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Keywords:

  • topiramate;
  • weight loss;
  • diet;
  • drug therapy;
  • behavioral modification

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Objective: To examine the safety and efficacy of topiramate (TPM) for maintaining weight following a low-calorie diet.

Research Methods and Procedures: Obese subjects (30 ≤ BMI < 50 kg/m2) 18 to 75 years old received a low-calorie diet for 8 weeks. Those who lost ≥8% of their initial weight received TPM (96 or 192 mg/d) or placebo; all were on a lifestyle modification plan. Sixty weeks of medication were planned. Sponsor ended study early to develop a new controlled-release formulation with the potential to enhance tolerability and simplify dosing in this patient population. Efficacy was analyzed in subjects who completed 44 weeks of treatment before study termination.

Results: Of the 701 subjects enrolled, 80% lost ≥8% of their initial body weight and were randomized; 293 were analyzed for efficacy. Most withdrawals were due to premature termination of the study. Subjects receiving TPM lost 15.4% (96 mg/d) and 16.5% (192 mg/d) of their enrollment weight by week 44, compared with 8.9% in the placebo group (p < 0.001). Subjects on TPM continued to lose weight after the run-in, whereas those on placebo regained weight. Significantly more TPM subjects lost 5%, 10%, or 15% of their randomization weight than placebo. Most adverse events were related to the central nervous system.

Discussion: During a treatment period of 44 weeks, TPM was generally well tolerated, and subjects maintained weight loss initially achieved by a low-calorie diet—and produced additional clinically significant weight loss beyond that achieved by a low-calorie diet.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Obesity is a serious and growing global problem (1). One large study in the United States reported a prevalence of 19.8% in 2000, a 61% increase from 1991 (2), whereas another large study found an increase from 22.9% in 1988 to 1994 to 30.5% in 1999 to 2000 (3). Two large-scale European surveys in the middle and late 1980s reported obesity prevalence ranging from 9% to 18% for men and from 12% to 24% for women (4). A 1997 World Health Organization (WHO)1 survey found rates of obesity in most countries of Western Europe ranging from 10% to 25% (5). Obesity in the rest of the world has been less well documented, but a prevalence of 5% has been reported in certain urban areas of Asia, with an increasing prevalence noted among rural populations, as well (6).

This epidemic of obesity has serious consequences for public health, increasing the risk of type 2 diabetes (7,8), hypertension (8,9,10), dyslipidemia (8,9), coronary artery disease (8,11), ischemic stroke (12), and osteoarthritis (13). For both sexes and at all ages, mortality from all obesity-related causes, including cancer and cardiovascular disease, increases with the severity of the obesity (14).

Dietary restriction, especially in combination with exercise programs and behavioral modification, remains the preferred initial treatment approach to weight reduction in obese subjects. Such approaches are often effective in the short term, but long-term results have generally been disappointing. Those who lose weight through dietary restriction and behavioral modification typically regain about two-thirds of the lost weight within 1 year and almost all of it by the end of 5 years (15). In the Diabetes Prevention Program, an intensive lifestyle treatment led to a weight loss of ∼6.6 kg in the 1st year; after the 1st year, weight started to increase gradually, resulting in approximately a 4-kg weight loss maintained at 4 years. Nonetheless, this weight loss was sufficient to reduce the incidence of type 2 diabetes in this high-risk population by 58% (16). A number of studies have examined the use of pharmacological therapies to assist weight loss and maintenance, including some in which medication effects were followed for as long as 2 years (17,18,19,20,21). To the best of our knowledge, however, only one previous study has examined the use of pharmacological therapy for maintenance and possible promotion of further weight loss in subjects who lost a predefined amount of weight by nonpharmacological means (21).

Preclinical studies of topiramate (TPM) in several animal models have suggested that TPM is likely to be an effective weight loss treatment (22). A subsequent 6-month dose-ranging study in which subjects were randomly assigned to either placebo or TPM in doses ranging from 64 to 384 mg/d (23) reported significantly greater weight loss on all doses compared with placebo.

The objective of the current study was to investigate the efficacy and safety of TPM for maintaining weight loss in obese subjects who had initially lost weight through a low-calorie diet without pharmacological assistance. The study was initially planned as 60-week duration on study medication.

Research Methods and Procedures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Study Population

Subjects were eligible for enrollment if they were between 18 and 75 years of age and had a BMI ≥30 to <50 kg/m2. Subjects with a BMI of ≥30 kg/m2 to <50 kg/m2 were eligible if they had controlled hypertension and/or dyslipidemia with a stable medication regimen. Subjects with diabetes were ineligible unless they were newly diagnosed with diabetes by means of oral glucose tolerance test at the enrollment visit, and antidiabetic medication was not deemed necessary by the investigator. Subjects were also ineligible if they had significant cardiovascular, hepatic, or renal disease, a history or family history of kidney stones, uncontrolled thyroid disease, or significant central nervous system (CNS)-related or psychiatric disorders. To be eligible, a subject's weight had to have been stable for at least 3 months and smoking habits stable for at least 2 months before enrollment. Female subjects of childbearing potential were required to use an approved method of contraception. Subjects were recruited from centers in Europe and Australia. The study was carried out from August 2000 to June 2002. It was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice and approved by Ethics Committees at all sites. All subjects provided written informed consent before enrollment.

