Evaluation of Phentermine and Topiramate versus Phentermine/Topiramate Extended-Release in Obese Adults

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1 Evaluation of and Topiramate versus /Topiramate Extended-Release in Obese Adults Louis J. Aronne 1, Thomas A. Wadden 2, Craig Peterson 3, David Winslow 4, Sarah Odeh 5 and Kishore M. Gadde 6 Objective: A 28-week, randomized, controlled trial compared the combination of phentermine and topiramate extended-release () with its components as monotherapies and with placebo in obese adults. Design and Methods: Subjects were randomized to placebo, phentermine 7.5 mg, phentermine 15 mg, topiramate ER 46 mg, topiramate ER 92 mg, 7.5/46 mg, or 15/92 mg. All subjects received lifestyle intervention counseling. Primary endpoints were percent weight loss (WL) and achievement of 5% WL. Results: At week 28, 7.5/46 (28.5%) and 15/92 (29.2%) achieved greater percentage WL versus placebo (21.7%; P < ) and their respective monotherapies (P < 0.05). The percentage of subjects achieving 5% WL was 15.5% for placebo, 43.3% for phentermine 7.5, 46.2% for phentermine 15, 39.2% for topiramate ER 46, 48.6% for topiramate ER 92, 62.1% for 7.5/46, and 66.0% for 15/92. was generally well tolerated; comprehensive assessment of cognitive functions with the Repeatable Battery for Assessment of Neuropsychological Status revealed impairment only in the attention domain. Conclusions: demonstrated greater WL when used in combination than when used as monotherapies, suggesting enhanced ability of the combination formulation to induce WL at doses lower than with available monotherapies. (2013) 21, doi: /oby Introduction hydrochloride, as a monotherapy, is the most commonly used weight-loss (WL) medication in the United States (US), but it is approved for short-term use only (1). The topiramate immediate-release (IR) formulation is approved as a monotherapy for the treatment of epilepsy and prevention of migraines (2), and although not approved for WL, it had been evaluated as a potential WL therapy (3-7). The efficacy and safety of phentermine and topiramate in combination to treat obesity have been extensively tested in long-term randomized, controlled trials (RCTs) (8-10), leading to approval of a once-daily combination of phentermine and an extended-release (ER) formulation of topiramate () for chronic weight management in obese (body mass index [BMI] 30 kg/m 2 ) individuals or overweight (BMI 27 and <30 kg/m 2 ) individuals with 1 weight-related comorbidities (11). 1 Weill Cornell Medical College, New York, New York, USA. Correspondence: Louis J. Aronne (ljaronne@mail.med.cornell.edu) 2 Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA 3 VIVUS, Inc., Mountain View, California, USA 4 Kentucky Research Group, Louisville, Kentucky, USA 5 The Lockwood Group, Stamford, Connecticut, USA 6 Duke University Medical Center, Durham, North Carolina, USA Disclosure: Louis J. Aronne, MD, has received grants and consulting fees or honoraria from VIVUS, Inc. He has served as an advisor, board member, and consultant for Amylin Pharmaceuticals Inc., Ethicon Endo-Surgery Inc., GlaxoSmithKline Consumer Healthcare, LP, Novo Nordisk, Orexigen Therapeutics, Inc., VIVUS, Inc., and Zafgen Inc. He has also served as a consultant for Takeda Pharmaceuticals. He has received grants from GI Dynamics, Inc., Novo Nordisk, and Aspire Bariatrics. He owns stocks in CardioMetabolic Support Network LLC, MYOS Corporation, and Zafgen Inc. Thomas Wadden, PhD, has served as a consultant and advisor for VIVUS, Inc. He has participated in clinical trials and has received grants on behalf of the University of Pennsylvania from Merck, Novo Nordisk, NutriSystems, Orexigen Therapeutics, Inc., Weight Watchers, and VIVUS, Inc. He has also served as an advisory board member for Novo Nordisk and Orexigen Therapeutics, Inc. Craig Peterson, MS, is an employee of VIVUS, Inc. David Winslow, MD, has served as an advisor and consultant and has received consulting fees, honoraria, and support for travel to meetings by VIVUS, Inc. He has also participated in clinical studies funded by VIVUS, Inc. Sarah Odeh, BS, CMPP, is an employee of The Lockwood Group. The Lockwood Group provided editorial support for the creation of this manuscript, which was funded by VIVUS, Inc. Kishore M. Gadde, MD, has received grant support and support for travel to meetings by VIVUS, Inc. He has also received grant support and has participated in clinical trials supported by Amylin, Medical University of South Carolina, and VIVUS, Inc. He holds stock in Orexigen Therapeutics, Inc. Funding agencies: Financial support for the studies and funding for editorial assistance was provided by VIVUS, Inc. Additional Supporting Information may be found in the online version of this article. Received: 27 April 2013; Accepted: 18 July 2013; Published online 17 October doi: /oby VOLUME 21 NUMBER 11 NOVEMBER

