or high heart rate or blood pressure for age, known hypersensitivity to any of the ingredients in the study medication or diagnostic agents to be used in the study, alteration of existing chronic therapy that could have a sub- stantial effect on IOP ocular activity of the study drugs, treatment with adrenergic-augmenting psy- chotropic drugs, and participation in a current or recent (last 30 days) research study.

Ophthalmic exclusions were corneal abnormali- ties, contact lens wear, active ocular disease, dry eye, Sj6gren syndrome, keratitis sicca, required use of other ocular medications, IOP asymmetry of more than 5 mm Hg, extensive visual field loss, laser treatment or ocular surgery within the past 6 months, and optic nerve head cup:disk ratio of <_0.8 in either eye.

DRUG ADMINISTRATION

At baseline, the patients were randomly assigned to receive, in a masked fashion, one drop of either brimonidine tartrate 0.2% or timolol 0.5% sterile ophthalmic solution instilled into each eye twice daily at 12-hour intervals. In Study 1, the randomization was 1:1 for brimonidine and timolol. In Study 2, which is ongoing, more patients were enrolled into the brimonidine group and the randomization was 3:2. The increased number of patients in the brimonidine group allow for additional data to be

SCHUMAN

collected on brimonidine.

EFFICACY AND SAFETY VARIABLES

The primary efficacy variable was intraocular pres- sure. Cup:disk ratios and visual fields were second- ary efficacy variables. IOP was measured at peak (2 hours after the morning instillation) and trough (12 hours after the evening administration).

Patients were monitored for adverse events and for other ocular and systemic safety parameters. At each visit, patients were queried specifically as to their ocular comfort (i.e., burning/stinging, blurring, foreign body sensation or photophobia) and general comfort (i.e., headache, dry mouth, fatigue/drowsiness). All adverse events were reported regardless of causality.

At each visit, biomicroscopy was performed and abnormalities recorded, visual acuity was measured with a Snellen chart, and pupil size with a pupillo- meter or millimeter ruler. At baseline and months 6 and 12, an automated perimetry test was used to evaluate visual field, direct or indirect ophthalmo- scopy was used to evaluate the fundus and optic nerve head, and the Schirmer tear test was performed to evaluate tear function. Heart rate and blood pres- sure were measured at each visit with patients in a resting position. Blood samples were obtained at baseline and months 6 and 12 for assessment of hematology parameters and blood chemistry.

STATISTICS

The categorical data for demographics was ana- lyzed by the Cochran-Mantel-Haenszel method. 1~ Subject age, IOP, cup:disk ratio, ocular safety vari- ables (pupil size, Schirmer tear test, visual acu- ity) and systemic safety variables were analyzed using two-way analysis of variance (ANOVA). Mean changes from baseline were calculated using a paired t-test. The null hypothesis, that there was no change from baseline, was tested against the two-sided al- ternate hypothesis that there was a change. The over- all mean change from baseline is calculated for the combined data only (up to six months). Visual fields were analyzed by Chi-square and biomicroscopy, oph- thalmoscopy and symptoms of general discomfort and ocular discomfort were analyzed by Chi-square or Fisher's exact test.

Statistical significance was set at p < 0.05. Data are reported as the mean plus or minus the stan- dard error (IOP) or plus or minus the standard de- viation (safety variables).

R e s u l t s

BASELINE DEMOGRAPHICS

The total enrolhnent in Study 1 was 443, with 221 in the brimonidine-treated group and 222 in the

CLINICAL EXPERIENCE W I T H B R I M O N I D I N E AND T I M O L O L $29

t imolol- treated group. T h e total enro l lment in Study 2 was 483, with 292 in the br imonidine- t rea ted group and 191 in the t imolol- t reated group (reflecting an uneven randomiza t ion of 3:2). Overall , 513 pat ients par t ic ipa ted in the b r imon id ine groups and 413 in the t imolol groups, for a total o f 926 in the two stud- ies. O f these, 837 me t the protocol criteria for effi- cacy evaluation, 466 in the b r imon id ine group and 371 in the t imolol group. All 926 par t ic ipants were included in the analysis o f safety.

Table 1 shows the combined d e m o g r a p h i c char- acteristics o f bo th compar i son studies. Open-ang le g laucoma was the most c o m m o n diagnosis, occur- r ing in 58% of all pat ients . Ocula r hype r t ens ion was seen in 39% of pa t ien t s , a n d a visual f ield defect in one eye and no field defect in the o ther occurred in 3% of patients. T h e m e a n age overall was 62.4 +- 11.0 and the m a l e : f e m a l e ra t io was 50:50. Most pa t i en t s were white, with d a r k iris color (hazel or brown). No s ignif icant be tween- g roup differences were seen in age, race, sex, iris color or diagnosis.

Fif ty- three pe rcen t o f pa t ien ts in the b r imon i - dine g roup and 55% of those in the t imolol g roup had been t rea ted previously with a beta-blocker .