Concomitant Medications

Medications that were not allowed during the study period included antiseizure medications, antiparkinsonian medications, antidepressants, tranquilizers, sedatives and agents that might affect weight or food absorption, such as glucocorticoids, anorexigenic agents (prescription or over-the-counter), orlistat, nonfiber laxatives, and thyroid hormone (except as part of a stable treatment regimen).

Study Design

The study was a randomized, double-blind, placebo-controlled, parallel-group multicenter trial. It was originally designed to last a total of 74 weeks: an 8-week nonpharmacological low-calorie (800 to 1000 kcal/d) weight-loss run-in phase, an 8-week titration phase, a 52-week maintenance phase, and a 6-week drug taper and follow-up phase (Figure 1). Due to the sponsor's decision to terminate the study prematurely, efficacy data were analyzed from a predefined (i.e., before unblinding) modified intent-to-treat (MITT) population. This MITT population consisted of randomized individuals who had at least one dose of study medication, at least one postbaseline efficacy assessment, and the opportunity to complete at least 44 weeks of medication (8-week titration phase and 36-week maintenance phase) before the sponsor's announcement of study termination. The rationale for the MITT analysis is provided in the statistical analysis section. The safety population consisted of all individuals who had at least one dose of study medication and who provided any postbaseline safety information while on medication.

image

Figure 1. Study design.

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Enrollment and Run-in Phase

At the initial enrollment visit (week −8), subjects were evaluated with a medical examination including history, physical examination, anthropometric measurements (weight, height, waist and hip circumferences), an oral glucose tolerance test, and a 12-lead electrocardiogram. Blood and urine samples were collected for laboratory analysis. Enrolled subjects who met inclusion/exclusion criteria then entered the 8-week nonpharmacological weight loss phase described below. Subjects who lost at least 8% of their enrollment body weight during the 8-week run-in phase were eligible for randomization to pharmacological treatment (TPM or placebo), provided that they continued to meet inclusion and exclusion criteria. BMI inclusion criteria at baseline were ≥30 to <50 kg/m2 or BMI ≥27 to <50 kg/m2 in the presence of controlled hypertension or dyslipidemia.

Nonpharmacological Treatment

During the initial 8-week run-in phase, subjects received a low-calorie, nutritionally balanced diet containing 800 to 1000 kcal/d. The diet make-up was at the discretion of individual centers; many centers used a proprietary liquid formula diet or mixed formula/solid diet.

At randomization to pharmacological therapy (after the 8-week low-calorie diet run-in), all subjects participated in a standardized commercially available behavioral modification program known as Pathways to Change (Johnson & Johnson Healthcare Systems Inc., Piscataway, NJ), which continued throughout the remainder of the study. Pathways to Change focuses on lifestyle and self-management as related to weight loss and obesity. The low-calorie diet was replaced by an individualized diet with an energy content ∼600 kcal/d less than the subject's calculated total energy requirement (24). At week 32, the total energy requirement was recalculated and the caloric content of the diet modified accordingly. A standardized lesson plan administered by clinic staff on a one-to-one basis concentrated on topics associated with diet, nutrition, physical activity, psychosocial structuring, and support. Each lesson topic for each subject visit was unique but consistent for that visit at all centers. In addition, each lesson was accompanied by interactive, user-friendly subject support materials.

Randomization, Titration, and Maintenance

Randomization codes were generated by the sponsor using the RandGen program. Subjects were allocated in randomly permuted blocks stratified by study center. Subjects, study investigators and staff, and sponsor were blinded throughout the study to the treatment allocation.

An 8-week titration schedule was used as shown in Figure 1. All subjects randomized to TPM were started on a dose of 16 mg in the evening for the 1st week and then titrated upward over an 8-week period. Doses of 16 mg were administered both morning and evening for the 2nd week, and TPM was administered daily in two divided doses thereafter. Each week thereafter, the dose was increased by 32 mg/d (in two divided doses) until the assigned dose was reached. This occurred at the beginning of week 4 for those assigned to 96 mg/d TPM and the beginning of week 7 for those assigned to 192 mg/d TPM. The subjects were then maintained at their assigned dose for the next 52 weeks. At completion or termination of the study, medication was tapered over a 2-week period.

Dosage Adjustment Related to Adverse Events

If intolerable side effects occurred at any dose, the clinical site could reduce the dose by one level and continue treatment at this reduced dose for the remainder of the study. Only one dose reduction was allowed. Subjects were withdrawn from the study if intolerable adverse events continued despite down-titration.