2 versus Individual Components Aronne et al. FIGURE 1 CONSORT diagram. Subjects who provided an endpoint assessment consist of those who completed the study, on or off study drug. *Two subjects in the topiramate ER 46 mg group and one subject in the 7.5/46 group discontinued without ever receiving a dose of the study drug and have not been included in the safety analyses. AE, adverse event; d/c, discontinued; f/u, follow-up; ITT, intention-to-treat; PHEN, phentermine; TPM ER, topiramate extended-release; 7.5/46, phentermine 7.5 mg and topiramate extended-release 46 mg; 15/92, phentermine 15 mg and topiramate extended-release 92 mg. This article describes EQUATE (clinicaltrials.gov: NCT ), a placebo-controlled trial that used a factorial design to compare the efficacy and safety in obese adults of the combination of PHEN/ TPM ER with phentermine and topiramate ER as monotherapies and with placebo. Methods Study design This phase 3 RCT examined seven treatment arms: placebo, phentermine 7.5 mg, phentermine 15 mg, topiramate ER 46 mg, topiramate ER 92 mg, phentermine 7.5 mg and topiramate ER 46 mg ( 7.5/46), and phentermine 15 mg and topiramate ER 92 mg ( 15/92; Figure 1). The trial incorporated an ancillary lifestyle intervention for all subjects based on the LEARN VR Manual (Lifestyle, Exercise, Attitude, Relationships, Nutrition) and included counseling to reduce energy intake by 500 kcal/day, to monitor calorie intake with a food diary, and to increase physical activity as tolerated (12). Subjects discussed at brief monthly visits their progress in meeting these goals. Subjects discontinuing the study drug were encouraged to complete all study visits off-drug. Settings and subjects The trial was conducted between December 2007 and September 2008 at 34 US centers, was approved by each center s institutional review board, and was overseen by an independent data and safety monitoring board. All subjects gave written informed consent. Eligibility criteria included age years and BMI 30 and 45 kg/m 2. Exclusion criteria included use of phentermine or topiramate for any indication within the past 3 months, as well as weight gain or loss of >5 kg, use of a very-low-calorie diet, use of pharmacotherapy for WL, or participation in a formal WL program, also within the past 3 months. Full exclusion criteria are available in Supporting Information appendix. Randomization and interventions Subjects were stratified by gender and randomized to the seven treatment groups in equal ratios. Study subjects, staff, and sponsors were masked to assignment until after the trial was complete. Study drug capsules were masked to look identical for all drugs and doses. After a 2-week screening period, eligible subjects were started on phentermine 3.75 mg/day, topiramate ER at 23 mg/day, or at 3.75/23 mg/day, and doses were increased on a weekly basis to reach the assigned dose over a 4-week titration period; placebo dosing was identical. The titration period was followed by 24 weeks at the randomization dose. All subjects received the same lifestyle prescription irrespective of treatment assignment (12) VOLUME 21 NUMBER 11 NOVEMBER

