Fixed Combination of Latanoprost and Timolol vs Individual Components for Primary Open-Angle Glaucoma or Ocular Hypertension: Title and subTitle BreakA Randomized, Double-Masked StudyFCLT vs Latanoprost or Timolol Monotherapy FREE

The benefits of lowering intraocular pressure (IOP) levels in patients with ocular hypertension¹ and glaucoma^{2 - 3} have been demonstrated in multicenter clinical trials. However, successful IOP control requires long-term patient adherence to prescribed medication regimens. Ocular hypotensive agents such as the prostaglandin analogues that offer convenient once-daily dosing may enhance adherence compared with more complex regimens.^{4 - 8} In fact, adherence and persistence among patients prescribed prostaglandin analogues have been shown to be superior to that achieved by patients prescribed classes of medicines requiring more frequent instillation.^{9 - 13}

A significant proportion of patients treated for ocular hypertension and glaucoma must use more than 1 ocular hypotensive medication to adequately reduce IOP to levels that may be expected to halt or slow glaucomatous progression.¹ For these patients, prescribing a fixed-combination formulation generally is deemed preferable to multidrug regimens to maximize patient adherence and quality of life.¹⁴

Latanoprost, 0.005%, and timolol maleate, 0.5%, have different mechanisms of action and have been shown to have an additive IOP-lowering effect when administered together.^{15 - 18} For example, Bucci¹⁶ observed a 28% additional reduction in diurnal IOP when once-daily latanoprost was added to twice-daily timolol. Morning dosing of fixed-combination latanoprost-timolol (FCLT) has been shown to reduce IOP levels more effectively than its individual components.^{19 - 20} However, these studies may have included a substantial proportion of timolol nonresponders because eligibility required an IOP level of at least 25 mm Hg following a 2- to 4-week timolol run-in period, and the morning dosing of FCLT may have minimized differences between the fixed combination and the individual components because evening administration appears to more effectively control daytime IOP levels.²¹

To address these potential limitations, the present study compared the efficacy and safety of FCLT administered in the evening, latanoprost administered in the evening, and timolol administered in the morning following washout of previous ocular hypotensive therapy.

This 12-week, randomized, double-masked, parallel-group study was planned to be conducted in 50 to 60 centers in the United States. Approval of the protocol by the institutional review board at each participating institution was obtained before the study initiation. The research was conducted in accordance with the ethical standards established in the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. Written informed consent was obtained from all participants.

Eligible participants were at least 18 years old with either unilateral or bilateral primary open-angle glaucoma (with pigmentary and pseudoexfoliation) or ocular hypertension who were receiving a β-adrenergic receptor antagonist either as monotherapy or as part of combination therapy for at least 4 weeks before screening. At screening, the mean of the 8 AM, 10 AM, and 4 PM IOP measurements was required to be less than 37 mm Hg in the eye with the higher mean IOP. At baseline (randomization), the mean of IOP measurements at the same 3 time points was required to be 26 through 36 mm Hg in the eye with the higher IOP. Minimum best-corrected visual acuity had to be 20/200 or better (Snellen equivalent) in each eye.

Participants were excluded if they had a closed or barely open anterior chamber angle, history of acute angle-closure glaucoma, or history of any ocular filtering surgical intervention (unfiltered eye could be enrolled); argon laser trabeculoplasty, selective laser trabeculoplasty, ocular procedure, or inflammation in the study eye within 3 months before screening (unlasered/unfiltered eye could be enrolled); or ocular infection within 3 weeks before the screening visit in the study eye or use of an investigational medication within 30 days preceding screening. In addition, participants were ineligible if they used a systemic medication known to affect IOP levels (including β-adrenergic antagonists) unless the participant and dosage were stable for 3 months before screening and the dosage was not expected to change during the study; had conditions in which treatment with a β-adrenergic receptor antagonist was contraindicated; had known hypersensitivity to benzalkonium chloride or any other component of study drugs; or had any abnormal ocular conditions/symptoms or any uncontrolled systemic disease that, in the opinion of the investigator, would prevent study entry. In addition, women of childbearing potential who were not using adequate contraceptive methods or who were pregnant or nursing were excluded.

Participants were assessed for eligibility at a screening visit that took place 4 weeks (±3 days) before the baseline visit. At screening, ocular and medical histories were documented; ophthalmoscopic, refraction, and biomicroscopic evaluation were performed; best-corrected visual acuity was measured; and IOP was measured in triplicate at 8 AM, 10 AM, and 4 PM with a calibrated Goldmann applanation tonometer. Ocular measurements were obtained for both eyes.

