Emerging Treatments and Technologies ORIGINAL ARTICLE 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 1 4 JULIO ROSENSTOCK, MD RICHARD STRAUSS, MD besity and weight gain are major 2 4 PRISCILLA HOLLANDER, MD ALBERT LEUNG, MD, PHD factors for type 2 diabetes (1,2), and 3 KISHORE M. GADDE, MD FOR THE OBD-202 STUDY GROUP 4 nearly 90% of the population with IANG UN PHD O X S , type 2 diabetes is considered overweight or obese (3). Weight reduction can signif- icantly improve multiple parameters of OBJECTIVE — This is a randomized, placebo-controlled study of the weight-loss efficacy metabolic control (4). and safety of a controlled-release (CR) formulation of topiramate in overweight and obese Topiramate has been approved in many patients with type 2 diabetes treated with diet and exercise alone or in combination with countries for the treatment of seizure disor- metformin. ders and the prophylaxis of migraine head- aches (5). Weight loss was incidentally but RESEARCH DESIGN AND METHODS — Patients with type 2 diabetes, BMI Ն27 consistently observed in most of the studies kg/m2, A1C Ͼ6.5 and Ͻ11.0%, treated with diet and exercise alone or in combination with in these neurologic indications, despite no metformin monotherapy were enrolled. Patients were randomized to placebo or topiramate CR specific dietary interventions. Recently re- titrated up to 175 mg/day. Treatment consisted of a 7-week titration phase followed by a 9-week ported placebo-controlled trials performed maintenance phase. in nondiabetic and diabetic populations have shown that treatment with topiramate RESULTS — A total of 111 subjects were randomized and analyzed. By the end of week (immediate release formulation dosed twice 16, patients in the placebo and topiramate groups lost 2.5 and 6.0 kg, which represented 2.3 daily) can induce significant weight loss (6– and 5.8%, respectively, of their baseline body weight (P Ͻ 0.001 vs. placebo). A1C im- 11). The controlled-release (CR) formula- proved from a baseline of 7.4% in the placebo and 7.6% in the topiramate groups to 7.1 and tion of topiramate that utilizes an osmotic 6.7%, respectively, representing a 0.4 and 0.9% reduction from baseline, respectively (P Ͻ pump technology was developed to deliver 0.001 vs. placebo). Topiramate also significantly reduced blood pressure and urinary albu- once-daily dosing with improved tolerabil- min excretion. Adverse events were predominantly neuropsychiatric or central and periph- ity (12). eral nervous system related. This study aimed to evaluate the effi- cacy and safety of topiramate CR as a phar- CONCLUSIONS — Topiramate CR treatment produced significant weight loss and mean- macological adjunct in patients with type 2 ingful improvements in A1C and blood pressure in obese patients with type 2 diabetes treated diabetes treated with diet and exercise alone with diet and exercise or in combination with metformin. However, the central nervous system or in combination with metformin. and psychiatric adverse event profile of topiramate CR makes it unsuitable for the treatment of obesity and diabetes. Diabetes Care 30:1480–1486, 2007 RESEARCH DESIGN AND METHODS — This study was spon- sored by Johnson & Johnson Pharmaceu- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● tical Research & Development, LLC From the 1Dallas Diabetes and Endocrine Center, Dallas, Texas; 2Baylor Hospital, Dallas, Texas; 3Duke (Raritan, NJ), conducted in accordance University School of Medicine, Durham, North Carolina; and 4Johnson & Johnson Pharmaceutical Research with the Declaration of Helsinki and ICH & Development, Raritan, New Jersey. Good Clinical Practice, and approved by Address correspondence and reprint requests to Julio Rosenstock, MD, Dallas Diabetes and Endocrine Center at Medical City, 7777 Forest Lane, C-685, Dallas, TX 75230. E-mail: [email protected]. ethics committees at all sites. All patients Received for publication 25 September 2007 and accepted in revised form 6 March 2007. provided full written informed consent Published online ahead of print at http://care.diabetesjournals.org on 15 March 2007. DOI: 10.2337/ before enrollment. dc06-2001. Clinical trial reg. no. NCT00231647, clinicaltrials.gov. This study was performed at 22 outpa- Abbreviations: CNS, central nervous system; CR, controlled release; DIS, Diagnostic Interview Schedule; HOMA, homeostasis model assessment; OGTT, oral glucose tolerance test. tient clinical centers in the U.S. that enrolled This report describes an investigational use of topiramate. Topiramate is not approved in any country for obese patients with type 2 diabetes treated