3 Outcome measures Primary efficacy variables were percent WL and the percentage of subjects achieving 5% WL by week 28 in the intention-to-treat (ITT) population. Other efficacy variables included absolute WL (kg), percentage of subjects achieving 10% WL, and change in systolic and diastolic blood pressure (SBP and DBP), waist circumference, fasting glucose, HbA 1c, and inflammatory biomarkers (adiponectin and high-sensitivity C-reactive protein [hscrp]). Adverse events were monitored at each visit. Subjects who discontinued treatment were encouraged to continue with data assessments through study completion. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a brief (20-30 min), clinician-administered test designed to determine the neuropsychological status of adults aged years. It assesses cognitive function across five core domains using 12 tests. The five domains are defined by summing the scores on the following component tests: immediate memory (list learning and story memory); visuospatial/ constructional (figure copy and line orientation); language (picture naming and semantic fluency); attention (digit span and coding); and delayed memory (list recall, list recognition, story recall, and figure recall). The five index scores, named after the domains they assess, take the subject s age into account. During this study, RBANS was administered to subjects at weeks 0, 4, and 28/early termination (13). Effect sizes of , , and >0.8 were considered small, moderate, and large, respectively. This definition establishes a standard of clinical relevance that occurs for effect sizes >0.5 (14). Depression and suicidality were also assessed at each visit using the Patient Health Questionnaire (PHQ)-9 and Columbia Suicide Severity Rating Scale (C-SSRS), as previously described (8,9). Statistical analyses Analysis of continuous variables, including percent WL and other efficacy variables, was performed using an analysis of covariance model with treatment and gender as fixed effects and baseline weight as a covariate. Analysis of categorical variables, including percentages of subjects with 5% WL, was performed using a logistic regression model with treatment and gender as fixed effects and baseline weight as a covariate. Efficacy analyses compared differences between baseline and week 28 across treatments in the ITT population (i.e., all randomized subjects who provided a baseline measurement of body weight, received 1 dose of study drug, and had 1 postdose assessment of body weight). For subjects who discontinued the study before completion, missing data were imputed using last observation carried forward (LOCF). Percent WL was also evaluated using a modified ITT analysis, which was defined as all randomized subjects who provided a baseline measurement of body weight, received 1 dose of study drug, and had 1 postdose assessment of body weight within 7 days of the last dose of study drug. To demonstrate the effectiveness of the combination therapy, significance for each of the three pairwise comparisons (i.e., combination vs. each single agent in the combination and combination vs. placebo) at the 5% alpha level using two-sided tests was tested. A stepdown multiple testing procedure was used to control the overall type I error. The hypothesis that the 15/92 dose was effective was tested first. If the efficacy of this dose was confirmed, then comparisons between the 7.5/46 dose and its constituents and between the 7.5/46 dose and the 15/92 dose constituents would be evaluated sequentially. Safety analyses were conducted on all randomized subjects who received 1 dose of study drug. Treatment-emergent adverse events were defined as starting on or after the first dose of the study drug and up to 28 days after the last dose. Changes in PHQ-9 scores were summarized by treatment group and using descriptive statistics and 95% confidence intervals (CIs). For each item of the C-SSRS, the number of yes responses at each study visit was summarized by treatment group. Changes from baseline in RBANS and corresponding effect sizes were summarized by treatment group using descriptive statistics and 95% CIs. Role of the funding source This work was fully funded by VIVUS, Inc. External authors, as well as the funding sponsor, participated in initial study design, data analysis, and reporting. Results In total, 756 subjects were randomized to one of the seven treatment arms (Figure 1). The majority of subjects were female (79.2%) and Caucasian (79.2%), with a mean age of years. At baseline, subjects had a mean weight of kg, BMI of kg/m 2, waist circumference of cm, SBP of mm Hg, DBP of mm Hg, and heart rate of beats per minute (Table 1). Of the 756 subjects, 541 (71.6%) completed all study visits, 495 (65.5%) completed all study visits on study drug, whereas 261 (34.5%) discontinued study drug, with rates similar between treatment groups (Figure 1). The most common reasons for discontinuation were adverse events (12.4%), loss to follow-up (8.7%), and withdrawal of consent (5.6%). Weight loss After 28 weeks of treatment, mean percent WL with PHEN/ TPM ER 7.5/46 was significantly greater than with either placebo (P < ) or the combination s individual components at all time points (P < 0.05; mitt and ITT-LOCF; Figure 2). The PHEN/ TPM ER 7.5/46 group also achieved statistically greater WL versus phentermine 15 or topiramate ER 92 at week 28 in the ITT-LOCF population (P < 0.05; Figure 2; Supporting Information Figure S1). 