INTRAOCULAR PRESSURE

In Study 1, which was comple t ed at 12 months

TABLE 1

Demographics of Patients Evaluated for Efficacy by Treatment Group. *

(Combined 12-month Data from Study 1 and 6-month Data from Study 2)

Variable

Treatment Group Brimonidine 0.2% Timolol 0.5%

(n = 466) (n = 371) Age (No. i SD) 62.9 + 11.2 61.8 ± 10.8

Range (No.) 27.9-86.4 32.8-83.4 Gender

Male 222(47.6%) 199(53.6%) Female 244(52.4%) 172(46.4%)

Race White 381(81.8%) 300(80.9%) Black 50(10.7%) 36 (9.7%) Hispanic 22 (4.7%) 26 (7.0%) Asian 10 (2.1%) 5 (1.3%) Other t 3 (0.6%) 4 (1.1%)

Iris Color Blue 163(35.0%) 128(34.5%) Green 21 (4.5%) 15 (4.0%) Hazel 84(18.0%) 62(16.7%) Brown 195(41.8%) 163(43.9%) Other~ 3 (0.6%) 3 (0.8%)

Diagnosis Open-angle glaucoma 272(58.4%) 216(58.2%) Ocular hypertension 180(38.6%) 144(38.8%) Both§ 14 (3.0%) 11 (3.0%) *The demographic characteristics of all 926 patients enrolled

were similar to those presented in this efficacy-evaluable subset. 1"Other race: Hawaiian, Arabic, Yemeni, Iraqi, Anglo-Asian ~Other eye color: gray, blue-gray, blue-green and mixed §One eye with open-angle glaucoma and other eye with ocular

hypertension.

26

" I -

E E

:3

13,.

L "E

24

22

20

18

16

= Brimonidine 0.2% ---o---Timolol 0.5%

J_

I I I I I I 2 4 6 8 10 12

Time (Months)

Fig. 1. Effect ofbrimonidine 0.2% and timolol 0.5% at peak (2 hours after the morning instillation of the drug) in two long- term studies. Figure shows combined data from one 12-month completed study (Study 1) and 6 months of an ongoing study (Study 2). Asterisks indicate statistically significantly lower IOP with brimonidine at week 1 (p = 0.011 ), week 2 (p = 0.001), and month 3 (p = 0.043). Lines show mean IOP and vertical bars the standard error of the means.

$30 Surv Ophtha lmo141 (Suppl 1) November 1996

a n d for which all 12 m o n t h s results are r epor t ed , p e a k I O P was m e a s u r e d at basel ine, week 2, a n d m o n t h s 1, 3, 6, a nd 12. T r o u g h I O P was m e a s u r e d at basel ine, weeks 1 a n d 2, a n d m o n t h s 1, 2, 3, 6, 9, a n d 12. T h e week 2 p e r i o d a nd t rough da ta were o b t a i n e d in a subset o f the popu l a t i on .

I n S tudy 2, wh ich is o n g o i n g a n d for which 6 m o n t h s o f in t e r im da ta are p resen ted , p e a k I O P was m e a s u r e d at b a s e l i n e , weeks 1 a n d 2, a n d m o n t h s 1, 3, a n d 6. T r o u g h I O P was m e a s u r e d at baseline, weeks 1 a n d 2, a n d m o n t h s 1, 2, 3, a n d 6.

T h e base l ine ( h o u r 0) I O P in the b r i m o n i d i n e g r o u p (n = 221) was 24.9 m m H g a n d in the t imolol g r o u p (n = 222) was 24.6 m m Hg. T h e be tween- g r o u p di f ferences were no t statistically significant.

SCHUMAN

At p e a k (2 hou r s af ter the m o r n i n g dose), the m e a n decreases f rom basel ine I O P were statistically sig- n i f icant at all fol low-up visits in b o t h g roups (Fig. 1). M e a n I O P decreases r a n g e d f rom 5.9 -+ 3.2 m m H g to 7.6 -+ 3.6 m m H g for b r i m o n i d i n e (p < 0.001) a n d 6 .0 -+ 3.4 m m H g to 6.6 -+ 3.6 m m H g fo r t imolol (p < 0.001). N o s ignif icant d i f fe rence was seen be tween g roups except fo r weeks 1 and 2 a n d m o n t h 3 (p _< 0.04), w h e n b r i m o n i d i n e - t r e a t e d pa- tients had grea te r m e a n decreases than those t rea ted with t imolol . M e a n I O P c h a n g e s f rom basel ine at p e a k are shown in Table 2 for the c o m b i n e d stud- ies, Table 3 for S tudy 1, a n d Table 4 for S tudy 2.

T h e m o r n i n g t r ough (hou r 12) base l ine I O P for bo th g roups was the same, 25.9 m m Hg. M e a n de-

TABLE 2

Intraocular Pressure (lOP) Baseline and Mean Change from Baseline at 2-hour Peak

(Combined 12-month Data from Study 1 and 6-month Data from Study 2) Brimonidine 0.2%

Timepoint mm Hg SD Range No. Pts. mm Hg SD Timolol 0.5%

Range No. Pts. p-value Baseline 24.93 3.22 Week 1 -7.57 3.58 Week 2 -7.14 3.40 Month 1 -6.64 3.34 Month 3 -6.83 3.38 Month 6 -6.30 3.50 Month 12 -5.92 3.19

16.0 to 36.0 410 24.64 3.08 -19.5 to +3.5 233 -6.64 3.60 - 18.5 to + i .0 284 -6.09 3.46 -18.5 to +7.0 373 -6.31 3.40 -21.0 to +3.0 338 -6.29 3.53 -17.5 to +6.0 297 -6.05 3.56 -13.5 to +0.5 103 --6.01 3.35

15.5 to 34.0 340 0.267 -19.5 to +2.0 164 0.011 -17.0 to +3.0 211 0.001 -16.0 to +3.0 319 0.262 -16.0 to +10.5 309 0.043 -16.0 to +5.5 291 0.442 -14.0 to +1.5 135 0.843