the treatment of obesity or diabetes. with diet and exercise alone or in combina- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion tion with metformin. Eligible patients had factors for many substances. BMI between 27 and 50 kg/m2, A1C 6.5– © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby 11.0%, and fasting plasma glucose 7.0– marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 13.3 mmol/l. Patients were excluded if they 1480 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007 Rosenstock and Associates had uncontrolled hypertension (systolic pletion or early withdrawal, the study Statistical analysis blood pressure Ն180 mmHg and diastolic drug was tapered over 2 weeks, and a final The sample size was selected to achieve at blood pressure Ն100 mmHg), diabetic mi- assessment was performed after a 2-week least 95% power to detect a 2.7% differ- crovascular complications, severe recurrent off-drug follow-up period. After the 1st ence between the mean percentage hypoglycemic episodes, any condition week of the study, a single reduction to weight loss in the placebo and the topira- likely to affect body weight, clinically signif- the next lower dose in a double-blind mate CR–treated arms. These calculations icant hepatic or renal disease, personal or manner was allowed if patients experi- used an SD of 3.8%, which was estimated family history of kidney stones, history of enced intolerable adverse events. Patients from the results of studies on immediate- neuropsychiatric disorder or central ner- on topiramate doses of 100 mg/day or release formation of topiramate (10,11). vous system (CNS) condition, including higher were down-titrated to 75 mg/day. The primacy efficacy analysis set was neuropsychiatric disorders diagnosed at Patients on topiramate doses of 75 and 50 predefined as a modified intention-to- screening using an abbreviated 11-item Di- mg/day were down-titrated to 50 and 25 treat analysis set, which consisted of all agnostic Interview Schedule (DIS) (13). In mg/day, respectively, and patients on randomized subjects who received at least addition, patients using medication ex- one dose of study drug and provided at topiramate 25 mg/day were withdrawn pected to influence weight or glycemic con- least one postbaseline efficacy evaluation. from the study. Placebo dose adjustments trol or using psychotropic medication were The primary end point was mean percent- were done similarly. also excluded. Patients receiving any an- age change in body weight from baseline tidiabetes medication, other than a stable to week 16 using the last observation car- dose of metformin, were excluded. Patients ried forward (LOCF) approach, which with changes in lipid or antihypertensive Assessments was analyzed by using ANCOVA with medications within 2 months of the study Weight was measured using calibrated treatment and diabetes treatment as fac- were also excluded. scales. Blood pressure was measured with tors and with baseline weight as covariate. This study was a randomized, dou- a wall-mounted sphygmomanometer and Response rates were analyzed using the ble-blind, placebo-controlled, multi- assessed as the mean of three sitting mea- Cochran-Mantel-Haenszel test stratified center, parallel-group study. There was surements taken after 5 min rest. Other by baseline diabetes treatment. Missing a 1-week screening phase, and eligible measurements included lipid profile, C- values were imputed on the basis of patients were randomized to placebo or reactive protein, and adiponectin. Oral LOCF. topiramate treatment and entered a glucose tolerance tests (OGTTs) (75 g) 7-week titration phase followed by a were administered at baseline and at the 9-week maintenance phase, a 2-week end of the maintenance phase (week 16) RESULTS taper, and a 2-week follow-up phase. with blood samples taken at 30 and 120 Randomization used an interactive min for the measurement of plasma glu- voice response system with a computer- Patient baseline characteristics and generated randomization schedule. Pa- cose, insulin, and C-peptide levels. A ho- disposition meostasis model assessment (HOMA) tients were stratified by concomitant ␤ The study began recruitment on 4 Febru- metformin monotherapy and study cen- was used to derive estimates of -cell ary 2004, and the last patient completed ter. Treatment assignment was blinded function and insulin sensitivity (14). Uri- the study on 16 December 2004. The to the investigators, study site staff, and nary albumin-to-creatinine ratio was clinical centers screened 345 patients for patients. measured from a random single void participation