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A Randomized Trial Assessing Dorzolamide in Patients With Glaucoma Who Are Younger Than 6 Years
Elyssa Z. Ott, BS;
Monte D. Mills, MD;
Santiago Arango, MD;
Albert J. Getson, PhD;
Christopher A. Assaid, PhD;
Ingrid A. Adamsons, MD, MPH; for the Pediatric Dorzolamide Study Group
Arch Ophthalmol. 2005;123:1177-1186.
ABSTRACT
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Objective To evaluate dorzolamide hydrochloride in patients younger than 6 years who have an elevated intraocular pressure or glaucoma.
Design A 3-month, controlled, randomized, double-masked, multicenter, clinical trial. Patients were randomized to 2% dorzolamide 3 times daily or timolol maleate gel-forming solution (0.25% for patients <2 years and 0.5% for patients  2 but <6 years) once daily plus placebo twice daily. If the intraocular pressure was not controlled through monotherapy, younger patients received concomitant dorzolamide 3 times daily and 0.25% timolol gel-forming solution once daily and older patients received a fixed combination of 2% dorzolamide and 0.5% timolol twice daily. The primary safety variable was the proportion of patients who discontinued therapy for a drug-related adverse experience. Intraocular pressure reduction was a secondary measure.
Results One younger patient (1.8%) of 56 randomized to dorzolamide discontinued concomitant therapy because of bradycardia. Two older patients (3.0%) of 66 discontinued dorzolamide because of ocular adverse experiences. The most frequent ocular adverse experiences were discharge and ocular hyperemia (younger cohort) and ocular hyperemia and burning/stinging (older cohort). At week 12, the mean change in intraocular pressure for dorzolamide was statistically significant from baseline (–7.3 mm Hg [–20.6%] and –7.1 mm Hg [–23.3%]) in the younger and older cohorts, respectively; P<.001 for both.
Conclusion Dorzolamide was generally well tolerated and demonstrated efficacy for up to 3 months in patients younger than 6 years.
INTRODUCTION
Pediatric glaucoma encompasses a wide range of diseases, including primary congenital glaucoma, glaucoma associated with congenital ocular anomalies such as aniridia or Sturge-Weber syndrome, and secondary glaucoma following intraocular surgery or ocular inflammation. Surgical therapy is preferable for the treatment of primary congenital glaucoma and many of the glaucomas associated with congenital anomalies. Medications can be useful in reducing intraocular pressure (IOP) until surgery can be performed and in cases in which there has been a limited or poor response to surgery. Medications may play a greater role in the treatment of some acquired secondary forms of glaucoma, such as inflammatory glaucoma.
Systemic carbonic anhydrase inhibitors, primarily acetazolamide, have been used as a treatment for pediatric glaucoma,1-3 although adverse effects have been a problem.4-5 The topical carbonic anhydrase inhibitor dorzolamide hydrochloride (Trusopt; Merck & Co, Inc, Whitehouse Station, NJ) has been studied in pediatric glaucoma patients and has had good tolerability and has lowered IOP,4, 6-7 although not as much as oral acetazolamide.5 However, the information provided by these reports is less than comprehensive. Donohue and Wilensky4 described 4 infants who were followed up for an unspecified period, and did not specify whether other glaucoma therapies were taken concomitantly. Three studies observed a few pediatric patients (n = 11, 9, and 6) who received dorzolamide as concomitant therapy for about 6 months5-6 or up to 2 years.7 Meyer et al8 reported a 3-month study that included pediatric glaucoma patients as a subpopulation (unknown sample size). A sixth publication described retrospective cases in 15 infants and children treated before, in between, or after failure of surgical intervention.9 These reports provide encouraging evidence of the value of dorzolamide in the treatment of pediatric glaucoma. Additional information, through a randomized controlled trial, on the efficacy and tolerability of dorzolamide would be informative. The US Food and Drug Administration recently undertook an initiative to encourage evaluation of the safety and efficacy of a broad range of marketed medications in pediatric patients. As part of that initiative, Merck & Co, Inc, submitted a pediatric study request to the Food and Drug Administration and subsequently received a written request from the Food and Drug Administration for a pediatric study of dorzolamide. The written request included specifications regarding the patient population, number of patients, comparator medications, safety and efficacy measurements, and study duration. The study that was conducted was designed to meet the request of the Food and Drug Administration.