TABLE 3

Intraocular Pressure (lOP) Baseline and Mean Change from Baseline at 2-hour Peak

(12-month Data from Study 1) Brimonidine 0.2%

Timepoint mm Hg SD Range No. Pts. mm Hg SD Timolol 0.5%

Range No. Pts. p-value Baseline 24.75 2.97 16.0 to 34.5 170 Week 2 --6.83 3.42 -15.5 to +1.0 60 Month 1 -6.40 3.28 -14.5 to +7.0 155 Month 3 -6.97 3.06 -17.0 to +1.0 140 Month 6 -6.12 2.93 -13.5 to +4.0 124 Month 12 -5.92 3.19 -13.5 to 4).5 103

24.56 3.04 -5.21 3.59 -6.25 3.29 --6.12 3.60 -6.30 3.45 -6.01 3.35

15.5 to 34.0 173 0.701 -12.5 to +3.0 60 0.032 -15.5 to +2.0 163 0.480 -16.0 to +10.5 158 0.013 -16.0 to +3.5 147 0.806 -14.0 to +1.5 135 0.808

TABLE 4

lntraocular Pressure (lOP) Baseline and Mean Change from Baseline at 2-hour Peak

(6-month Data from Study 2) Brimonidine 0.2%

Timepoint mm Hg SD Range No. Pts. mm Hg Timolol 0.5%

SD Range No. Pts. p-value Baseline 25.06 3.38 Week 1 -7.57 3.58 Week 2 -7.23 3.40 Month 1 -6.80 3.38 Month 3 -6.74 3.60 Month 6 -6.44 3.86

17.5 to 36.0 240 -19.5 to +3.5 233 -18.5 to 0.0 224 -18.5 to +1.0 218 -21.0 to +3.0 198 -17.5 to +6.0 173

24.73 -6.64 -6.45 -6.37 -6.47 -5.80

3.12 3.60 3.36 3.52 3.46 3.66

16.5 to 33.5 167 0.228 -19.5 to +2.0 164 0.004 -17.0 to +0.5 151 0.007 -16.0 to +3.0 156 0.111 -15.5 to +3.0 151 0.335 -16.0 to +5.5 144 0.171

CLINICAL E X P E R I E N C E W I T H B R I M O N I D I N E A N D T I M O L O L $31

26

24 A

22

ta

20 '-s ¢d, O

e--

18

16

-- Brimonidine 0.2% ---o---Timolol 0.5%

I I I I I I 0 2 4 6 8 10 12

Time (Months)

Fig. 2. Effect ofbrimonidine 0.2% and timolol 0.5% at trough (12 hours after the evening instillation of the drug) in two long- term studies. Figure shows combined data from one 12-month completed study (Study 1) and 6 months of an ongoing study (Study 2). Asterisks indicate statistically significantly lower IOP with timolol at all visits (p _< 0.001). Lines show mean IOP and vertical bars the standard error of the means.

c reases f r o m b a s e l i n e at t r o u g h were s ta t i s t ica l ly sig- n i f i c a n t in b o t h t r e a t m e n t g r o u p s a t a l l f o l l o w u p visi ts (Fig. 2). M e a n dec rea se s f r o m b a s e l i n e r a n g e d f r o m 3.7 +_ 4.0 m m H g to 5 .0 _+ 3.0 m m H g fo r b r i m o n i d i n e (p < 0 .001) a n d 5.9 + 3.4 m m H g to 6.6 _+ 3.0 m m H g for t i m o l o l (p < 0.001). T h e m e a n dec rea se s in I O P were g r e a t e r wi th t i m o l o l t h a n wi th b r i m o n i d i n e , b u t t h e b e t w e e n - g r o u p d i f f e r e n c e s were n o t c l in ica l ly s ign i f i can t (-<2 m m Hg) . M e a n I O P c h a n g e s f r o m b a s e l i n e at t r o u g h a re shown in Tab le 5 for t he c o m b i n e d s tud ies , Tab le 6 for S tudy

1, a n d Tab le 7 for S tudy 2. B o t h d r u g s s h o w e d a s u s t a i n e d t h e r a p e u t i c ef fec t

a t b o t h p e a k a n d t r o u g h . N o I O P d r i f t was s e e n ove r t he 12 m o n t h s o f S tudy 1 a n d f irst 6 m o n t h s o f S tudy 2, wh ich is o n g o i n g .

SECONDARY EFFICACY VARIABLES

M e a n c h a n g e s f rom b a s e l i n e c u p : d i s k r a t i o val- ues s h o w e d n o s ign i f i can t d i f f e r ences b e t w e e n t h e b r i m o n i d i n e a n d t i m o l o l t r e a t m e n t g r o u p s ove r t he s tudy p e r i o d s .