Efficacy Evaluations

The primary efficacy end point was the mean percentage change in body weight from enrollment (including the 8-week low-calorie diet run-in) to week 44, using the last observation carried forward (LOCF) approach. Secondary end points included the percentage change in body weight from baseline (randomization to study drug, after completion of the 8-week low-calorie diet run-in), absolute change in body weight from enrollment and baseline, number and proportion of subjects losing at least 5%, 10%, and 15% of their body weight (5%, 10%, and 15% responders) from enrollment and from baseline, and the number and proportion of subjects who, during titration and maintenance periods, maintained 50%, 75%, and 100% of the weight loss achieved during the 8-week low-calorie diet run-in period. Changes in lipid profile and systolic and diastolic blood pressure were also predefined end points.

Safety Evaluation

Safety evaluations were based on adverse events either spontaneously reported by the subject or elicited by general, nondirect questioning and were coded according to a modified WHO Adverse Reaction Terminology dictionary. Severity was assessed as mild, moderate, or marked in accordance with the impact on the subject's daily life, i.e., minimal, noticeable, or substantial, respectively. Safety was also assessed by physical examination, pulse and blood pressure measurements, 12-lead electrocardiogram, and standard urinalysis, hematology, and blood chemistry panels.

Statistical Analysis

The sample size was determined based on the aim of achieving at least 90% power to detect a 5% difference in the mean percentage weight loss between the placebo and the TPM-treated arms. These calculations used an estimated SD of 11.0%, which was obtained from previously published work on pharmacological weight loss. Commercial (nQuery) software was used to perform the calculations.

The primary efficacy analysis population was predefined (before unblinding) as an MITT population. This modification was necessary because after the announcement of the premature termination of the study, it was not possible to guarantee that data collected subsequently would not be subject to many uncontrollable factors or biases. The original intent-to-treat (ITT) population consisted of all randomized subjects who received at least one dose of study drug and provided at least one postbaseline efficacy evaluation. The MITT population decision allowed only data collected before the closedown announcement and only from subjects who had the opportunity to complete a predetermined number of weeks (44 weeks for this study) of treatment before the study closedown announcement. Therefore, subjects were included in this population if their enrollment date was on or before a particular date before the announcement of the program termination. All subjects meeting this criterion were included if they received at least one postrandomization efficacy assessment. The primary population for efficacy analysis is designated an MITT population to reflect the fact that it was the ITT population that was appropriately modified to omit all subjects randomized after the specified date and to omit all data collected after the announcement of the closedown of the study.

To evaluate the effect of TPM at different dose levels compared with placebo and to adjust for multiple comparisons for the two active doses, the step-down multiple testing framework of Dunnett and Tamhane (25) for comparing treatments with a control was used. This method provides a family-wise false-positive protection rate of 0.05. For the primary efficacy measure, the two-sided significance level was 0.05. The primary efficacy end point was analyzed using analysis of covariance, with treatment, center, and treatment-by-center as factors and with enrollment values and gender as covariates. Response rates were analyzed using the Cochran-Mantel-Haenszel test stratified by gender and center. Except as otherwise noted, missing values were imputed on the basis of LOCF.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Study Population

A total of 701 subjects were enrolled, of whom 561 (80%) were randomized to treatment after losing at least 8% of their initial body weight during the 8-week nonpharmacological run-in period. Of these, 557 were included in the safety population, whereas 293 were randomized early enough to potentially allow completion of week 44 and were, therefore, included in the MITT population. The sponsor's decision to prematurely terminate the study accounted for the majority (308/561 or 55%) of withdrawals of randomized subjects (Figure 2). The first patient visit occurred on August 25, 2000 and the last on June 14, 2002.

image

Figure 2. Disposition of subjects.

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Demographic and baseline characteristics (at randomization after 8-week low-calorie diet run-in) for the safety population are listed in Table 1. The average age of subjects was 43.8 years. Seventy-six percent were women, and almost all were white. Treatment groups were well-balanced, with no notable differences on any variable. During the titration and maintenance phases, 75 subjects (13%) withdrew due to an adverse event (discussed in detail below), 49 (9%) due to subject choice, 7 (1%) for lack of efficacy, and20 (4%) for other reasons. Nine subjects (2%) were lost to follow-up (Figure 2). One subject in the 192 mg/d group withdrew due to an adverse event during follow-up phase.

Table 1.  Baseline demographic characteristics (safety population)*
 PlaceboTPM (96 mg/d)TPM (192 mg/d)All
  • *

    Baseline is defined as “at randomization, after 8-week low-calorie diet run-in phase.”

Subjects (N)185190182557
Age (years)    
 Mean (SD)44.1 (10.9)43.6 (10.4)43.6 (11.0)43.8 (10.7)
Sex [N (%)]    
 Men39 (21)53 (28)43 (24)135 (24)
 Women146 (79)137 (72)139 (76)422 (76)
Race [N (%)]    
 White180 (97)188 (99)179 (98)547 (98)
 Black4 (2)1 (1)2 (1)7 (1)
 Asian1 (1)1 (1)1 (1)3 (1)
Baseline weight (kg)    
 Mean (SD)96.5 (14.75)98.8 (13.78)99.2 (15.00)98.2 (14.53)
Baseline BMI (kg/m2)    
 Mean (SD)34.6 (3.98)34.8 (3.74)35.0 (3.98)34.8 (3.89)
Waist circumference    
 Mean (SD)105.2 (11.5)105.5 (11.3)106.5 (11.4)105.7 (11.4)
Waist/hip ratio    
 Mean (SD)0.90 (0.10)0.90 (0.09)0.90 (0.09)0.90 (0.09)

Efficacy

During the 8-week low-calorie diet run-in phase, all groups in the MITT population experienced a similar mean percentage weight loss: 10.6%, 10.9%, and 10.8% for those subsequently randomized to placebo and 96 and 192 mg/d, respectively, corresponding to mean decreases in weight of 11.6, 11.9, and 12.3 kg.