15/92 also induced greater WL than either placebo (P < 0.05) or the combination s individual components at all time points in both the mitt and ITT-LOCF analyses (P < 0.05; Figure 2; Supporting Information Figure S1). This percent WL translated to an absolute WL of 8.3 kg for the 7.5/46 group and 9.0 kg for the 15/92 group, compared with 1.5 kg for placebo, 5.3 kg for phentermine 7.5, 4.7 kg for topiramate ER 46, 6.0 kg for phentermine 15, and 6.4 kg for topiramate ER 92. More subjects receiving 7.5/46 achieved 5% and 10% WL than with placebo (P < ; Table 2) or with its individual components, phentermine 7.5 and topiramate ER 46. Subjects in the 7.5/46 group also achieved 5% and 10% WL at higher percentages than did those assigned to phentermine 15 or topiramate ER 92 (P < 0.05 for all comparisons except 5% WL VOLUME 21 NUMBER 11 NOVEMBER

4 versus Individual Components Aronne et al. TABLE 1 Baseline demographics and clinical characteristics (randomized population) Parameter Placebo (n 5 109) 7.5 (n 5 109) 46 (n 5 108) 7.5/46 (n 5 107) 15 (n 5 108) 92 (n 5 107) 15/92 (n 5 108) Mean age, years (SD) 45.0 (11.43) 46.4 (11.57) 46.9 (12.62) 44.6 (11.07) 45.7 (12.38) 45.8 (11.21) 44.6 (12.84) Female, n (%) 86 (78.9) 86 (78.9) 86 (79.6) 85 (79.4) 86 (79.6) 85 (79.4) 85 (78.7) Race, n (%) Caucasian 83 (76.1) 81 (74.3) 95 (88.0) 80 (74.8) 90 (83.3) 82 (76.6) 88 (81.5) African 25 (22.9) 26 (23.9) 11 (10.2) 26 (24.3) 14 (13.0) 22 (20.6) 16 (14.8) Asian 0 (0.0) 2 (1.8) 2 (1.9) 0 (0.0) 1 (0.9) 2 (1.9) 2 (1.9) Other a 1 (0.9) 2 (1.8) 2 (1.9) 1 (0.9) 3 (2.8) 2 (1.9) 3 (2.8) Mean weight, kg (SD) b (12.96) (15.06) (16.32) (16.48) (16.36) (15.61) 99.3 (15.59) Mean BMI, kg/m 2 (SD) c 36.2 (3.94) 36.3 (3.97) 36.1 (4.10) 36.6 (3.94) 36.2 (4.22) 37.0 (4.31) 35.9 (3.91) Mean WC, cm (SD) b (9.49) (10.77) (11.48) (12.87) (11.34) (11.28) (10.53) Mean SBP, mm Hg (SD) b (14.11) (12.91) (13.65) (12.15) (13.35) (14.06) (12.39) Mean DBP, mm Hg (SD) b 78.5 (9.64) 78.8 (7.67) 78.8 (8.65) 80.2 (8.62) 78.1 (8.89) 80.8 (9.29) 77.7 (10.25) Mean heart rate, bpm (SD) b 72.4 (9.74) 72.9 (9.57) 72.2 (9.54) 72.8 (9.96) 72.5 (10.64) 73.4 (9.49) 72.7 (9.57) Use of selective serotonin reuptake inhibitors b,d 10 (9.2) 14 (12.8) 14 (13.2) 13 (12.3) 14 (13.0) 11 (10.3) 11 (10.2) History of hypertension, n (%) b 36 (33.0) 35 (32.1) 24 (22.6) 25 (23.6) 37 (34.3) 29 (27.1) 32 (29.6) History of dyslipidemia, n (%) b 24 (22.0) 28 (25.7) 33 (31.1) 18 (17.0) 38 (35.2) 29 (27.1) 26 (24.1) BMI, body mass index; bpm, beats per minute; DBP, diastolic blood pressure; 15/92, phentermine 15 mg and topiramate extended-release 92 mg; 7.5/46, phentermine 7.5 mg and topiramate extended-release 46 mg; SBP, systolic blood pressure; SD, standard deviation; WC, waist circumference. a Other includes American Indian, Alaskan native, native Hawaiian, or other Pacific Islander. b Two topiramate ER 46 and one 7.5/46 were missing baseline values. c Two topiramate ER 46 and two 7.5/46 were missing baseline values. d Safety set (additional data regarding antidepressant medication use can be found in Supporting Information Table S3) VOLUME 21 NUMBER 11 NOVEMBER

5 FIGURE 2 LS mean percent weight loss overtime (mitt). P < 0.05 vs. placebo at all time points except week 0 for all comparisons between and placebo or the individual components except 7.5/46 vs. topiramate ER 92 at weeks 20, 24, and 28 in the mitt population. All week 28 comparisons between and placebo or the individual components in the ITT- LOCF population were significant. LS, least squares; 15/92, phentermine 15 mg and topiramate extended-release 92 mg; PHEN 15, phentermine 15 mg; TPM ER 92, topiramate extended-release 92 mg; 7.5/46, phentermine 7.5 mg/topiramate extended-release 46 mg; PHEN 7.5, phentermine 7.5 mg; TPM ER 46, topiramate extended-release 46 mg. for 7.5/46 vs. topiramate ER 92). In addition, the 15/92 group had greater