After the screening visit and before treatment with study medication, eligible participants discontinued therapy with their current ocular hypotensive medications. Required washout periods were 5 days for cholinergic agonists and carbonic anhydrase inhibitors, 2 weeks for adrenergic agonists, and 4 weeks for β-adrenergic antagonists and prostaglandin analogues. An IOP safety check was performed 2 weeks (±3 days) after the screening visit.

At the baseline visit, best-corrected visual acuity was measured and biomicroscopic evaluation was performed. The IOP levels were measured by evaluators in triplicate in each eye at 8 AM, 10 AM, and 4 PM with a calibrated Goldmann applanation tonometer. A window of 30 minutes was permitted for all IOP assessments, but at least 2 hours must have elapsed between the 8 AM and 10 AM measurements.

Eligible participants were assigned to treatment groups using a centralized web randomization design via the Pfizer Impala system. Participants were stratified into 3 categories (≥26 to <30 mm Hg, ≥30 to <34 mm Hg, and ≥34 to <37 mm Hg) based on the mean baseline IOP in the eye with the higher IOP; if the IOP was the same in both eyes, the right eye measurement was used. Within each stratum, participants were randomly assigned to 1 of the 3 treatment groups in a 1:1:1 ratio. Randomization codes were generated by Pfizer according to standard operating procedures and were kept at Global Pharmacy Operations (New York, New York).

At weeks 2, 6, and 12, each participant's IOP level was measured in triplicate in each eye at 8 AM (predose), 10 AM, and 4 PM. For a given participant, the protocol requested that the same masked examiner use the same calibrated Goldmann applanation tonometer to measure IOP at each time point and at each visit. Biomicroscopic and visual acuity measurements were collected at each visit, and refraction and ophthalmoscopy were performed at week 12. Any change in the use of concomitant medications was noted at every visit.

All adverse events, whether observed by investigators or self-reported by participants, were monitored by investigators throughout the study. The severity of events (mild, moderate, or severe) and the investigator's opinion about whether the event was related to the study drug were noted. Serious adverse events were defined as events that were life-threatening, required inpatient hospitalization/prolongation of hospitalization, caused persistent or significant disability/incapacity, or resulted in a congenital anomaly, birth defect, or death. Adverse events were followed up until they resolved or stabilized. The protocol requested that the same masked examiner perform the same safety evaluations at each visit for a given participant throughout the study; assessments were to begin with the right eye. Adverse events were considered treatment-emergent if onset or worsening occurred on or after the baseline visit. Adverse events were classified by body system and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) coding system, version 10 (www.meddramsso.com/public_faq_meddra.asp).

During the double-masked phase, participants assigned to the FCLT group instilled 1 drop (active ingredients: 0.005% latanoprost and 0.5% timolol maleate) once daily in the evening and 1 drop of placebo once daily in the morning. Those randomized to receive latanoprost monotherapy administered 1 drop (active ingredient: 0.005% latanoprost) in the evening and 1 drop of placebo in the morning, whereas participants randomized to timolol monotherapy instilled 1 drop (active ingredient: 0.5% timolol maleate) in the morning and 1 drop of placebo in the evening. Morning and evening instillations were to occur at 8 AM and 8 PM, respectively, with a 30-minute variation allowed. Placebo was the vehicle of the fixed combination for each group. The initial morning dose of study medication was instilled the morning after randomization, and the last dose was instilled after the 8 AM IOP measurement at the final visit (week 12 [discontinuation visit]).

Participants received a kit of study medications (2.5-mL bottles sufficient for 4 weeks' use) at baseline and week 6. Each kit included 1 carton of bottles for the morning medication and 1 carton for the evening medication (3 bottles each, labeled “AM” and “PM,” respectively). Participants were advised that supplies should be protected from light and stored at between 2°C and 8°C before opening; opened bottles were to be stored at room temperature and used within 4 weeks.

The mean of the 3 IOP measurements taken in each eye at a given visit represented the mean IOP for that eye. The IOP of the eye that met all inclusion and no exclusion criteria (study eye) represented the subject's IOP; if both eyes qualified, the mean IOP of the 2 eyes was used. Efficacy analyses used only IOP measurements of study eye(s). A participant's diurnal IOP was the mean of IOP measurements at 8 AM, 10 AM, and 4 PM; if a measurement was missing, the diurnal IOP was the mean of nonmissing IOP measurements.