From enrollment (including the 8-week low-calorie diet run-in) to the end of week 44, TPM significantly decreased weight by 15.4% and 16.5% in the 96 and 192 mg/d groups, respectively, compared with 8.9% in the placebo group (MITT population, LOCF) (p < 0.001) (Figure 3). This corresponds to mean decreases in weight of 9.9, 17.0, and 18.7 kg in the placebo and 96 and 192 mg/d TPM groups, respectively, with corresponding mean enrollment values of 108.3, 109.5, and 111.9 kg. A supportive analysis of the 554 ITT subjects (i.e., all randomized with at least one on-treatment efficacy evaluation) yielded similar highly significant results.

image

Figure 3. Mean percentage change in body weight from enrollment to week 44. Includes 8 weeks of low-calorie diet, 8 weeks of pharmacological titration, and 36 weeks of pharmacological maintenance (MITT, LOCF).

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When analyzed from randomization (i.e., after completion of the low-calorie diet run-in), TPM treatment further decreased weight by 5.2% and 6.4% in the 96 and 192 mg/d groups, respectively, to week 44 compared with a gain of 1.8% in the placebo group (MITT population, LOCF) (p < 0.001). This corresponds to mean decreases in weight of 5.0 and 6.4 kg in the TPM 96 and 192 mg/d groups compared with a gain of 1.7 kg in the placebo group.

In subjects who completed 44 weeks of pharmacological therapy, TPM significantly decreased weight from enrollment to week 44 by 17.0% and 17.4% in the 96 and the 192 mg/d groups, respectively, compared with 9.4% in the placebo group (p < 0.001). This corresponds to mean decreases in body weight of 18.8 and 20.0 kg in the 92 and 196 mg/d groups, compared with a decrease of 10.2 kg in the placebo group. Weight loss over time from enrollment through to week 60 for the MITT population, using all nonmissing weight data at every time-point, is shown in Figure 4. For both the TPM 96 and 192 mg/d groups, weight loss was ongoing after the completion of the 8-week low-calorie diet and plateaued by week 44 through to week 60. For the placebo group, weight loss reached a plateau shortly after completion of the low-calorie diet run-in and weight began to increase after week 24.

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Figure 4. Mean percentage change from enrollment body weight over time to week 60. Includes the 8-week low-calorie diet phase. Each time-point uses all nonmissing observations at that time-point (observed MITT population). Because of the gradual attrition (withdrawals) that occured during the course of the trial, the number of subjects (and nonmissing observations) decreased at each subsequent time-point. The plot also includes data from subjects who had received therapy beyond week 44 when the decision was made to terminate the study. After week 44, the number of observations rapidly decreased.

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The number and percentage of subjects who lost at least 5%, 10%, or 15% (5%, 10%, and 15% treatment responders) of their enrollment (before 8-week low-calorie diet) body weight at week 44 are shown in Figure 5A. TPM-treated subjects consistently demonstrated a greater proportion of 5%, 10%, and 15% responders from enrollment compared with placebo. Additionally, more TPM-treated subjects maintained ≥50%, 75%, and 100% of the run-in weight loss at 44 weeks compared with placebo-treated subjects (Figure 5B).

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Figure 5. (A) Percentage of subjects losing ≥5%, 10%, or 15% of enrollment body weight (MITT population, LOCF). Includes the 8-week low-calorie run-in phase. (B) Mean percentage of run-in weight loss maintained at week 44 (MITT population, LOCF).

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Improvements were observed in cardiovascular and metabolic risk factors in all treatment groups, although most of these changes occurred during the 8-week low-calorie run-in phase. The TPM groups demonstrated greater changes than the placebo group from baseline to week 44.

All groups experienced reductions in blood pressure from enrollment to week 44; the decreases in systolic pressure were 6.4 mm Hg in the placebo group, 7.4 mm Hg in the TPM 96 mg/d group (p = 0.014 vs. placebo), and 10.2 mm Hg in the TPM 192 mg/d group (p < 0.001 vs. placebo), with corresponding mean enrollment values of 131.0, 127.3, and 129.0 mm Hg. The decreases in diastolic blood pressure were 2.8, 3.5 (not statistically significant), and 4.5 mm Hg (p < 0.05), with corresponding mean enrollment values of 81.6, 79.9, and 80.3 mm Hg, respectively. Heart rate decreased by 5.6, 5.7 (not statistically significant), and 7.5 (p = 0.04) beats per minute, with corresponding enrollment values of 75.9, 72.8, and 75.2. There was no statistical difference between the two TPM doses. Modest improvements from enrollment (before 8-week low-calorie diet) were seen in fasting lipids in all treatment groups (Table 2).