numbers of subjects with 5% WL versus placebo, phentermine 15, or topiramate ER 92 treatment groups (P < 0.05, all comparisons; Table 2). Cardiometabolic parameters Greater improvements in SBP were observed among subjects receiving compared with placebo (P < 0.05 vs. placebo; Figure 3). Improvements in DBP were not significant versus placebo or versus the individual phentermine and topiramate ER components (Figure 3). Significantly greater improvements with the combination doses versus placebo or some of the individual components were observed in waist circumference, HbA 1c, and adiponectin, but improvements were not significant with fasting glucose and hscrp (Table 3). Adverse events Most treatment-emergent adverse events (Table 4) were mild to moderate in severity. There were no deaths during the study. In total, seven (0.9%) subjects had a serious adverse events: two (1.8%) subjects in the phentermine 7.5 mg group (pelvic mass, hypotension, jaundice cholestatic, and malignant neoplasm of ampulla of vater), one (0.9%) in the 7.5/46 group (appendicitis), one (0.9%) in the phentermine 15 mg group (chest pain), one (0.9%) in the topiramate ER 92 group (arrhythmia), and two (1.9%) with 15/92 (blurred vision and humerus TABLE 2 Percentage of subjects achieving 5% or 10% weight loss from baseline to week 28 (ITT-LOCF) Variable Placebo (n 5 103) 7.5 (n 5 104) 46 (n 5 102) 7.5/46 (n 5 103) 15 (n 5 106) 92 (n 5 105) 15/92 (n 5 103) 5% weight loss, n (%) 16 (15.5) 45 (43.3) 40 (39.2) 64 (62.1) a-e 49 (46.2) 51 (48.6) 68 (66.0) a,d,f 10% weight loss, n (%) 7 (6.8) 13 (12.5) 19 (18.6) 40 (38.8) a-d,f 22 (20.8) 25 (23.8) 42 (40.8) a,d,f ITT, intention-to-treat; LOCF, last observation carried forward; 15/92, phentermine 15 mg and topiramate extended-release 92 mg; 7.5/46, phentermine 7.5 mg and topiramate extended-release 46 mg. a P < vs. placebo. b P < 0.01 vs. phentermine 7.5. c P < 0.01 vs. topiramate ER 46. d P < 0.05 vs. phentermine 15. e P vs. topiramate ER 92. f P < 0.05 vs. topiramate ER VOLUME 21 NUMBER 11 NOVEMBER

6 FIGURE 3 LS mean change in systolic and diastolic blood pressure from baseline to week 28 in the ITT-LOCF population. *P vs. placebo; P vs. phentermine 7.5; P vs. placebo. ITT, intention-to-treat; LOCF, last observation carried forward; LS, least squares; 15/92, phentermine 15 mg and topiramate extended-release 92 mg; PHEN 15, phentermine 15 mg; TPM ER 92, topiramate extended-release 92 mg; PHEN/ TPM ER 7.5/46, phentermine 7.5 mg and topiramate extended-release 46 mg; PHEN 7.5, phentermine 7.5 mg; TPM ER 46, topiramate extended-release 46 mg. TABLE 3 Change in cardiometabolic parameters and inflammatory biomarkers from baseline to week 28 Variable Placebo / /92 Waist circumference (ITT-LOCF) n Baseline mean, cm (SD) (9.62) (10.99) (11.57) (12.80) (11.24) (11.05) (10.06) LS mean change, cm (SE) 23.3 (0.72) 26.4 (0.72) 25.4 (0.72) 28.8 (0.73) a-e 26.6 (0.71) 26.2 (0.72) 28.7 (0.72) a,d,e HbA 1c (ITT-LOCF) n Baseline mean, % (SD) 5.4 (0.41) 5.5 (0.40) 5.5 (0.43) 5.4 (0.42) 5.4 (0.37) 5.5 (0.38) 5.5 (0.43) LS mean change, % (SE) 0.1 (0.02) 0.1 (0.02) 0.1 (0.02) 20.0 (0.02) a-c 0.1 (0.02) 20.0 (0.02) 20.0 (0.02) a,d Fasting glucose (ITT-LOCF) n Baseline mean, mmol/l (SD) 5.3 (0.59) 5.2 (0.53) 5.2 (0.55) 5.2 (0.55) 5.2 (0.53) 5.3 (0.5) 5.3 (0.55) LS mean change, mmol/l (SE) (0.06) (0.06) (0.06) (0.06) (0.08) (0.06) (0.06) hscrp (safety set) n Baseline mean, mg/l (SD) 5.41 (4.991) 6.37 (9.073) 6.38 (8.377) 5.40 (4.887) 6.31 (6.176) 6.94 (6.151) 7.44 (7.322) LS mean change, mg/l (SE) (1.036) (1.027) (1.044) (1.019) (1.027) (1.008) (1.012) Adiponectin (safety set) n Baseline mean, mg/ml (SD) 8.39 (4.885) 8.41 (4.863) 9.27 (5.775) 7.87 (4.868) 8.12 (4.386) 8.50 (4.756) 8.10 (4.122) LS mean change, mg/ml (SE) (0.235) 0.41 (0.233) 0.16 (0.233) 0.62 (0.231) a,e 0.65 (0.231) (0.230) 1.21 (0.226) a,e n is the number of subjects with a measurement at both baseline and week 28. hscrp, high-sensitivity C-reactive protein; ITT, intention-to-treat; LOCF, last observation carried forward; LS, least squares; 15/92, phentermine 15 mg and topiramate extended-release 92 mg; 7.5/46, phentermine 7.5 mg and topiramate extended-release 46 mg; SE, standard error. a P vs. placebo. b P < 0.05 vs. phentermine 7.5. c P < 0.05 vs. topiramate ER 46. d P < 0.05 vs. phentermine 15. e P < 0.05 vs. topiramate ER 92.