The primary efficacy analysis was based on mean IOP assessments of study eye(s) at 8 AM, 10 AM, and 4 PM at weeks 2, 6, and 12. At each time point for each of the 3 visits, an analysis of variance with treatment factor was used to compare IOP measurements in the FCLT group with corresponding measurements in each monotherapy group, resulting in 18 pairwise comparisons. For each set of comparisons, 95% confidence intervals (CIs) were constructed, and FCLT was considered statistically superior to monotherapy if the null hypothesis that the mean IOP in the combination-therapy group was less than or equal to the mean IOP in the monotherapy group was rejected at an α = .05 level. All 18 pairwise comparisons had to have statistically significant results to conclude that FCLT was superior to the monotherapies. Pairwise comparisons between monotherapies were not performed. The robustness of the analysis of variance was assessed using an analysis of covariance with treatment and baseline IOP strata as factors and baseline IOP as the covariate.

Other secondary efficacy end points were mean diurnal IOP at weeks 6 and 12; percentages of participants achieving prespecified percentage reductions in IOP from baseline to weeks 6 and 12 (from ≥5% to ≥40% in 5% increments); and percentages of participants attaining prespecified IOP levels after 6 and 12 weeks (from ≤22 to ≤15 mm Hg in 1–mm Hg increments). Between-group differences in mean diurnal IOP levels were analyzed using an analysis of covariance model with treatment and baseline IOP strata as factors and baseline IOP as the covariate. Differences in percentages were assessed using the Cochran-Mantel-Haenszel test (Fisher exact test where the expected marginal size was <5), controlling for baseline IOP strata.

All randomized participants were included in the intent-to-treat population. The intent-to-treat population, with observed and imputed cases (last observation carried forward), was used only to perform tests of superiority. Baseline evaluations were not carried forward, and missing week 2 IOP or diurnal IOP values were not imputed by the last observation carried forward. The safety population included all eyes of all randomized participants who received at least 1 dose of study medication. Safety analyses were conducted on observed cases with no imputation of missing values. Statistical analyses were performed using SAS statistical software, version 8.2 (SAS Institute Inc, Cary, North Carolina).

The sample size calculation was based on the goal of statistical significance at a 2-sided .05 level for an analysis of variance of all 18 pairwise comparisons between FCLT vs each of its individual components. Based on results from previous studies,^{19 - 20} measured IOP values were assumed to have an SD of approximately 3.4 mm Hg; therefore, 118 participants were required in each of the 3 treatment groups for the test to have a power of 0.92 to detect a 1.5–mm Hg treatment difference. Assuming that 5% of participants would have no postbaseline efficacy data, the study needed to randomize a total of 372 participants, 124 in each of the 3 treatment groups.

Fifty-eight centers enrolled 656 participants in the washout period between December 16, 2005, and June 12, 2007. A total of 421 participants (64.2%) were randomized (Figure 1). Twenty-seven participants (6.4%) were excluded from data analyses because of the loss of source data or protocol deviations; none had any serious adverse event reported during the study. Both the intent-to-treat and safety populations included 394 participants: FCLT, n = 129; latanoprost monotherapy, n = 134; and timolol monotherapy, n = 131. In all, 338 participants (85.8%) completed the study; reasons for premature withdrawal are summarized in Figure 1. The percentage of participants who did not complete the study was low and comparable across treatment groups (range, 11.6% for FCTL to 15.7% for latanoprost monotherapy). Twenty participants (5.9%), equally distributed across treatment groups, were considered protocol deviations because they were enrolled without meeting eligibility criteria and without prior sponsor approval.

Treatment groups were similar with respect to baseline demographic and clinical characteristics (Table 1). The primary diagnosis in the study eye was primary open-angle glaucoma, reported in more than 65% of participants in each group. Mean IOP levels were similar at both screening and baseline.

The median duration of treatment was 84.0 days in all groups. The mean IOP difference between the FCLT and latanoprost monotherapy groups (FCLT minus latanoprost monotherapy) ranged from –1.52 to –0.54 mm Hg and favored FCLT at all 9 measurement time points at the 3 study visits (Table 2). The superior efficacy of FCLT compared with latanoprost monotherapy was statistically significant at 7 of 9 time points, excluding the 4 PM measurement times at weeks 2 and 6. Mean IOP differences between the FCLT and timolol monotherapy groups (FCLT minus timolol) ranged from –3.79 to –2.14 mm Hg, favoring FCLT at all time points; differences were all statistically significant (Table 2). These findings were confirmed by analyses of variance based on observed cases and by analysis of covariance models (data not shown).