Table 2.  Mean changes from enrollment to 44 weeks in fasting lipid values (MITT population, LOCF)
 nPlacebonTPM (96 mg/d)nTPM (192 mg/d)
  • LDL, low-density lipoprotein; HDL, high-density lipoprotein. Enrollment is defined as “before the 8-week low-calorie diet run-in phase.”

  • *

    p < 0.05 vs. placebo.

  • p ≤ 0.01 vs. placebo.

Triglycerides (mM/L)      
 Mean enrollment value (SD) 1.6 (0.9) 1.6 (0.8) 1.6 (0.8)
 Mean change (SD)87−0.23 (1.05)76−0.46 (0.63)*86−0.45 (0.63)*
Total cholesterol (mM/L)      
 Mean enrollment value (SD) 5.6 (1.1) 5.7 (0.9) 5.6 (1.0)
 Mean change (SD)87−0.03 (0.75)76−0.28 (0.66)*86−0.35 (0.68)
LDL-cholesterol (mM/L)      
 Mean enrollment value (SD) 3.6 (1.0) 3.6 (0.9) 3.6 (0.9)
 Mean change (SD)83−0.06 (0.63)75−0.22 (0.60)86−0.21(0.62)
HDL-cholesterol (mM/L)      
 Mean enrollment value (SD) 1.3 (0.4) 1.3 (0.4) 1.3 (0.3)
 Mean change (SD)870.14 (0.26)760.13 (0.22)860.06 (0.24)*
Ratio of LDL-cholesterol to HDL-cholesterol      
 Mean enrollment value (SD) 2.9 (1.1) 3.0 (1.1) 3.0 (1.0)
 Mean change (SD)83−0.32 (0.66)75−0.37 (0.79)86−0.26 (0.70)

Safety

Adverse events that occurred in at least 5% of TPM-treated subjects and were more frequent in TPM-treated subjects than in those receiving placebo are shown in Table 3. Most of these events were related to the CNS. Paresthesia was the most common, seen in 46% of subjects receiving 96 mg/d TPM and 73% of those receiving 192 mg/d, compared with 15% of those on placebo. This frequent occurrence of paresthesia, especially at the higher dose, was not unexpected: TPM is known to be an inhibitor of carbonic anhydrase (26) (exhibiting selectivity for the CA isoforms II and IV), and paresthesia is a typical symptom of this effect. Although common, paresthesia was mild to moderate in nature and led to the withdrawal of only 13 (3%) of 372 TPM-treated subjects. Other CNS-related events occurring more frequently in TPM-treated subjects compared with those on placebo included fatigue (24% vs. 19%), dizziness (20% vs. 12%), difficulty with memory (16% vs. 6%), difficulty with concentration/attention (14% vs. 5%), depression (13% vs. 8%), and mood problems (8% vs. 3%). Overall, incidences were higher in the 192 mg/d TPM group compared with the 96 mg/d group. The majority of CNS-related adverse events resolved by the time of last follow-up. The percentages of resolved CNS-related adverse events were 95%, 94%, and 97% in the placebo and the TPM 96 and 192 mg/d groups, respectively.

Table 3.  Common adverse events in the safety population
  TPM dose 
 Placebo [n (%)]96 mg/d [n (%)]192 mg/d [n (%)]All TPM [n (%)]
  • Commonly defined as events occurring in at least 5% of all TPM-treated subjects and more frequently on TPM compared with placebo. Statistical comparison for all TPM group vs. placebo was not performed.

  • *

    p ≤ 0.05 vs. placebo (Fisher's exact test two-sided).

  • p < 0.001 vs. placebo (Fisher's exact test two-sided).

Paresthesia28 (15)87 (46)132 (73)219 (59)
Upper respiratory tract infection39 (21)45 (24)48 (26)93 (25)
Fatigue36 (19)47 (25)43 (24)90 (24)
Dizziness23 (12)30 (16)45 (25)*75 (20)
Memory difficulty11 (6)26 (14)*33 (18)59 (16)
Concentration/attention difficulty10 (5)22 (12)*31 (17)53 (14)
Depression14 (8)24 (13)23 (13)47 (13)
Nausea14 (8)20 (11)25 (14)45 (12)
Diarrhea13 (7)18 (9)23 (13)41 (11)
Injury16 (9)22 (12)14 (8)36 (10)
Gastroenteritis12 (6)11 (6)20 (11)31 (8)
Mood problems5 (3)18 (9)*11 (6)29 (8)
Sinusitis9 (5)14 (7)11 (6)25 (7)
Alopecia8 (4)10 (5)13 (7)23 (6)
Asthenia5 (3)12 (6)9 (5)21 (6)
Dry mouth4 (2)11 (6)10 (5)21 (6)
Taste perversion1 (1)9 (5)*10 (5)*19 (5)
Myalgia6 (3)9 (5)9 (5)18 (5)
Pruritis5 (3)10 (5)8 (4)18 (5)

For the total cohort, adverse events led to withdrawal of 15 subjects (8%) in the placebo group, 24 (13%) receiving 96 mg/d TPM (p = 0.177 vs. placebo), and 37 (20%) receiving 192 mg/d TPM (p < 0.001 vs. placebo). Adverse events that led to withdrawal and that were more frequent among TPM-treated subjects vs. placebo-treated subjects are listed in Table 4.