7 TABLE 4 Summary of treatment-emergent adverse events (5% of subjects in any treatment group) by preferred term (safety set) Preferred term, n (%) Placebo (n 5 109) 7.5 (n 5 109) 46 (n 5 106) 7.5/46 (n 5 106) 15 (n 5 108) 92 (n 5 107) 15/92 (n 5 108) Paresthesia 4 (3.7) 3 (2.8) 12 (11.3) 17 (16.0) 5 (4.6) 24 (22.4) 25 (23.1) Dry mouth 0 (0.0) 8 (7.3) 7 (6.6) 14 (13.2) 13 (12.0) 7 (6.5) 20 (18.5) Headache 14 (12.8) 14 (12.8) 8 (7.5) 16 (15.1) 11 (10.2) 11 (10.3) 17 (15.7) Constipation 9 (8.3) 4 (3.7) 7 (6.6) 7 (6.6) 9 (8.3) 6 (5.6) 17 (15.7) Dysgeusia 0 (0.0) 1 (0.9) 7 (6.6) 9 (8.5) 1 (0.9) 2 (1.9) 16 (14.8) Upper respiratory tract infection 12 (11.0) 9 (8.3) 13 (12.3) 14 (13.2) 9 (8.3) 14 (13.1) 14 (13.0) Nasopharyngitis 11 (10.1) 6 (5.5) 10 (9.4) 3 (2.8) 10 (9.3) 9 (8.4) 11 (10.2) Insomnia 6 (5.5) 7 (6.4) 4 (3.8) 13 (12.3) 12 (11.1) 5 (4.7) 11 (10.2) Fatigue 7 (6.4) 3 (2.8) 8 (7.5) 6 (5.7) 6 (5.6) 7 (6.5) 10 (9.3) Dizziness 2 (1.8) 5 (4.6) 7 (6.6) 4 (3.8) 3 (2.8) 4 (3.7) 9 (8.3) Cough 7 (6.4) 2 (1.8) 4 (3.8) 1 (0.9) 6 (5.6) 1 (0.9) 9 (8.3) Nausea 5 (4.6) 5 (4.6) 8 (7.5) 9 (8.5) 6 (5.6) 5 (4.7) 8 (7.4) Back pain 6 (5.5) 9 (8.3) 4 (3.8) 3 (2.8) 0 (0.0) 3 (2.8) 8 (7.4) Influenza 5 (4.6) 3 (2.8) 6 (5.7) 6 (5.7) 5 (4.6) 2 (1.9) 6 (5.6) Diarrhea 5 (4.6) 1 (0.9) 3 (2.8) 4 (3.8) 4 (3.7) 6 (5.6) 6 (5.6) Bronchitis 3 (2.8) 2 (1.8) 2 (1.9) 6 (5.7) 3 (2.8) 2 (1.9) 5 (4.6) Sinusitis 6 (5.5) 3 (2.8) 5 (4.7) 2 (1.9) 8 (7.4) 5 (4.7) 4 (3.7) Disturbance in attention 1 (0.9) 1 (0.9) 2 (1.9) 7 (6.6) 1 (0.9) 4 (3.7) 4 (3.7) Vision blurred 5 (4.6) 6 (5.5) 8 (7.5) 7 (6.6) 7 (6.5) 7 (6.5) 5 (4.6) Irritability 2 (1.8) 6 (5.5) 3 (2.8) 2 (1.9) 2 (1.9) 1 (0.9) 5 (4.6) 7.5/46, phentermine 7.5 mg and topiramate extended-release 46 mg; 15/92, phentermine 15 mg and topiramate extended-release 92 mg. fracture). None of the serious adverse events was considered by the investigators to be related to study drug. A total of 94 (12.5%) subjects discontinued study drug owing to any adverse event, with more subjects discontinuing study drug from the 7.5/46 (15.1%) and 15/92 (21.3%) groups than from the placebo group (7.3%). Seventy-two (9.6%) subjects discontinued study drug owing to a drug-related treatment-emergent adverse event (based on investigator attribution), and one subject from the PHEN/ TPM ER 15/92 group discontinued treatment owing to a serious adverse event (humerus fracture). One subject in the topiramate 92 group experienced a serious adverse event (arrhythmia), which resolved with sequelae; the remaining serious adverse events resolved without sequelae. An increase in heart rate was observed in the phentermine monotherapy groups, whereas the placebo, topiramate ER monotherapy, and combination groups all experienced a decrease in heart rate (Table 5). The RBANS assessment of cognitive function demonstrated a doserelated decrement in total index score among subjects treated with both doses of relative to placebo at week 4 with placebo-compared effect sizes of 0.30 and 0.42 for 7.5/46 and 15/92, respectively (Supporting Information Table S1). This cognitive deficit was mainly due to changes in the attention (placebo-compared effect sizes of 0.58 and 0.66 for TABLE 5 Changes in heart rate from baseline to week 28 (safety set) Placebo / /92 Heart rate (bpm) n Baseline mean (SD) 72.4 (9.74) 72.9 (9.57) 72.2 (9.54) 72.8 (9.96) 72.5 (10.64) 73.4 (9.49) 72.7 (9.57) Mean change (SD) 21.9 (9.42) 0.9 (9.90) 23.8 (10.00) 21.6 (10.46) 1.1 (10.57) 24.5 (9.13) 21.6 (11.68) n is the number of subjects with a measurement at both baseline and week 28. bpm, beats per minute; 7.5/46, phentermine 7.5 mg and topiramate extended-release 46 mg; 15/92, phentermine 15 mg and topiramate extended-release 92 mg, SD, standard deviation. VOLUME 21 NUMBER 11 NOVEMBER

8 versus Individual Components Aronne et al. 7.5/46 and 15/92 at week 4, respectively) and delayed memory index scores (placebo-compared effect sizes of 0.25 and 0.30 for 7.5/46 and PHEN/ TPM ER 15/92, respectively). Although effects on total index score were attenuated at week 28 (placebo-compared effect sizes of 0.14 and 0.32 for 7.5/46 and 15/92, respectively), impairments in the attention domain (placebo-compared effect sizes of 0.39 and 0.70 for 7.5/46 and 15/92, respectively) remained constant throughout study treatment. Effects on cognitive domains were comparable to the effects observed with topiramate ER monotherapy (Supporting Information Table S1). Attention was the only domain that exceeded the clinically relevant effect size threshold of 0.5 with PHEN/TPM ER (i.e., effect sizes of were considered small, were considered moderate, and >0.8 were considered large) (14). With regard to mood changes, all treatment groups experienced an improvement from baseline in the PHQ-9 total score, and no clinically important differences were