TABLE 5

Intraocular Pressure (lOP) Baseline and Mean Change from Baseline at 12-hour Trough

(Combined 12-month Data from Study I and 6-month Data from Study 2) o Brimonidine 0.2

Timepoint mm Hg SD Range No. Pts. mm Hg SD

Timolol 0.5% Range No. Pts. p-value

Baseline 25.90 2.75 Week 1 -4.99 2.95 Week 2 -4.56 2.95 Month 1 -4.14 3.02 Month 2 -4.21 3.14 Month 3 -4.22 3.14 Month 6 -3.83 3.38 Month 9 -4.20 3.51 Month 12 -3.67 3.98

22.5 to 34.5 460 -16.5 to +6.0 436 -16.0 to +4.0 317 -13.5 to +11.0 422 -13.5 to +11.5 392 -13.5 to +5.0 384 -12.5 to +7.0 328 -12.5 to +6.5 119 -11.5 to +8.5 106

25.86 2.80 -6.45 3.01 -6.08 3.05 -6.37 3.05 -6.63 3.04 -6.26 3.19 -6.25 3.17 -6.16 3.10 -5.88 3.38

23.0 to 34.0 368 0.895 -17.0 to +1.5 348 <0.001 -15.0 to +2.5 229 <0.001 -16.5 to +1.5 350 <0.001 -15.0 to +2.5 336 <0.001

16.0 to +4.0 331 <0.001 -15.0 to +3.5 321 <0.001 -14.0 to +4.0 153 <0.001

16.0 to +6.5 149 <0.001

$32 Surv Ophthalmol 41 (Suppl 1) November 1996 SCHUMAN

TABLE 6

lntraocular Pressure (lOP) Baseline and Mean Change from Baseline at 12-hour Trough

(12-month Data from Study 1) Brimonidine 0.2%

Timepoint mm Hg SD Range No. Pts. mm Hg SD Timolol 0.5%

Range No. Pts. p-value Baseline 25.80 2.31 Week 1 -5.32 2.90 Week 2 -4.45 2.82 Month 1 -4.35 3.27 Month 2 -4.26 3.25 Month 3 -4.49 3.10 Month 6 -3.89 3.40 Month 9 -4.20 3.51 Month 12 -3.67 3.98

23.0 to 32.0 186 25.87 2.81 -16.5 to +6.0 171 ~ .47 3.00 -10.0 to +2.0 63 -5.81 2.89 -13.5 to +11.0 172 ~ .57 2.92 -11.5 to +11.5 153 ~ .84 3.03 -12.0 to +3.5 154 ~ .32 3.40 - l l .0 to +6.0 130 ~ .40 3.21 -12.5 to +6.5 119 ~ .16 3.10 -11.5 to +8.5 106 -5.88 3.38

23.0 to 34.0 188 0.662 -13.5 to +1.5 174 <0.001 -12.0 to +1.5 65 0.030 -16.5 to +1.0 179 <0.001

15.0 to +2.5 171 <0.001 -16.0 to +4.0 168 <0.001 -15.0 to +3.5 162 <0.001 -14.0 to +4.0 153 <0.001 -16.0 to +6.5 149 <0.001

TABLE 7

Intraocular Pressure (lOP) Baseline and Mean Change from Baseline at 12-hour Trough

(6-month Data from Study 2) Brimonidine 0.2%

Timepoint mm Hg SD Range No. Pts. Timolol 0.5%

mm Hg SD Range No. Pts. p-value Baseline 25.96 3.01 22.5 to 34.5 274 Week 1 -4.78 2.96 -16.5 to +4.5 265 Week 2 -4.59 2.98 -16.0 to +4.0 254 Month 1 -3.98 2.84 -11.5 to +8.0 250 Month 2 -4.18 3.07 -13.5 to +3.0 239 Month 3 -4.04 3.15 -13.5 to +5.0 230 Month 6 -3.79 3.37 -12.5 to +7.0 198

25.85 2.80 23.0 to 34.0 180 0.273 ~i.44 3.02 -17.0 to +0.5 174 <0.001 ~i.18 3.12 -15.0 to +2.5 164 <0.001 ~ .16 3.18 -14.0 to +1.5 171 <0.001 ~i.42 3.04 -14.5 to +2.5 165 <0.001 ~ .20 2.97 -14.5 to +2.5 163 <0.001 ~ .10 3.12 -15.0 to +2.5 159 <0.001

No change in visual acuity occurred in 488 (95.1%) of pat ients in the b r imon id ine t r ea tment g roup and 385 (93.2%) o f pa t ien ts in the t imolol t r e a t m e n t group (p = 0.137). Worsening o f visual acuity o f two lines or more occurred in 24 (4.7%) of pat ients in the b r imon id ine group and 28 (6.8%) of those in the t imolol group. These findings can be assumed to be not drug-re la ted and may have been associ- a ted with the progress ion o f cataracts, which can be expec ted given the d e m o g r a p h i c profile o f this pa- tient populat ion. T h e vast majori ty (346/369; 93.8%) of visual fields were u n c h a n g e d or within 5 dB of baseline in bo th t r ea tment groups in bo th studies.

Results f rom the Schi rmer tear test showed a clini- cally significant decrease f rom baseline in 89 of 500 pat ients (17.8%) tested in the b r imon id ine g roup and 78 of 403 pat ients (19.4%) in the t imolol group. A clinically significant decrease was def ined as ei- ther a basel ine < 10 m m and follow-up < 5 m m , or a baseline > 10 m m , follow-up < 10 m m and a de- crease f rom baseline >5 mm. T h e be tween-group difference was not significant (p = 0.550). Overall , there were negligible m e a n changes f rom baseline in bo th t r ea tment groups o f bo th studies.

ADVERSE EVENTS

T h e overall incidence of adverse events was simi- lar in bo th t r ea tmen t g roups in bo th studies. No serious t r ea tmen t -as soc ia t ed adverse events were r epor t ed or observed in any patient .