This trial was designed to prospectively evaluate the safety and efficacy of 2% dorzolamide 3 times daily (TID) in children (aged 1 week-<6 years) with pediatric glaucoma or elevated IOP. The active comparator for this study was timolol maleate gel-forming solution (GS) (Timoptic-XE; Merck & Co, Inc). The size of the timolol GS group was not determined by the goal of detecting clinically meaningful differences between the 2 treatments with sufficient statistical power. It was reasoned that if dorzolamide was tolerated in at least 3 of 4 pediatric patients, the drug would have utility in this age group. Therefore, the primary hypothesis was that in pediatric patients, the true proportion of patients who will discontinue therapy due to a drug-related adverse experience was 25% or less when the initial treatment was 2% dorzolamide TID for up to 3 months. This hypothesis was evaluated separately for the younger than 2 years cohort and the 2 years and older but younger than 6 years cohort.
METHODS
PROCEDURES
This was a 3-month, double-masked, in-house–masked, randomized, active treatment, controlled study conducted at 22 sites in the United States and 13 sites in Latin America, Europe, Egypt, and the Philippines. All sites received ethical review committee approval of the protocol, and informed consent was obtained for each patient from a parent or legal guardian before beginning the study. Male and female patients, aged 1 week to younger than 6 years, with an elevated IOP of 22 mm Hg or higher and the diagnosis of glaucoma or ocular hypertension were eligible for enrollment. Neonates were required to be at least 36 weeks’ gestational age. Among the ocular conditions for which patients were excluded were the use of continuous wear contact lenses (use of daily wear lenses was permitted); history or evidence of goniotomy or trabeculotomy within 1 month of study start; filtration or implantation surgery, cyclodestructive surgery, or history or evidence of significant ocular trauma within 3 months of study start; evidence of acute or recent ocular inflammation and/or infection within 1 month of study start; chronic conjunctivitis; chronic keratitis; or lacrimal deficiency. Patients may have had intraocular laser therapy up to 3 months before study start. Other reasons for exclusion included any contraindication to timolol or carbonic anhydrase inhibitors, known severe or serious hypersensitivity to sulfonamides, concomitant systemic or topical medications known to affect IOP unless therapy remained constant throughout the study, history or evidence of impaired renal function, and participation in a study involving an investigational drug within 4 weeks.
Before enrolling in the study, patients discontinued any topical or systemic ocular hypotensive medications for at least 24 hours before study day 1. A longer washout of ocular hypotensive medication was available at the discretion of the investigator according to the following schedule: 21 days for topical  -blockers,  -agonists, topical prostaglandin analogues, and oral or topical carbonic anhydrase inhibitors; 7 days for epinephrine or dipivefrin; and 72 hours for pilocarpine, carbachol, or echothiophate iodide. Patients were also required to undergo a complete physical examination within 3 months of study start to ensure that the patient was generally healthy. After this washout period, patients returned to the clinic on day 1 for baseline examinations. On day 1, if the patient was eligible and met the enrollment criterion of an IOP of 22 mm Hg or higher in 1 or both eyes, the patient was then randomly assigned in a 2:1 ratio to masked treatment with dorzolamide or timolol GS. Treatment assignment was determined by a computer-generated allocation schedule that was prepared by a Merck & Co, Inc, staff member who was not involved in the analysis of the study results. Patients aged 1 week to younger than 2 years (hereafter referred to as the younger patients or cohort) received either 2% dorzolamide TID or 0.25% timolol GS once daily plus placebo twice daily. Patients 2 years or older but younger than 6 years (hereafter referred to as the older patients or cohort) received either 2% dorzolamide TID or 0.5% timolol GS once daily plus placebo twice daily. If during the study the investigator determined that the IOP was not controlled, the study therapy was changed to open-label concomitant therapy of 2% dorzolamide TID and 0.25% timolol GS once daily (10 minutes after the first drop) for younger patients and to open-label therapy of the fixed combination of 2% dorzolamide hydrochloride and 0.5% timolol maleate (Cosopt; Merck & Co, Inc) twice daily for older patients. Because of concerns about the systemic adverse effects of timolol in young children, the younger cohort was assigned the lower concentration of 0.25% timolol GS therapy, while the older cohort was assigned the higher concentration of 0.5% timolol GS therapy. The data analyzed and presented include data from masked monotherapy for safety and efficacy. Limited patient accounting and safety data are also provided for open-label concomitant or combination therapy and are indicated as such.