Table 4.  Adverse events leading to discontinuation from study in safety population
  TPM dose 
 Placebo [n (%)]96 mg/d [n (%)]192 mg/d [n (%)]All TPM [n (%)]
  • Adverse events leading to discontinuation in which any TPM-treated group had a higher percentage of discontinuations than placebo. One subject in the 192 mg/d group discontinued during follow-up and is included in the table. Statistical comparison for all TPM group vs. placebo was not performed.

  • *

    p ≤ 0.05 vs. placebo.

  • p ≤ 0.001 vs. placebo.

Any15 (8)24 (13)37 (20)61 (16)
Fatigue1 (1)6 (3)8 (4)*14 (4)
Depression1 (1)5 (3)8 (4)*13 (3)
Paresthesia03 (2)10 (5)13 (3)
Concentration/attention difficulty1 (1)3 (2)6 (3)9 (2)
Memory difficulty1 (1)4 (2)5 (3)9 (2)
Mood problems05 (3)2 (1)7 (2)
Dizziness03 (2)2 (1)5 (1)
Confusion1 (1)03 (2)3 (1)
Hypoesthesia02 (1)02 (1)
Language problems002 (1)2 (1)
Nausea01 (1)1 (1)2 (1)

Most injuries reported by subjects were sprains and fractures not deemed to be associated with study drug intake. Three percent of subjects in the TPM 96 mg/d group and 6% of subjects in the 192 mg/d group who had normal bicarbonate values at baseline had persistent abnormally low values (<17 mM/L during the titration and maintenance phases confirmed at two successive treatment visits). None of the 180 subjects in the placebo group had abnormally low values at two successive visits. In the TPM 96 mg/d group, one case of asymptomatic metabolic acidosis was reported as a treatment-emergent adverse event based on laboratory findings (low bicarbonate). This event resolved after stopping study drug.

Serious adverse events occurred in 16 placebo-treated subjects (9%) and 25 subjects in the combined TPM groups (7%). Four serious adverse events, occurring in three subjects in the TPM group, were considered to be at least possibly related to drug therapy: cholecystitis (TPM treatment continued), conjunctivitis (TPM treatment continued), and difficulty with memory and hallucinations, both in the same subject (TPM treatment discontinued and subject withdrawn from study). All of these serious adverse events resolved. One subject, assigned to the placebo group, died due to an abdominal aneurysm rupture.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

It is generally recognized that the major difficulty in obesity management is not inducing weight loss but maintaining it. After completion of an 8-week low-calorie diet on which all groups lost ∼11% of body weight, subjects subsequently randomized to TPM not only demonstrated greater maintenance of weight loss compared with placebo-treated subjects, but continued to lose more weight for up to 44 weeks. In contrast, placebo-treated subjects did not maintain the initial weight loss from the low-calorie diet and began to regain weight after 24 weeks. In addition, a significantly greater proportion of TPM-treated subjects lost 5%, 10%, or 15% of their enrollment (before 8-week low-calorie diet) weight compared with placebo. Also, a greater percentage of subjects maintained 50%, 75%, or 100% of run-in weight loss on TPM vs. placebo. An important observation was the similar efficacy between 96 and 192 mg/d in weight maintenance. In a recently reported 6-month weight loss dose-ranging study, a clear difference was demonstrated in efficacy between these doses when the drug was administered in a weight loss paradigm (23). Therefore, this finding highlights the potential for lower doses of TPM to be effective in long-term weight maintenance vs. higher doses required for induction of weight loss.

Major safety-related observations included an increased reporting of CNS-related adverse events, which are described in the previous section. Paresthesia was the most common event, although it was generally mild to moderate in severity and led to withdrawal in only a small proportion of subjects who experienced it. Additionally, subsequent to the completion of this study, a report was issued through the Food and Drug Administration MedWatch program alerting health care professionals that TPM causes hyperchloremic, nonanion gap metabolic acidosis (decreased serum bicarbonate) and recommending measurement of serum bicarbonate at commencement of drug therapy and periodically thereafter. It is also relevant to note that the proportions of adverse event withdrawals previously mentioned may not take into account potential censoring due to early study termination. However, the proportions of withdrawals described are similar to a previously completed and published study of TPM in obese subjects (23) and are, therefore, likely to be representative of the adverse event withdrawal data if the study had been allowed to continue to completion. The mechanism by which TPM induces weight loss remains unclear but appears to be distinct from that of sibutramine or any of the serotonergic or noradrenergic appetite suppressants. If increased thermogenesis were a major contributor to the weight loss, it would have been expected that heart rate would have increased with TPM, but no hemodynamic signs of increased energy expenditure were observed. However, on a daily basis, only a small increase in total energy expenditure is needed to make a substantial contribution to the improved weight maintenance (27), and such an effect would need assessment by indirect calorimetry or other methods to be detected.