Table 8 shows the side effects in bo th t r ea tment groups in bo th studies. U p o n specific inquiry, the mos t c o m m o n l y r e p o r t e d adverse events in bo th groups were dry mouth , ocular hyperemia , burning/ stinging, headache, and foreign body sensation.

Dry mou th , ocular allergic reac t ions and con- junct ival follicles were r epor t ed significantly more f r e q u e n t l y in p a t i e n t s r e c e i v i n g b r i m o n i d i n e (p < 0.001), while burn ing / s t ing ing was r e p o r t e d m o r e often in t imolol- t reated pat ients (p < 0.001).

Ocular allergic reactions, which were def ined by the investigators as pat ients who had an allergic re- sponse to the medicat ion, such as allergic conjunc- tivitis, allergic blepharoconjunctivi t is , and/or folli- cular conjunctivitis, were seen in 49 (9.6%) of patients t reated with br imonid ine , and caused discontinua- t ion of the d rug in 38 (7.4%). N o n e o f the t imolol- t reated pat ients deve loped ocular allergy and very few were t e rmina ted f rom ei ther study for any rea-

CLINICAL EXPERIENCE WITH BRIMONIDINE AND TIMOLOL

TABLE 8

Summary of Adverse Events by Treatment Group (Combined 12-month Data from Study 1 and 6-month Data from Study 2)

$33

Brimonidine 0.2% Timolol 0.5% (n = 513) (n = 413)

Overall Exited Overall Exited Adverse Events* No. (%) No. (%) No. (%) No. (%) p-value Ocular

Allergy1" 49 (9.6) 38 (7.4) 1 (0.2) 1 (0.2) <0.001 Blurred Vision 90 (17.5) 4 (0.8) 83 (20.1) 2 (0.5) 0.322 Burning/Stinging 123 (24.0) 3 (0.6) 168 (40.7) 1 (0.2) <0.001 Corneal Staining/Erosion 41 (8.0) 0 (0.0) 44 (10.7) 0 (0.0) 0.163 Conjunctival follicles 40 (7.8) 0 (0.0) 12 (2.9) 0 (0.0) 0.001 Foreign body sensation 87 (17.0) 1 (0.2) 62 (15.0) 0 (0.0) 0.423 Hyperemia 135 (26.3) 5 (1.0) 95 (23.0) 0 (0.0) 0.246 Pruritus 52 (10.1) 1 (0.2) 36 (8.7) 0 (0.0) 0.464

Systemic Dry mouth 154 (30.0) 7 (1.4) 64 (15.5) 1 (0.2) <0.001 Fatigue/drowsiness 81 (15.8) 13 (2.5) 56 (13.6) 1 (0.2) 0.342 Headache 96 (18.7) 5 (1.0) 78 (18.9) 1 (0.2) 0.947 *Data reflect events with an incidence of _> 10% or those with a significant between-group difference. Lens and fundus

pathologies were excluded as the incidence was similar in both groups and assumed not to be drug related. ?Allergy = allergic blepharitis, blepharoconjunctivitis or conjunctivitis; ocular allergic reaction; follicular conjunctivitis

son. Th i s m a y be e x p l a i n e d by the se lec t ion bias o f the studies.

Mydrias is a n d eyel id re t rac t ion , c o m m o n l y seen with ap r ac lon id ine , 7 were no t seen in e i the r study.

SYSTEMIC SAFETY

N o clinically s ignif icant c h a n g e s in systolic b l o o d

p ressure or h e a r t ra te were n o t e d in any pa t i en t . Fig. 3 shows h e a r t ra tes for b o t h d rugs a n d Fig. 4 shows systolic a n d diastol ic b l o o d pressures .

Pat ients rece iv ing t imolol e x p e r i e n c e d statistically s ignif icant m e a n decreases f r o m base l ine h e a r t ra te at every s chedu led fol low-up visit ( -1 .8 to - 3 . 0 bea t s p e r m inu t e ; p < 0.001). M e a n h e a r t r a t e r e m a i n e d

76

~" 74 t -

F=

72

m 70 -i- .

68

-- Brimonidine 0.2% ---o---Timolol 0.5%

- - . . . . . . . . -

*

0 2 4 6 8 10 12

Time (Months)

big. 3. Effect ofbrimonidine 0.2% and timolol 0.5% on heart rate in two long-term studies. Figure shows combined data from one 12-month completed study and 6 months of an ongoing study. Asterisks indicate statistically significantly lower heart rate with tirnolol 0.5% (p _< 0.042) at all time points except month 9, which had data from first study only. Lines show mean heart rate and vertical bars the standard deviation.

$34 Surv Ophthalmol 41 (Suppl 1) November 1996 SCHUMAN

145 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

"1"

E E

:3

13. "13 0 0

m

El

140

135

130

-- Brimonidine 0.2%---o---Timolol 0.5%

125 , , . . . .

0 2 4 6 8 10 12

Time (Months)

Fig. 4A. Effect of brimonidine 0.2% and timolol 0.5% on systolic blood pressure in two long-term studies. Figure shows combined data from one 12-month completed study and 6 months of an ongoing study. In the brimonidine-treated group, the standard deviations for systolic blood pressure ranged from 0.80 to 1.80 mm Hg. In the timolol-treated group, the standard deviations ranged from 0.88 to 1.36 mm Hg. Lines show mean blood pressure and vertical bars the standard deviation.

relatively unchanged in patients receiving brimoni- dine (-0.1 to -0 .5 beats pe r minute; p _> 0.146). M e a n d e c r e a s e s we re s i g n i f i c a n t l y g r e a t e r (p > 0 .042) in the t i m o l o l g r o u p t h a n in the br imonidine group at every follow-up visit except mon th 9.