All study medications for the masked and open-label phases were provided by the sponsor (Merck & Co, Inc, Whitehouse Station, NJ) as sterile ophthalmic solutions in identical containers labeled with the patient’s allocation number (for masked therapy only) and instillation instructions. A sealed disclosure envelope, which identified the treatment group for each allocation number when unsealed, was kept in a secure location at the site. In the event of an emergency requiring the identification of test drug, the disclosure envelope could have been opened to determine the treatment group. No allocation numbers were unmasked during the study by the investigators or by sponsor personnel directly involved with the study. An individual not otherwise involved in the study monitored patient accrual. Parents or legal guardians of the patients were instructed to instill the medications in the morning, afternoon, and evening at consistent times throughout the entire study. Study visits occurred on day 1 and weeks 1, 4, and 12. If a change in therapy was required at week 1 or 4, the patient returned to the clinic for follow-up at week 2 or 5, respectively. If at weeks 2 or 5 the IOP was not controlled, then the patient was discontinued from the study. Physicians were requested to measure each patient’s IOP at consistent times throughout the study, and the method of measurement was left to their discretion. The IOP was measured by 1 of 3 methods (Goldmann, TonoPen, or Perkins tonometry), and physicians were asked to use the same method for each patient throughout the study. Two readings per eye were required for Goldmann and Perkins tonometry, and the average value was reported. Two IOP readings with a 5% confidence level were required for TonoPen tonometry, except when this confidence was not achieved and then 3 or 4 isolated readings were taken, and the average value was reported. Patient cooperation and whether sedation was used during the IOP measurement were also reported. Intraocular pressure, ocular signs, visual acuity, alertness, vital signs, and adverse experiences were measured and recorded at each visit. Patient alertness was assessed using a 5-point scale (responds readily to name spoken in normal tone, lethargic response to name spoken in normal tone, responds only after name is called loudly and/or repeatedly, responds only after mild prodding or shaking, does not respond to mild prodding or shaking) that was adapted from the validated Observer’s Assessment of Alertness/Sedation Scale.10 The drug relationship of all adverse experiences was assessed by the investigator; adverse experiences were considered drug related if they were assessed as possibly, probably, or definitely related. Additional measurements performed at prestudy or day 1 and poststudy visits included a physical examination (if not performed within the past 3 months), dilated ophthalmoscopy, corneal diameter measurement, and the chemistry laboratory test of venous total carbon dioxide (CO2) level (serum). Since oral carbonic anhydrase inhibitors induce metabolic acidosis, total CO2 level was included as a special safety variable to assess the effect of dorzolamide on serum bicarbonate levels in a pediatric population.
STATISTICAL ANALYSIS
The primary hypothesis of the study was that among pediatric patients, the true proportion of patients who discontinued therapy because of a drug-related adverse experience was 25% or less when the initial treatment was 2% dorzolamide TID for up to 3 months. It was reasoned that if dorzolamide was tolerated in at least 3 of 4 pediatric patients, the drug would have utility in this age group. A sample size of approximately 50 patients randomized to dorzolamide in each cohort was selected. With 50 patients, if the observed proportion of patients who discontinued therapy because of a drug-related adverse experience was 15%, then the primary hypothesis would be supported because the upper limit of the 95% confidence interval would be 24.9%.
The analysis of the primary study end point was based on the all-patients-as-treated analysis population, which included all patients who were randomized to double-masked therapy and received at least 1 dose of study therapy. Patients were analyzed according to the treatment received and according to the age cohort to which they actually belonged at study start, irrespective of the cohort to which they were randomized (patients enrolled who were >6 years at randomization were counted in the older cohort).