It is well established that TPM decreases the efficiency of energy use in a variety of animal models (22,28), with inconsistent effects on food intake across the models. Effects on efficiency of energy use in animal models may reflect TPM's ability to stimulate lipoprotein lipase in brown adipose tissue and skeletal muscle, with a resulting increase in thermogenesis (22,28). In addition, TPM enhances expression of uncoupling proteins 2 and 3 (29) in adipose tissue and skeletal muscle, directly diminishing the efficiency of energy use. The precise mechanisms of action on energy balance of TPM are currently under investigation.

TPM also modulates the effects at receptors for the γ-aminobutyric acid receptor and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainite subtype of glutamate receptor (30,31). In addition, TPM exhibits state-dependent blockade of voltage-dependent Na+ or Ca2+ channels (32). These mechanisms are believed to contribute to its antiepileptic properties, but their relationship to its effects on body weight is unknown.

The TPM immediate-release program in obesity and diabetes was discontinued by the sponsor to develop a new controlled-release formulation with the potential to enhance tolerability and simplify dosing in this patient population. This decision was driven not by findings from this study but by those from a previous study that utilized higher doses and demonstrated that weight loss could be obtained at lower doses, potentially with improved tolerability (23). Importantly, no new major safety issues were identified in this study.

In conclusion, treatment with TPM for 44 weeks was effective for maintaining weight loss initially achieved by a low-calorie diet, and it produced additional clinically significant weight loss beyond that achieved by a low-calorie diet. It also appears that lower doses than those previously required for weight loss induction may be effective for weight maintenance. Further investigation of TPM's efficacy and safety in obesity is warranted.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

This trial was supported by Johnson & Johnson Pharmaceutical Research and Development, LLP. The members of the OBES-004 Study Group are: Norbert Balarac (St. Laurent du Var, France), Serge Halimi (Grenoble, France), Boyd Strauss (Clayton, Australia), Joe Proietto (Melbourne, Australia), Gary Wittert (Adelaide, Australia); G.H. de Groot (Hilversum, The Netherlands), M.L. Drent (Amsterdam, The Netherlands), Ottavio Bosello (Verona, Italy), Carlo Maria Rotella (Firenze, Italy), Jacques Bringer (Montpellier, France), Soeren Toubro (Frederiksberg, Denmark), Francesco Cavagnini (Milan, Italy), Arnaud Cocaul (Paris, France), Bernard Guy-Grand (Paris, France), Michel Krempf (Nantes, France), Jean-Pierre Louvet (Toulouse, France), Paul Valensi (Bondy, France), Olivier Ziegler (Dommartin Les Toul, France), and Monique Roman (Lille, France).