Mean diurnal IOP levels were comparable at baseline across groups but means were from 1.0 to 3.1 mm Hg lower in the FCLT group than in either monotherapy group at follow-up (P ≤ .03 for each pairwise comparison; Table 3). Results of analyses of percentages of participants achieving prespecified percentage reductions in diurnal IOP and reaching specific diurnal IOP levels also significantly favored FCLT over the monotherapies, particularly at the upper thresholds (week 12 findings are shown in Figure 2 and Figure 3, respectively).

All 3 ocular hypotensive therapies were safe and well tolerated. In all, 38 of 129 participants (29.5%) in the FCLT group, 49 of 134 (36.6%) in the latanoprost monotherapy group, and 31 of 131 (23.7%) in the timolol monotherapy group reported a total of 58, 68, and 48 adverse events, respectively. Serious adverse events were reported for 7 participants: 2 each in the FCLT and timolol monotherapy groups, 1 in the latanoprost monotherapy group, and 2 during the prerandomization phase of the study; none of these events was considered to be related to study medication. Two participants, both in the latanoprost monotherapy group, discontinued treatment because of adverse events. No deaths were reported during the study period.

The most commonly reported adverse events affected the eye. The overall incidence of ocular-related adverse events was similar in the FCLT and latanoprost monotherapy groups (23 of 129 [17.8%] and 32 of 134 [23.9%], respectively) and lower in the timolol group (14 of 131 [10.7%]). The most frequently occurring ocular adverse event in all 3 treatment groups was conjunctival hyperemia, affecting 9 participants (7.0%) treated with FCLT, 14 (10.4%) receiving latanoprost monotherapy, and 4 (3.1%) treated with timolol monotherapy (Table 4).

This study demonstrated that once-daily FCLT and once-daily monotherapy with the individual components all significantly reduce IOP levels from baseline. The superiority of FCLT was statistically significant at 7 of 9 measurement time points when compared with latanoprost monotherapy and at all 9 time points when compared with timolol monotherapy. The 2 points at which the fixed combination's superiority was not demonstrated with respect to latanoprost occurred at the 4 PM measurements at weeks 2 and 6; at week 12, the difference was statistically significant at 4 PM. In addition, FCLT was superior to both monotherapies in reducing mean diurnal IOP levels, and patients treated with FCLT were significantly more likely to achieve prespecified IOPs and IOP percentage reductions from baseline, especially at the upper thresholds. All 3 study treatments were well tolerated.

Although differences in latanoprost dosing schedules, outcome measures, and follow-up time frames between the present study and previous research^{19 - 20} limit direct comparisons, our findings concerning reductions in diurnal IOP levels in those treated with FCLT vs latanoprost generally are comparable to the findings of these earlier studies. In research conducted by Pfeiffer,²⁰ patients instilled FCLT or latanoprost once daily in the morning. The author found a –1.2-mm Hg difference favoring FCLT in mean change from baseline in diurnal IOP levels from weeks 2 to 26 (95% CI, –1.8 to –0.5; P < .001). The study by Higginbotham et al¹⁹ differed from the Pfeiffer study in that latanoprost was administered in the evening. During the 26-week study period, the least-squares mean difference between FCLT and latanoprost in IOP change from baseline was –1.0 mm Hg (95% CI, –1.7 to –0.3; P = .005).¹⁹ In the present study, in which both FCLT and latanoprost monotherapy were administered in the evening, the adjusted mean difference between FCLT and latanoprost monotherapy in diurnal IOP reduction from baseline to week 12 was –1.29 mm Hg (95% CI, –2.06 to –0.52; P = .001). Thus, the magnitude of the incremental diurnal IOP reduction with FCLT was similar across studies notwithstanding differences in designs.