The primary safety end point was the observed proportion of patients in each age cohort who discontinued therapy with dorzolamide because of a drug-related adverse experience. An exact (Clopper-Pearson11) 95% confidence interval on the primary end point was calculated by age cohort (for patients initially treated with dorzolamide) to document an acceptable safety profile. The prespecified decision rule stated that the safety profile for an age cohort would be declared acceptable, with respect to the primary safety end point, if the upper limit of the 95% confidence interval for patients receiving dorzolamide who discontinued therapy was 25% or less. Data for the remaining safety measures are descriptively summarized.
The primary efficacy (IOP) analysis was based on the all-patients-treated population, which consisted of all patients as randomized (regardless of actual age) who had a baseline IOP and at least 1 subsequent efficacy measurement. The IOP-lowering effect of dorzolamide was characterized by summarizing IOP values by study visit, in addition to summary statistics for change from baseline and percentage change from baseline. The change from baseline was calculated using the patient’s "worse eye," which was defined as the eye with the higher IOP on day 1. If the IOP was the same for both eyes on day 1, the right eye was selected. This analysis included a 95% confidence interval on the difference between treatment groups for mean change and mean percentage change from baseline based on the student t distribution. Missing data at week 12 were estimated by the last-observation-carried-forward method, which uses previous time-matched observations occurring within the study period. As noted previously, the sample sizes were not determined by the need to detect clinically meaningful differences between the 2 treatments in IOP.
RESULTS
DEMOGRAPHICS
Table 1 provides the baseline demographic characteristics of the study population. A total of 83 patients were enrolled in the younger cohort, 56 of whom were randomized to dorzolamide. Approximately twice as many male as female patients were randomized to each treatment group. The mean baseline IOPs were 32.6 and 29.9 mm Hg in the dorzolamide and timolol GS treatment groups, respectively. A total of 101 patients were enrolled in the older cohort, 66 of whom were randomized to dorzolamide. Comparable proportions of male and female patients were randomized to each treatment group. The mean baseline IOPs were 28.7 and 30.3 mm Hg in the dorzolamide and timolol GS treatment groups, respectively. For both cohorts, comparable distributions between treatment groups were observed for race, iris color, and age. The most common glaucoma causes were congenital glaucoma and aphakic glaucoma. Table 2 provides data on specific glaucoma causes for the study population. There were more patients in the older cohort with other glaucoma causes who received dorzolamide. Included in these other causes are 2 patients in the dorzolamide group and 1 patient in the timolol GS group with the cause of glaucoma and 2 patients in both treatment groups with the cause of pseudophakia. In addition, each of the following causes was reported in 1 patient in the dorzolamide group but in no patients in the timolol GS group: oculocerebrorenal syndrome, surgical aphakia, corticosteroid-induced glaucoma, microphthalmos, corneal opacity, retinopathy of prematurity, retinal surgery, and vitreous surgery.
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Table 1. Baseline Demographic Characteristics*
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Table 2. Patients With Specific Glaucoma Causes*
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Previous glaucoma surgery was reported for approximately 40% of patients in the younger cohort, 23 (41.1%) patients randomized to dorzolamide and 11 (40.7%) randomized to timolol GS. Previous glaucoma surgery was reported more frequently for the patients in the older cohort, 41 (62.1%) patients randomized to dorzolamide and 22 (62.9%) randomized to timolol GS.
PATIENT ACCOUNTING
Patient accounting is detailed in Figure 1A for the younger cohort and in Figure 1B for the older cohort. In the younger cohort, 13 patients were screened but not randomized. Of the remaining 83 patients, 66 (79.5%) completed the study, 44 (53.0%) while undergoing masked monotherapy and 22 (26.5%) while undergoing open-label concomitant therapy. Seventeen patients from the younger cohort discontinued therapy. In the older age cohort, 19 patients were screened but not randomized. Of the remaining 101 patients, 81 (80.2%) completed the study, 62 (61.4%) while undergoing masked monotherapy and 19 (18.8%) while undergoing open-label combination therapy. Twenty patients from the older cohort discontinued therapy. The most frequent reason for discontinuation in both age cohorts was "IOP not controlled; patient went to surgery" (10 [58.8%] of 17 patients in the younger cohort and 11 [55.0%] of 20 patients in the older cohort). The most frequent reasons given for nonrandomization in both cohorts were an IOP lower than the enrollment criterion (4 patients in the younger cohort and 7 patients in the older cohort) and withdrawal of consent (3 patients in the younger cohort and 4 patients in the older cohort). Five patients were randomized to the incorrect age cohort: 3 who were older than 2 years were randomized to the younger cohort, and 2 who were older than 6 years were randomized to the older cohort.