noted among treatment groups (Supporting Information Table S2). There were also no differences in response to the C-SSRS assessment of suicidal ideation and behavior among treatment groups. Discussion This 28-week study found that combining phentermine with an ER formulation of topiramate produced significantly greater WL than either component as a monotherapy. Importantly, the PHEN/ TPM ER 7.5/46 dose produced greater WL than did higher doses of monotherapy. This suggests that the combination of is more effective in increasing WL than is increasing the dose of monotherapies and also satisfies FDA guidance for fixed-dose combination drug treatments for obesity (15,16). The combination formulation of was designed to allow once-daily dosing, with phentermine released in the morning and topiramate ER released in the evening. When taken in the morning, the immediate release of phentermine allows for peak exposure in the morning, whereas the delayed release of topiramate ER lowers the maximum observed plasma drug concentration by 29% and delays the time to maximum plasma concentration by 7 h, allowing for peak topiramate ER exposure to occur in the late afternoon and evening. The apparent half-life of phentermine and topiramate was shown to be 20 and 65 h, respectively. This pharmacokinetic profile may be responsible for the improved efficacy and tolerability of the combination doses versus their monotherapy counterparts (17). The American Diabetes Association, the American Heart Association, and the National Heart, Lung, and Blood Institute recommend WL of 5-10% for obese and overweight subjects with or without weight-related comorbidities (18-20). The combinations of PHEN/ TPM ER 7.5/46 and 15/92 helped more subjects achieve these goals, with significantly more subjects achieving WL of 5% and 10% compared with all monotherapy arms except for topiramate ER 92. The efficacy of 15/92 further exceeded that of each individual agent and placebo. This suggests that the doses used in this combined formulation allow for a decreased dosing level without loss of efficacy. The improvements in SBP in this study induced by 7.5/46 and 15/92 were greater than those achieved with phentermine monotherapy. The 7.5/46 dose produced reductions in SBP that also were greater than those observed with phentermine 15 or topiramate ER 92 monotherapy. As with previous studies of an IR topiramate for WL (3,4,7), SBP was improved with topiramate ER in this study. Because of the significant influence of the topiramate ER component, the PHEN/ TPM ER combination group did not always show improvements in SBP that were significantly greater versus the topiramate ER monotherapy arms. HbA 1c was also improved with the 7.5/46 dose versus its individual components, but the improvement with 15/92 was not statistically significant versus topiramate ER. This is in line with a previous RCT of topiramate controlled release, in which the mean change from baseline for HbA 1c was significantly improved with topiramate controlled release (20.9%) versus placebo (20.4%) after 16 weeks in obese and overweight subjects with type 2 diabetes (P < 0.001) (4). The combination led to greater improvements in waist circumference compared with the individual component arms. Taken together, this suggests that the combination of may provide greater WL and related metabolic improvements than either agent as a monotherapy. The risk of increased heart rate with phentermine appeared to be mitigated by the addition of topiramate ER. This may have occurred because of the additional WL achieved with topiramate ER, which would tend to reduce or minimize an increase in heart rate (21,22). Further, psychomotor slowing, difficulty with memory and concentration/ attention, and confusion are well-documented adverse effects of topiramate (2). In this study, cognitive deficits at weeks 4 and 28 were driven primarily by changes in the attention index score of the RBANS tests of cognitive function. At week 28, no clinically important treatment differences in immediate memory, visuospatial/constructional, language, and delayed memory scores were noted. Small decrements were observed with the combination arms and topiramate ER monotherapy, suggesting that topiramate ER, when given alone or in combination with phentermine, may lead to some impairment in cognition, with attention being the most affected. The EQUATE study had several limitations. The study duration was only 28 weeks, which may have been too short to observe maximum changes in weight and cardiometabolic parameters, including blood pressure, and in lipid and glycemic parameters. In this trial, for topiramate monotherapy, an ER formulation was used, thus making comparisons to the FDA-approved topiramate IR challenging. In addition, a low-intensity program of behavior modification