Mean changes from baseline in systolic and dia- stolic blood pressure in bo th t rea tment groups in both studies were not clinically significant. T h e ef- fect on systolic b lood pressure was limited to a mean change ranging from -2.27 to +0.64 mm H g for br imonidine and -1.86 to +0.46 mm Hg for timolol. No significant between-group differences were seen at any t ime point. Mean changes in diastolic blood pressure r a n g e d f rom -0 .9 to -1 .7 m m Hg for b r imonid ine and -0.2 to -1 .3 mm Hg for timolol. B r i m o n i d i n e - t r e a t e d pa t ien ts had g rea te r m e a n decreases in diastolic b lood pressure than those t reated with timolol at months 1 (p = 0.028) and 6 (p = 0.042). In bo th t rea tment groups, there were

sporadic incidences of significant changes in b lood pressure. In this study popula t ion, these changes had no clinical significance.

Al though several statistically significant within- g roup changes f rom base l ine l abora to ry values, inc luding b lood l ipid levels, occu r r ed with bo th br imonid ine and timolol t reatment , these changes remained within normal range and were not clini- cally significant.

Discussion

T h e results of these combined studies show that br imonidine , 0.2%, given twice daily as mono the r - apy in patients with glaucoma or ocular hyper ten- sion, has IOP-lowering effects comparable to timolol and no loss o f efficacy for up to 1 year. At the 2-hour peak, b r imonid ine had significantly lower IOP than timolol at weeks 1 and 2 and m o n t h 3. At the 12-hour trough, timolol had _< 2 m m Hg greater IOP-lowering effect than br imonidine.

CLINICAL EXPERIENCE W I T H B R I M O N I D I N E AND TIMOLOL $35

"I-

E E

== t~ .= Q_

"10 O O rn

90

85

80

75

70

-= Brimonidine 0.2%---o---Timolol 0.5%

~ - - - - - - - " " ~ - - ~ ' " ~ ~ - i i i i i i . . . . I

~t

| | l l | i

0 2 4 6 8 10 12

Time (Months)

Fig. 4B. Effect ofbrimonidine 0.2% and timolol 0.5% on diastolic blood pressure in two long-term studies. Asterisks indicate statistically significantly lower diastolic blood pressure with brimonidine at month 1 (p = 0.028) and month 6 (p = 0.042). For diastolic blood pressure the standard deviations ranged from 0.45 to 1.05 mm Hg for the brimonidine group and 0.50 to 0.78 mm Hg for the timolol group. Lines show mean blood pressure and vertical bars the standard deviation.

Brimonidine had minimal effect on cardiovascu- lar parameters and a low rate of ocular allergy. A relatively low incidence of side effects was seen over- all in the present study, despite the fact that the protocol called for eliciting many of the side ef- fects commonly associated with alpha 2 agonists or beta-blockers. Ocular allergy, dry mouth and conjunctival follicles were seen more frequently with brimonidine, while burning and stinging was reported more frequently with timolol.

The timolol group in the present study had low incidences of side effects and a low number of pa- tients who exited the study because of adverse events (Table 8). The study design was biased in favor of beta-blockers because the majority of patients had been exposed to topical beta-blockers just prior to enrollment. This may explain why adverse events typically associated with beta-blocker therapy were not observed in this group.

The ocular allergy rate for brimonidine in this study (9.6%) was significantly less than that previ- ously reported for apraclonidine. Apraclonidine 0.5% caused ocular allergy severe enough to require discontinuation of the drug in 15% to 36% of pa- tients in clinical trials? ~ The mean follow-up in one trial was 5.6 months (range 2-15 months). 5 Other

studies, from 8 weeks to 24 months in duration, showed ocular allergy rates ranging from 22% to 30%. 1,16,17,19,22 Ocular al lergy associa ted with apraclonidine 1% caused discontinuation of the drug in up to 48% of patients, with a mean latency period to onset of allergy of 4.7 months. 4

The IOP-lowering efficacy ofbrimonidine and its lower rate of ocular allergy versus apraclonidine may be due to the difference in chemical structures, brimonidine's selectivity for the alpha 2 over the al- pha I receptors and the fact that it is a more stable compound than apraclonidine. Brimonidine has a quinoxaline ring (double ring structure) that is be- lieved to enhance its alpha 2 selectivity? 4 Brimoni- dine is almost 1000-fold selective for the alpha 2 versus the alpha~ receptors, which minimizes alpha~ mediated side effects, including vasoconstriction? In contrast, clonidine and apraclonidine are only 100-fold selective for the alpha s versus the alpha~ receptors? Additionally, brimonidine and clonidine are oxidatively stable, while apraclonidine has an oxidation potential similar to known allergy- inducing agents. 15

In the studies presented here, brimonidine had no negative effect on heart rate, a clinically insig- nificant effect on systemic blood pressure, and caused

$36 Surv Ophthalmol 41 (Suppl 1) November 1996

no change f rom no rm a l b lood lipid levels. As an al- phaz agonist , it would not be expec ted to cause bronchoconstr ic t ion, and indeed, does not have an adverse effect on respiratory function. TM

T h e clinical safety and efficacy profile o fb r imon i - dine suggests its use as monotherapy , part icularly in pat ients with a relative or absolute contraindica- tion to beta-blockers. Addi t ional studies should be under taken to explore the potent ia l o f b r i m o n i d i n e as an addit ive agent in pat ients for whom concom- itant therapy is appropr ia te .