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Figure 1. Patient accounting in those younger than 2 years (A) and in those 2 years and older but younger than 6 years (B). Dorzolamide was administered as dorzolamide hydrochloride, and timolol as timolol maleate gel-forming solution (GS). AE indicates adverse event; and IOP, intraocular pressure.
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SAFETY
In the younger cohort, 1 patient (1.8%) who was initially randomized to dorzolamide discontinued study therapy while undergoing open-label dorzolamide plus timolol GS therapy because of a drug-related adverse experience. This patient discontinued therapy because of bradycardia, which was determined by the investigator to be related to the timolol GS therapy. The resulting 95% confidence interval for the true proportion of discontinuations was 0.1% to 9.6%. None of the 27 patients initially randomized to the timolol GS treatment group discontinued study therapy because of a drug-related adverse experience. In the older age cohort, 2 patients (3.0%) initially randomized to dorzolamide discontinued study therapy while taking dorzolamide because of the drug-related adverse experiences of eye pain, ocular hyperemia, ocular burning/stinging, or ocular itching. The resulting 95% confidence interval for the true proportion of discontinuations was 0.4% to 10.5%. One patient (2.9%) initially randomized to the timolol GS treatment group discontinued study therapy because of the drug-related adverse experience of ocular hyperemia. Thus, for both age cohorts, because the upper bounds of the 95% confidence intervals were each less than 25%, it could be concluded that dorzolamide was generally well tolerated in patients younger than 6 years with an elevated IOP or glaucoma.
Table 3 summarizes the clinical adverse experiences for both age cohorts. In both cohorts, approximately equal numbers of patients in both treatment groups had a clinical adverse experience or a drug-related adverse experience. Table 4 provides the most common adverse experiences for the younger and older cohorts. The most common adverse experiences for both treatment groups were fever, cough, and upper respiratory tract infections. The most frequently reported ocular adverse experiences were ocular discharge and ocular hyperemia for the younger cohort and ocular hyperemia and ocular burning/stinging for the older cohort. Although many patients (approximately 75% in both age cohorts) reported an adverse experience, only 14.3% and 25.8% reported an adverse experience that was considered related to dorzolamide therapy for the younger and older cohorts, respectively. None of the drug-related adverse experiences reported during treatment with monotherapy, either dorzolamide or timolol GS, was considered serious by the investigators. Few of the drug-related adverse experiences were systemic.
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Table 3. Clinical Adverse Experience Summary (Masked Monotherapy)*
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Table 4. Patients With Specific Clinical Adverse Events (Incidence >5% in 1 Treatment Group) in Both Age Cohorts (Masked Monotherapy)*
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Vital sign measurements were summarized for each treatment group, and the mean changes from baseline to the end of monotherapy were calculated. For the younger cohort, the mean changes were comparable between treatment groups (dorzolamide vs timolol) for systolic blood pressure (–1.1 vs 0.3 mm Hg), diastolic blood pressure (–1.6 vs –1.2 mm Hg), and respiratory rate (–1.7/min vs –1.4/min). An unexpected increase in the mean pulse rate in the timolol group was seen (–2.0 vs 10.6 beats/min). For the older cohort, comparable mean changes were seen between treatment groups (dorzolamide vs timolol) for the vital signs of systolic blood pressure (0.7 vs –2.9 mm Hg), diastolic blood pressure (–0.4 vs –2.4 mm Hg), and respiratory rate (–0.5/min vs 0.0/min). The mean changes in pulse rate were 0.9 and –4.9 beats/min for the dorzolamide and timolol groups, respectively.