Footnotes
  • 1

    Nonstandard abbreviations: WHO, World Health Organization; TPM, topiramate; CNS, central nervous system; MITT, modified intent-to-treat; LOCF, last observation carried forward; ITT, intent-to-treat.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
  • 1
    James, P. T., Leach, R., Kalamara, E., Shayeghi, M. (2001) The worldwide obesity epidemic. Obes Res. 9(Suppl 4): S228S233.
  • 2
    Mokdad, A. H., Bowman, B. A., Ford, E. S., Vinicor, F., Marks, J. S., Koplan, J. P. (2001) The continuing epidemics of obesity and diabetes in the United States. JAMA 286: 11951200.
  • 3
    Flegal, K. M., Carroll, M. D., Ogden, C. L., Johnson, C. L. (2002) Prevalence and trends in obesity among US adults, 1999-2000. JAMA 288: 17231727.
  • 4
    Bergström, A., Pisani, P., Tenet, V., Wolk, A., Adami, H-O (2001) Overweight as an avoidable cause of cancer in Europe. Int J Cancer 91: 421430.
  • 5
    WHO Press Release WHO/46;12 June 1997. Obesity epidemic puts millions at risk from related diseases [press release]. Available at: http:www.who.intarchivesinf-pr-1997enpr97-46.html. Accessed August 13, 2003.
  • 6
    Tee, E. S. (2002) Obesity in Asia: prevalence and issues in assessment methodologies. Asia Pac J Clin Nutr. 11(Suppl 8): S694S701.
  • 7
    Resnick, H. E., Valsania, P., Halter, J. B., Lin, X. (2000) Relation of weight gain and weight loss on subsequent diabetes risk in overweight adults. J Epidemiol Community Health 54: 596602.
  • 8
    Wilson, P. W. F., D'Agostino, R. B., Sullivan, L., Parise, H., Kannel, W. B. (2002) Overweight and obesity as determinants of cardiovascular risk: the Framingham experience. Arch Intern Med. 162: 18671872.
  • 9
    Brown, C. D., Higgins, M., Donato, K. A., et al. (2000) Body mass index and the prevalence of hypertension and dyslipidemia. Obes Res. 8: 605619.
  • 10
    Kaufman, J. S., Durazo-Arvizu, R. A., Rotimi, C. N., McGee, D. L., Cooper, R. S. (1996) Obesity and hypertension prevalence in populations of African origin: the Investigators of the International Collaborative Study on Hypertension in Blacks. Epidemiology 7: 398405.
  • 11
    Rimm, E. B., Stampfer, M. J., Giovannucci, E., et al. (1995) Body size and fat distribution as predictors of coronary heart disease among middle-aged and older US men. Am J Epidemiol. 141: 11171127.
  • 12
    Rexrode, K. M., Hennekens, C. H., Willett, W. C., et al. (1997) A prospective study of body mass index, weight change, and risk of stroke in women. JAMA 277: 15391545.
  • 13
    Hochberg, M. C., Lethbridge-Cejku, M., et al. (1995) The association of body weight, body fatness and body fat distribution with osteoarthritis of the knee: data from the Baltimore Longitudinal Study of Aging. J Rheumatol. 22: 488493.
  • 14
    Calle, E. E., Thun, M. J., Petrelli, J. M., Rodriguez, C., Heath, C. W. (1999) Body-mass index and mortality in a prospective cohort of U.S. adults. New Engl J Med. 341: 10971105.
  • 15
    NIH Technology Assessment Conference Panel. (1993) Methods for voluntary weight loss and control: Consensus Development Conference, 30 March to 1 April 1992. Ann Intern Med. 119: 764770.
  • 16
    Knowler, W. C., Barrett-Connor, E., Diabetes Prevention Program (DPP) Research Group. (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 346: 393403.
  • 17
    Sjöström, L., Rissanen, A., Andersen, T., et al. (1998) Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese subjects: European Multicentre Orlistat Study Group. Lancet. 352: 167172.
  • 18
    Davidson, M. H., Hauptmann, J., DiGirolamo, M., et al. (1999) Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA 281: 235242.
  • 19
    Rössner, S., Sjöström, L., Noack, R., Meinders, A. E., Noseda, G. (2000) Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity: European Orlistat Obesity Study Group. Obes Res. 8: 4961.
  • 20
    James, W. P. T., Astrup, A., Finer, N., et al. (2000) Effect of sibutramine on weight maintenance after weight loss: a randomised trial. Lancet. 356: 21192125.
  • 21
    Apfelbaum, M., Vague, P., Ziegler, O., Hanotin, C., Thomas, F., Leutenegger, E. (1999) Long-term maintenance of weight loss after a very-low-calorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine. Am J Med. 106: 179184.
  • 22
    Richard, D., Ferland, J., Lalonde, J., Samson, P., Deshaies, Y. (2000) Influence of topiramate in the regulation of energy balance. Nutrition 16: 961966.
  • 23
    Bray, G. A., Hollander, P., Klein, S., et al. (2003) A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obes Res. 11: 722733.
  • 24
    Energy and protein requirements: report of a joint FAO/WHO/UNU expert consultation. (1985) WHO Geneva, Technical report series no. 72471.
  • 25
    Dunnett, C. W., Tamhane, A. C. (1991) Step-down multiple tests for comparing treatments with a control in unbalanced one-way layout. Stat Med. 10: 939947.
  • 26
    Dodgson, S. J., Shank, R. P., Maryanoff, B. E. (2000) Topiramate as an inhibitor of carbonic anhydrase isoenzymes. Epilepsia 41(Suppl 1): S35S39.
  • 27
    Hill, J. O., Wyatt, H. R., Reed, G. W., Peters, J. C. (2003) Obesity and the environment: where do we go from here? Science 299: 853855.
  • 28
    Richard, D., Picard, F., Lemieux, C., Lalonde, J., Samson, P., Deshaies, Y. (2002) The effects of topiramate and sex hormones on energy balance of male and female rats. Int J Obes Relat Metab Disord. 26: 344353.
  • 29
    York, D. A., Singer, L., Thomas, S., Bray, G. A. (2000) Effect of topiramate on body weight and body composition of Osborne-Mendel rats fed a high-fat diet: alterations in hormones, neuropeptide, and uncoupling-protein mRNAs. Nutrition 16: 967975.
  • 30
    White, H. S., Brown, S. D., Woodhead, J. H., Skeen, G. A., Wolf, H. H. (1997) Topiramate enhances GABA-mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold. Epilepsy Res. 28: 167179.
  • 31
    Gibbs, J. W., 3rd, Sombati S, DeLorenzo RJ, Coulter DA (2000) Cellular actions of topiramate: blockade of kainate-evoked inward currents in cultured hippocampal neurons. Epilepsia 41(Suppl 1): S10S16.
  • 32
    Taverna, S., Sancini, G., Mantegazza, M., Franceschetti, S., Avanzini, G. (1999) Inhibition of transient and persistent Na+ current fractions by the new anticonvulsant topiramate. J Pharmacol Exp Ther. 288: 960968.