C o n c l u s i o n

Brimonidine 0.2% instilled twice-daily effectively lowered elevated IOP in pat ients with open-ang le g laucoma or ocular hyper tens ion. T h e ocular hy- potensive efficacy of b r imon id ine was comparab le to tha t o f t imolo l . T h e I O P - l o w e r i n g e f fec t o f b r imon id ine was sustained for up to 12 months . Br imonid ine was well to lera ted by patients, evoked a low allergic response, and had a favorable ocular and systemic safety profile.

Study Participants and Sites

Study 1. Diane Albracht, MD, Castro Valley, California Walter Atlas, MD, Nalle Clinic; Charlotte, North Carolina Howard Barnebey, MD, University of Washington;

Seattle, Washington Neil Chopin, MD, US Naval Hospital; San Diego, Cali-

fornia E. Randy Craven, MD, Glaucoma Associates; Denver,

Colorado Ronald Gross, MD, Baylor College of Medicine; Houston,

Texas Stanley Hersh, MD, Waterbury, Connecticut Barry Horwitz, MD, Houston, Texas Robert Jones, MD, Newport Beach, California L. Jay Katz, MD, Wills Eye Hospital; Philadelphia,

Pennsylvania Itamar Klemperer, MD, Ben-Gurion University of the

Negev; Beer-Sheva, Israel Larry Labarta, MD, Miami Beach, Florida Kathleen Lamping, MD, South Euclid, Ohio Norman Levy, MD PhD, Florida Ophthalmic Institute;

Gainesville, Florida Howard E Perell, MD, North Arundal Physicians Cen-

ter; Glen Burnie, Maryland Michael Rotberg, MD, Charlotte EENT Associates;

Charlotte, North Carolina Joel S. Schuman, MD, New England Eye Center; Boston,

Massachusetts Les Siegel, MD, Glaucoma Center of Michigan;

Southfield, Michigan David Silverstone, MD, New Haven Connecticut Frank Sloan, MD, Myrtle Beach, California Richard Sturm, MD, Lynbrook, New York Stuart Terry, MD, South Texas Cataract and Glaucoma

Center; San Antonio, Texas Christopher Tortora, MD, Hawaiian Eye Center; Wahiawa,

Hawaii

SCHUMAN

Jacob Wilensky, MD, University of Illinois at Chicago; Chicago, Illinois

Thom Zimmerman, MD, University of Louisville; Louisville, Kentucky

Study 2. Mark B. Abelson, MD, North Andover, Massachusetts A. Gordon Balazi, MD, Montr6al, Quebec, Canada Cecil C. Beehler, MD, Fort Myers, Florida J. Elliott Blaydes, MD, Bluefield, West Virginia Anne M.V. Brooks, MD PhD, East Melbourne, Australia Louis Cantor, MD, Indiana Univ. Med. Ctr., Indianapolis,

Indiana David L. Cooke, MD, St. Joseph, Michigan Andrew C.S. Crichton, MD, Calgary, Alberta, Canada Monte Dirks, MD, Fitzsimons Army Med. Ctr., Aurora,

Colorado Richard A. Fichman, MD, Manchester, Connecticut Robert J. Foerster, MD, Colorado Springs, Colorado Douglas Gaasterland, MD, Univ. Ophthal Consultants,

Washington, DC Ivan Goldberg, MB, Sydney, Australia Benjamin Hasty, MD, Panama City, Florida Oscar Kasner, MD, Montr6al, Quebec, Canada Raymond P. LeBlanc, MD, Nova Scotia Eye Centre,

Halifax, Canada Richard A. Lewis, MD, Sacramento, California James McCulley, MD, University of Texas, Dallas, Texas Schlomo Melamed, MD, Chaim Sheba Med. Ctr.,

Tel-Hashomer, Israel Frederick Mikelberg, MD, Vancouver, Canada John C. Morrison, MD, Oregon Health Sci. Univ., Port-

land, Oregon Thomas K. Mundorf, MD, Charlotte, North Carolina Paul Murphy, MD, Saskatoon, Saskatchewan, Canada Franklin H. Spirn, MD, Clark, New Jersey Robert Stamper, MD, San Francisco, California Uriel Ticho, MD, Hadassah Univ. Hospital, Jerusalem,

Israel David P. Tingey, MD, Ivey Inst. Ophthalmol, London,

Ontario, Canada Graham E. Trope, MB PhD, Toronto Hospital-Western

Div., Ontario, Canada Thomas R. Walters, MD, Austin, Texas

R e f e r e n c e s 1. Araujo SV, Bond JB, Wilson RP, et al: Long term effect of

apraclonidine. BrJ Ophthalmol 79(12):1098-1101, 1995 2. Barnebey H for the Brimonidine Study Group: Long-term

efficacy of brimonidine on IOP lowering (abstract). Invest Ophthalmol Vis Sci 37(3 suppl):S1102, 1996

2a.Burke J: Preclinical evaluation of brimonidine. Surv Oph- thalmol 41(Suppl 1):$9-S18, 1996

3. Burke J, Manlapaz C, Kharlamb A, et al: Therapeutic use of %-adrenoceptor agonists in glaucoma. In: Lanier S, Limbird L, eds. Alpha2-Adrenergic Receptors: Structure, Function and Therapeutic Implications. Reading, UK: Harwood Academic Publishers, 1996 (in press)