For the alertness assessment, in both cohorts, nearly all of the patients responded readily at baseline and week 12. Two patients in the younger cohort experienced a worsening of alertness; in one patient treated with timolol GS, the assessment was performed during an examination under anesthesia, and, while no cause was provided for the other patient (who was treated with concomitant therapy), the investigator did not believe that this was an adverse experience. No patients in the older cohort experienced a worsening in alertness.
Changes in corneal diameter for the younger and older cohorts were small overall and were comparable across treatment groups (±0.1 mm). No statistically significant changes from baseline were observed (younger cohort, P = .8; older cohort, P = .4). The number of emergent or worsening signs reported (from a slitlamp or dilated ophthalmoscopic examination) was similar between treatment groups in the younger and older cohorts. The most common sign reported in the younger cohort was corneal enlargement, which occurred in 3 patients receiving dorzolamide monotherapy. This was reported in patients who were 5, 8, and 10 months old who were reported to have developed mild, moderate, or severe corneal enlargement, respectively, during the study. The corneal diameter measurements that were recorded at baseline and week 12 for each of these patients were as follows: 13.5 mm and 13.75 mm; 12.0 mm and 11.5 mm; and 12 mm and 12 mm, respectively. Thus, the more objective corneal evaluation showed no, or a minimal, change. The most common sign reported in the older cohort was conjunctival hyperemia, which occurred in 3 patients receiving timolol monotherapy. All other signs were reported in 1 or 2 patients in either cohort.
There were 2 laboratory adverse events, 1 in each cohort. In the younger cohort, one patient experienced decreased venous total CO2 (baseline, 26.4 mmol/L; week 12, 16.3 mmol/L; normal range, 20-28 mmol/L) while receiving concomitant therapy. In addition to this laboratory adverse experience, the same patient from the younger age cohort experienced malnutrition, vomiting, diarrhea, and fever around the time the laboratory test was performed. In the older cohort, one patient experienced decreased capillary PCO2 (the incorrect laboratory test was performed) (baseline, 5.1 kPa; week 12, 4.3 kPa; normal range, 4.8-6.1 kPa) while undergoing dorzolamide monotherapy. Both of these events were considered by the investigators to be drug related.
EFFICACY
The IOP summary statistics on monotherapy for both age cohorts are provided in Table 5. Figure 2 and Figure 3 display the IOP treatment means and SEs for the younger and older cohorts, respectively. For the patients in the younger cohort, the mean baseline IOP was higher in the dorzolamide group than in the timolol GS group (32.6 vs 29.9 mm Hg). Statistically significant (P<.001) decreases in IOP were seen at week 1 through 12 with both treatments. At week 12, the mean decreases (mean percentage changes) in IOP for the dorzolamide and timolol GS groups were –7.3 mm Hg (–20.6%) and –7.8 mm Hg (–24.9%), respectively. The 95% confidence interval for the mean difference between the 2 treatments at week 12 was –3.4 to 4.5. Because the confidence interval includes 0, this indicates a similar effect for both therapies.
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Table 5. The IOP Summary Statistics in the Worse Eye (Masked Monotherapy)*
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Figure 2. Mean (SE) intraocular pressure (IOP) in the worse eye by treatment group for those younger than 2 years at baseline and at each study visit for masked monotherapy (all patients–treated analysis/last-observation-carried-forward approach). GS indicates gel-forming solution.
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Figure 3. Mean (SE) intraocular pressure (IOP) in the worse eye by treatment group for those 2 years and older but younger than 6 years at baseline and at each study visit for masked monotherapy (all patients–treated analysis/last-observation-carried-forward approach). GS indicates gel-forming solution.
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For the patients in the older cohort, the mean baseline IOP was slightly higher in the timolol GS group than in the dorzolamide group (30.3 vs 28.7 mm Hg). Statistically significant (P<.001) decreases in IOP were seen at week 1 through 12 with both treatments. At week 12, the mean decreases (mean percentage changes) in IOP for the dorzolamide and timolol GS groups were –7.1 mm Hg (–23.3%) and –7.4 mm Hg (–25.3%), respectively. The 95% confidence interval for the mean difference between the 2 treatments at week 12 was –2.5 to 3.2. Because the confidence interval includes 0, this indicates a similar effect for both therapies. As noted earlier, the study was not necessarily powered to find a difference in treatment effect between the 2 medications.