A somewhat greater difference between FCLT and timolol monotherapy was found in the present study than was reported by Pfeiffer²⁰ or Higginbotham et al¹⁹ (mean difference in diurnal IOP reduction from baseline to week 12: –3.02 mm Hg [95% CI, –3.79 to –2.24; P < .001]; mean change from baseline in diurnal IOP from week 2 to week 26: –1.9 mm Hg [–2.5 to –1.2; P < .001]; and least-squares mean difference in change from baseline during 26 weeks: –2.9 mm Hg [–3.5 to –2.3; P < .001], respectively). This greater differential may be related to the once-daily instillation of timolol in the present study vs twice-daily administration.^{19 - 20} However, timolol administered once daily has been shown to achieve maximum IOP reduction.²² A study by Konstas et al²³ assessed 24-hour IOP control in patients treated with once-daily FCLT in the evening vs timolol monotherapy twice daily for 8 weeks. Both treatments significantly lowered IOP levels compared with untreated baseline values, and the difference between FCLT and timolol for the 24-hour curve was close in magnitude to that for mean diurnal IOP reduction found in the present study in which timolol was instilled once daily.

Differences between FCLT and each monotherapy at 4 PM were smaller than those at the morning (8 and 10 AM) measurement times at weeks 2 and 6. It is possible that the lower baseline IOP levels at 4 PM restricted IOP reductions at follow-up, making it more difficult to detect statistically significant between-treatment differences. This same consideration may apply to findings by Konstas et al,²⁴ whose 8-week crossover study evaluated the 24-hour efficacy of FCLT vs latanoprost both dosed once daily in the evening. The mean (SD) IOP reduction was greater in the morning for FCLT and latanoprost at 10 AM (10.1 [2.4] and 7.2 [2.5] mm Hg, respectively) than at 2 PM (7.3 [2.8] and 5.5 [2.3] mm Hg, respectively), but baseline mean IOP levels were 2 mm Hg higher at 10 AM than at 2 PM (26.5 vs 24.5 mm Hg, respectively). Differences between the present study and the Konstas et al study²⁴ make findings difficult to compare directly, however. For example, herein, all patients were being treated with a β-blocker at screening, whereas 5 of 37 patients included in the previous study²⁴ were treatment naive. In addition, we evaluated IOP during office hours only and did not exclude patients based on a history of noncompliance; in contrast, Konstas et al²⁴ assessed IOP levels over 24 hours and excluded those with a history of noncompliance.

As in previous studies,^{19 - 20} all 3 therapies were safe and well tolerated with no major differences among treatments in the occurrence of clinically relevant adverse events. No serious adverse event was judged to be related to any study medication, and discontinuations because of adverse events were rare. Hyperemia, the most common adverse event associated with prostaglandin use,^{25 - 27} occurred more frequently in the FCLT and latanoprost monotherapy groups than in the timolol monotherapy group.

The benefits of a fixed-combination drug to treat patients with either ocular hypertension or glaucoma include convenience, potential cost savings, and reduced exposure to preservatives (eg, purite, sofZia [Alcon, Fort Worth, Texas], benzalkonium chloride). Improved patient adherence is the ultimate goal because use of ocular hypotensive medication as prescribed over the long term can be expected to increase the probability of slowing or halting the progression of glaucoma. More complex medication regimens have been associated with poorer adherence in this patient population,^{4 - 8} suggesting that those treated with a fixed-combination therapy would be more likely to have better adherence compared with administration of the individual components. Physicians are interested in the likelihood of achieving a predetermined target pressure, which is based on the status of the patient's disease. The present study found that 58.1% of patients treated with FCLT had a 35% or greater reduction in diurnal IOP compared with baseline, which was statistically significantly greater than that achieved with the latanoprost or timolol monotherapies (39% and 16%, respectively; P = .002 and P < .001, respectively, for both between-group comparisons). In the Collaborative Initial Glaucoma Treatment Study,²⁸ aggressive medical treatment leading to IOP reductions of at least 35% was shown to halt progression over a 5-year period. Moreover, 55.0% of FCLT-treated patients achieved a target IOP of 18 mm Hg or less, the visual field progression threshold designated in the Advanced Glaucoma Intervention Study.³ The simplicity of FCLT coupled with the efficacy and tolerability of the formulation contribute to its utility in clinical practice, particularly among patients who require substantial IOP reductions.

In summary, FCLT is safe and effective in patients with either glaucoma or ocular hypertension. When used in clinical practice, it is important to assess the tolerability and the efficacy of the medication in each patient and to individualize care based on these assessments. The likelihood of achieving prespecified IOP levels when using FCLT vs either of its individual components is important in patient treatment. However, any given medical plan must be based on well-tolerated, effective, and simple therapeutic options. Although cost-effective treatment can be achieved for many patients with monotherapy, the combination should be considered when 2 drugs are needed to achieve the therapeutic goal.