4. Butler P, Mannschreck M, Lin S, et al: Clinical experience with long-term use of 1% apraclonidine. Arch Ophthalmol 113:293-296, 1995

5. Butler PJ, Jones B: Incidence of characteristics of allergic reaction to apraclonidine 0.5%. Invest Ophthalmol Vis Sci 37(3):$201, 1996

6. Cambridge D: UK-14,304, a potent and selective ct-agonist for the characterization of ~x-adrenoceptor subtypes. Eur J Pharmacol 72:413~115, 1981

7. Chacko DM, Camras CB: The potential of%-adrenergic ago- nists in the medical treatment of glaucoma. Curr Opinion

CLINICAL EXPERIENCE WITH BRIMONIDINE AND TIMOLOL $37

Ophthalmol 5(II):76--84, 1994 8. Derick RJ, Wahers TR, Robin AL, et al: Brimonidine tar-

trate: a one month dose response study (abstract). Invest Ophthalmol Vis Sci 34(4 suppl):929, 1993

9. Dirks M for the Brimonidine Study Group: Long-term safety and IOP-lowering efficacy of brimonidine tartrate 0.2% in glaucoma and ocular hypertension (abstract), In- vest Ophthalmol Vis Sci 37(3 suppl):S832, 1996

10. Hodapp E, Kolker AE, Kass MA, et al: The effect of topical clonidine on intraocular pressure. Arch Ophthalmol 99: 1208-1211, 1981

11. Landis RJ, Heyman ER, Koch GG: Average partial asso- ciation in three-way contingency tables: A review and dis- cussion of alternative tests. Int Statistical Review 46:237- 254, 1978

12. Morrison JC: Side effects of alpha-adrenergic agonists. J Glaucoma 4(suppl 1):$36-$38, 1995

13. Munk SA, Gluchowski C, Dolby L, et al: Analogs of UK 14,304 as %-adrenoceptor agonists. Twist and agent po- larity as design elements. Bioorg Med Chem Lett 4(3):459- 462, 1994

14. Munk SA, Harcourt D, Arasasingham P, et al: Analogs of UK 14,304: structural features responsible for alpha 2 adrenoceptor activity. Bioorg Med CheIn Lett 28;5(15): 1745-50, 1995

15. Munk SA, Wiese A, Thompson CD, et al: Oxidation poten- tial and allergic response of alpha 2 agonists (abstract). In- vest Ophthalmol Vis Sci 37(3):$832, 1996

16. Nagasubramanian S, Hitchings RA, Demailly P, et al: Com- parison of apraclonidine and timolol in chronic open angle glaucoma. A three-month study. Ophthalmology 100:1318- 1323, 1993

17. Nguyen KD, Shin DH: Prevalence of apraclonidine allergy and its relationship to PROPINE ® allergy (abstract). In- vest Ophthalmol Vis Sci 37(3):S1103, 1996

18. Nordlund JR, Pasquale LR, Robin AL, et al: A comparison of the cardiovascular and puhnonary effects of brimonidine 0.2%, timolol 0.5% and betaxolol suspension 0.25%. Arch Ophthalmol 113:77-83, 1995

19. Pineyro A, Gross RL, Orengo-Nania S: Long term experi- ence with apraclonidine 0.5% (IOPIDINE) in clinical prac- tice (abstract). Invest Ophthalmol Vis Sci 37(3):S 1100, 1996

20. Robin AL: Questions concerning the role of apraclonidine in the m a n a g e m e n t of glaucoma. Arch Oph tha lmo l 113:712-713, 1995

21. Rosenthal AL, Wahers T, Berg E, et al: A comparison of the safety and efficacy of brimonidine 0.2%, BID versus TID (abstract). Invest O p h t h a l m o l Vis Sci 37(3 suppl):S1102, 1996

22. Sheth BP, Kalenak JW: Frequency of al lergy to apraclonidine in a clinical practice (abstract). Invest Ophthalrnol Vis Sci 37(3):S1099, 1996

23. Stewart WE, Ritch R, Shin DH, Lehmann RP, et al: The efficacy of apraclonidine as an adjunct to timolol therapy. Arch Ophthalmol 113:287-292, 1995

24. Toris CB, Gleason ML, Camras CB, et al: Effects ofbrimoni- dine on aqueous humor dynamics in human eyes. Arch Ophthalmol 113:1514-1517, 1995

24a.Wahers TR: Development and use ofbrimonidine in treat- ing acute and chronic IOP elevations: A review of safety, efficacy, dose response, and dosing studies. Surv Ophthal- tool 41(Suppl 1):S19-$26, 1996

25. Wilkerson M, Lewis RA, Shields MG: Follicular conjunc- tivitis associated with apraclonidine. Am J Ophthalmol 111:105-206, 1991

The author wishes to thank Kuankuan S. Chen, M.S., princi- pal biostatistician, Allergan, Inc., for statistical analyses of the data.

Presented in part at the American Glaucoma Society, Vancouver, British Columbia, July 30-August 2, 1996

Dr. Schmnan has no proprietary interest in Allergan, Inc., or brimonidine.

Reprint address: Joel S. Schuman, MD, New England Eye Center, New England Medical Center Hospitals, Tufts Uni- versity School of Medicine, 750 Washington Street, Box 450, Boston, MA 02111. Telephone: 617-636-7950; Facsimile: 617- 636-4866.