COMMENT
This study demonstrated acceptable safety of dorzolamide in patients younger than 6 years. The primary hypothesis of the study was confirmed, namely, that the true proportion of patients who discontinued therapy because of a drug-related adverse experience was less than 25%. In the younger cohort, the proportion (95% confidence interval) of patients who discontinued therapy because of drug-related adverse experiences was 1.8% (0.1%-9.6%); and in the older cohort, it was 3.0% (0.4%-10.5%). Previously published studies of 2% dorzolamide in pediatric patients found the medication to be well tolerated, with few adverse effects.4-9,12 The safety profile of dorzolamide in this study is consistent with that reported in the earlier smaller pediatric studies. To our knowledge, this prospective, randomized, controlled study is the largest of its kind in pediatric patients. This may be in part because of the difficulty in performing such large studies in a pediatric population. In fact, this study was planned only as a US study when enrollment began on November 14, 2000. Because of slow enrollment, the study was expanded worldwide and the last patient completed the study on January 15, 2003.
The most common adverse experiences reported in both treatment groups were common childhood illnesses for these age groups, and most were not considered drug related. The most common drug-related adverse experiences reported for dorzolamide in this study were ocular hyperemia (5.4%) in younger patients and ocular burning/stinging (12.1%) in older patients. The higher incidence of burning/stinging in the older group may reflect that the younger age cohort was preverbal. Local adverse effects were also the most common drug-related adverse experiences in adults in whom ocular burning/stinging was the most commonly reported ocular adverse experience.13 For the most part, the safety profile of dorzolamide in this pediatric study reflected that seen in adult studies.14-15 Systemic drug-related adverse experiences were infrequently reported in adult and pediatric populations.
Secondary measures assessed during the study, including vital signs, visual acuity, and alertness, also supported the safety of dorzolamide and timolol GS in these patients. The few adverse experiences (n = 2) reported for venous total CO2 and capillary PCO2 for patients treated with dorzolamide demonstrates systemic safety in this patient population. One of these reports was in the setting of malnutrition, vomiting, diarrhea, and fever, which could also have adversely affected the child’s electrolyte imbalance.
The IOP-lowering effect of dorzolamide seen in this study was statistically significant and was comparable to the IOP-lowering effect of 27% reported in the 6-month study in children by Portellos et al.5 This is the only other study in the literature, to our knowledge, to report a numeric value for IOP reduction in a pediatric population. All other studies found in the literature for this population stated there was a general IOP reduction, but no values were typically provided.4, 6-8,12 The IOP-lowering effects in this study and in the study by Portellos et al were greater than those that have been seen in adults.13 In this pediatric study, the mean changes (mean percentage changes) in IOP at week 12 in younger and older patients were –7.3 mm Hg (–20.6%) and –7.1 mm Hg (–23.3%), respectively, compared with a change of –3 to –5 mm Hg in adults.13 This difference in IOP effect between pediatric and adult patients could be because of the higher baseline IOPs in the pediatric patients. The mean baseline IOPs for the 2% dorzolamide group were 32.6 and 28.7 mm Hg for younger and older patients, respectively, compared with baseline IOPs that ranged from 24.6 to 28.3 mm Hg in adult studies.14-15 In addition, pediatric glaucomas have different causes than adult glaucoma, and this may play a role in the differential IOP reduction. Given these differences, while the long-term efficacy of dorzolamide has been studied in randomized clinical trials in adults,14-15 conclusions about long-term efficacy in pediatric glaucoma cannot necessarily be drawn from these pediatric studies of 3- to 6-month duration.