Correspondence: Eve J. Higginbotham, MD, Office of the Senior Vice President for Health Sciences, Howard University, 2041 Georgia Ave NW, Ste 6000–Tower Building, Washington, DC 20060 (fcwejh6786@aol.com).

Submitted for Publication: March 16, 2009; final revision received June 30, 2009; accepted July 8, 2009.

Group Information: The United States Fixed-Combination Study Group Investigators are Dr Marc A. Abrams, Cleveland, Ohio; Dr Aaron J. Affleck, Idaho Falls, Idaho; Dr Lama A. Al-Aswad, New York, New York; Dr Louis M. Alpern, El Paso, Texas; Dr Kathleen F. Archer, Houston, Texas; Dr Gregg J. Berdy, Creve Coeur, Missouri; Dr Michael R. Bernstein, Birmingham, Alabama; Dr Ettaleah C. Bluestein, Charleston, South Carolina; Dr James D. Branch, Winston-Salem, North Carolina; Dr Bruce D. Cameron, Seattle, Washington; Dr Moiz M. Carim, Reading, Pennsylvania; Dr Tomas Coronado, San Antonio, Texas; Dr William F. Davitt, El Paso; Dr Donald J. Digby, Greensboro, North Carolina; Dr Richard M. Evans, San Antonio; Dr Brian E. Flowers, Fort Worth, Texas; Dr David G. Godfrey, Dallas, Texas; Dr Benjamin R. Hasty, Jr, Panama City, Florida; Dr Leon Herndon, Durham, North Carolina; Dr Andrew G. Iwach, San Francisco, California; Dr Mark S. Juzych, Detroit, Michigan; Dr Bruce E. Kanengiser, Piscataway, New Jersey; Dr Michale S. Korenfeld, Washington, Missouri; Dr Theodore Krupin, Chicago, Illinois; Dr Mark Anthony Latina, Reading, Massachusetts; Dr Howard S. Lazarus, New Albany, Indiana; Dr Charles M. Lederer, Jr, Kansas City, Missouri; Dr David A. Lee, Charleston, South Carolina; Dr Richard K. Lee, Miami, Florida; Dr Norman S. Levy, Gainesville, Florida; Dr Richard A. Lewis, Sacramento, California; Dr Andrew C. Lipka, Princeton, New Jersey; Dr Jonathan I. Macey, Los Angeles, California; Dr David L. McGarey, Flagstaff, Arizona; Dr Charles D. McMahon, Colorado Springs, Colorado; Dr Arash Mansouri, Fredericksburg, Virginia; Dr Joseph I. Markoff, Philadelphia, Pennsylvania; Dr Sayoko E. Moroi, Ann Arbor, Michigan; Dr Kenneth W. Olander, Maryville, Tennessee; Dr Kyle A. Parrow, Lecanto, Florida; Dr Jody R. Piltz-Seymour, Philadelphia; Dr Cadmus C. Rich, Durham; Dr Jay M. Rubin, San Antonio; Dr Kenneth N. Sall, Artesia, California; Dr Howard I. Schenker, Rochester, New York; Dr Charles E. Shrader, Wichita, Kansas; Dr Siriam Sonty, Calumet City, Illinois; Dr Jeffrey A. Spitzer, Brooklyn, New York; Dr John F. Stamler, Iowa City, Iowa; Dr Robert H. Stewart, Jr, Houston; Dr Andrew W. Tharp, Newburgh, Indiana; Dr Daniel B. Thatcher, Colorado Springs; Dr Jean H. Tibbetts, Bangor, Maine; Dr Carl B. Tubbs, Stillwater, Minnesota; Dr Thomas R. Walters, Austin, Texas; Dr Jon-Marc Weston, Roseburg, Oregon; Dr Robert D. Williams, Louisville, Kentucky; Dr David L. Wirta, Newport Beach, California.

Financial Disclosure: Drs Grunden, Kim, and Tressler and Mr Kwok are employees of Pfizer Inc.

Funding/Support: This research was supported by Pfizer Inc.

Additional Contributions: Jane G. Murphy, PhD, of Zola Associates provided editorial support, including revising the manuscript based on author feedback and styling the manuscript for journal submission. Gerald Bean, BS, an independent consultant, critically reviewed the manuscript.