was used; larger WLs may have been achieved with a higher intensity program of lifestyle modification (23). In conclusion, phentermine and topiramate ER demonstrated an additive effect on WL when used in combination, and PHEN/TPM ER was generally well tolerated. Importantly, the combination dose of 7.5/46 induced greater WL, not only compared with its individual components, phentermine 7.5 and topiramate ER 46, but also compared with phentermine 15 and topiramate ER 92. The 7.5/46 dose was also associated with improvements in some cardiometabolic parameters versus placebo and phentermine 7.5 monotherapy, with additional WL and cardiometabolic benefits seen with 15/92. These results suggest the enhanced ability of the combination, once-daily ER formulation,, to induce WL and improve cardiometabolic parameters at doses lower than with available monotherapies. O 2170 VOLUME 21 NUMBER 11 NOVEMBER

9 Acknowledgments Study design was performed by TW, CP, and KMG. Data collection was performed by LJA, TW, DW, and KMG. Data analysis was performed by LJA, CP, and KMG. Data interpretation was performed by LJA, TW, CP, DW, SO, and KMG. All authors were involved in writing the paper and had final approval of the submitted and published versions. Barbara Troupin, MD, MBA (VIVUS, Inc.), provided review for medical accuracy. The Lockwood Group provided editorial assistance for this manuscript. VC 2013 The Society References 1. Bray GA, Ryan DH. Medical therapy for the patient with obesity. Circulation 2012; 125: Topamax VR [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; Bray GA, Hollander P, Klein S, et al. A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obes Res 2003;11: Rosenstock J, Hollander P, Gadde KM, Sun X, Strauss R, Leung A; OBD-202 Study Group. A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of topiramate controlled release in the treatment of obese type 2 diabetic patients. Diabetes Care 2007;30: Tonstad S, Tykarski A, Weissgarten J, et al. Efficacy and safety of topiramate in the treatment of obese subjects with essential hypertension. Am J Cardiol 2005;96: Toplak H, Hamann A, Moore R, et al. Efficacy and safety of topiramate in combination with metformin in the treatment of obese subjects with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Int J Obes 2007;31: Wilding J, Van Gaal L, Rissanen A, Vercruysse F, Fitchet M; OBES-002 Study Group. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects. Int J Obes Relat Metab Disord 2004;28: Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/ topiramate in severely obese adults: a randomized controlled trial (EQUIP). 2012;20: Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet 2011;377: Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr 2012;95: Qsymia VR (phentermine and topiramate extended-release) [package insert]. Mountain View, CA: VIVUS, Inc.; Brownell K. The LEARN VR Program for Weight Management. Dallas, TX: The Life Style Company; Randolph C. Repeatable Battery for the Assessment of Neuropsychological Status. San Antonio, TX: The Psychological Coporation; Wyrwich KW, Bullinger M, Aaronson N, Hays RD, Patrick DL, Symonds T; Clinical Significance Meeting Group. Estimating clinically significant differences in quality of life outcomes. Qual Life Res 2005;14: Boozer CN, Leibel RL, Love RJ, Cha MC, Aronne LJ. Synergy of sibutramine and low-dose leptin in treatment of diet-induced obesity in rats. Metabolism 2001;50: U.S. Department of Health and Human Services. Food and Drug Administration. Guidance for industry developing products for weight management: draft guidance 2007 [WWW document]. URL ucm pdf. 17. VI-0521 (QNEXA VR ) Advisory Committee Briefing Document. NDA [WWW document]. URL CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCom mittee/ucm pdf. 18. American Diabetes Association. Standards of medical care in diabetes Diabetes Care 2013;36 (Suppl 1):S11-S Klein S, Burke LE, Bray GA, et al.; American Heart Association Council on Nutrition, Physical Activity, and Metabolism. Clinical implications of obesity with specific focus on cardiovascular disease: a statement for professionals from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology Foundation. Circulation 2004;110: National Heart, Lung, and Blood Institute. Identification, evaluation, and treatment of overweight and obesity in adults [WWW document]. URL Arone LJ, Mackintosh R, Rosenbaum M, Leibel RL, Hirsch J. Autonomic nervous system activity in weight gain and weight loss. Am J Physiol 1995;269:R222-R Hirsch J, Mackintosh RM, Aronne LJ. The effects of drugs used to treat obesity on the autonomic nervous system. Obes Res 2000;8: Wadden TA, Berkowitz RI, Womble LG, et al. Randomized trial of lifestyle modification and pharmacotherapy for obesity. N Engl J Med 2005;353: VOLUME 21 NUMBER 11 NOVEMBER