Finally, although systemic carbonic anhydrase inhibitors, such as acetazolamide, have been a mainstay in the medical treatment of pediatric glaucoma, their use has been limited by the relatively high incidence of systemic adverse effects.5 In one adult study,16 in which timolol was given adjunctively with dorzolamide or acetazolamide, the efficacy between the 2 groups was similar, with acetazolamide demonstrating an approximately 1–mm Hg advantage over dorzolamide. In contrast, adverse events were reported more frequently and discontinuation rates were higher in patients receiving acetazolamide, indicating that dorzolamide possessed significantly better tolerability.
In summary, 2% dorzolamide TID taken for up to 3 months was generally well tolerated and demonstrated efficacy in pediatric patients younger than 6 years with an elevated IOP or glaucoma. In addition, 2% dorzolamide monotherapy seemed to be comparable in safety in this study population to that reported in previous adult studies14-15 and comparable in efficacy to that reported in the published pediatric literature.5
AUTHOR INFORMATION
Correspondence: Ingrid A. Adamsons, MD, MPH, Merck Research Laboratories, Inc, BLX-30, PO Box 4, West Point, PA 19486.
Submitted for Publication: June 11, 2004; final revision received April 26, 2005; accepted May 14, 2005.
Financial Disclosure: At the time of this study, Ms Ott and Drs Getson, Assaid, and Adamsons were employees of Merck & Co, Inc, and potentially own stock and/or hold stock options in the company; and Drs Mills and Arango have received research grants from Merck & Co, Inc.
Funding/Support: This study was supported by Merck & Co, Inc.
Previous Presentation: This study was presented at the Association for Research in Vision and Ophthalmology Annual Meeting; April 28, 2004; Ft Lauderdale, Fla.
Acknowledgment: We thank Sharon Freedman, MD (Duke University Eye Center, Durham, NC), Michael Kass, MD (Department of Ophthalmology, Washington University School of Medicine, St Louis, Mo), and David Walton (Boston, Mass) for their scientific advice.
| The Pediatric Dorzolamide Study Group
Norman Aquino, MD, Manila, Philippines; Santiago Arango, MD, Medellin, Colombia; David Coats, MD, Houston, Tex; Janusz Czajkowski, MD, Lodz, Poland; Pedro Debess, MD, Caracas, Venezuela; Mohammed El Sada, MD, Cairo, Egypt; Ales Filous, MD, Prague, Czech Republic; Nikica Gabric, MD, Zagreb, Croatia; Flor Galvez, MD, Lima, Peru; Sai Gandham, MD, Albany, NY; David Godfrey, MD, Dallas, Tex; Federico Hermes, MD, Ciudad, Guatemala; Maria Hurtado, MD, Bogota, Colombia; Joseph Kubacki, MD, Philadelphia, Pa; Gregg Lueder, MD, St Louis, Mo; Michael May, MD, Aurora, Colo; Norman Medow, MD, New York, NY; Monte D. Mills, MD, Philadelphia; David Plager, MD, Indianapolis, Ind; Jaroslav Rehurek, MD, Brno, Czech Republic; Manuel Rodriquez Almaraz, MD, Mexico City, Mexico; John Samples, MD, Portland, Ore; Colin Scher, MD, San Diego, Calif; Jonathan Song, MD, Los Angeles, Calif; Manuela Spagarino, MD, Caracas, Venezuela; C. Gail Summers, MD, Minneapolis, Minn; M. Edward Wilson, MD, Charleston, SC; Kenneth Wright, MD, Los Angeles; and Johan Zwaan, MD, San Antonio, Tex. Merck & Co, Inc, Personnel: Ingrid A. Adamsons, MD, MPH; Elyssa Z. Ott, BS; Coleen Clineschmidt; Scott Reines, MD, PhD; Cynthia Rusk; Albert J. Getson, PhD; Michael Nessly, MS; Christopher A. Assaid, PhD; and Charles Liss.
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Author Affiliations: Departments of Clinical Research (Ms Ott) and Biostatistics (Drs Getson and Assaid), and Clinical Risk Management and Safety Surveillance (Dr Adamsons), Merck Research Laboratories, West Point, Pa; Department of Ophthalmology, Children’s Hospital of Philadelphia, Philadelphia, Pa (Dr Mills); and Clinica Oftalmologia Sandiego, Medellin, Colombia (Dr Arango).
REFERENCES
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