Topiramate: Long-Term Maintenance of
Weight Loss Induced by a Low-Calorie Diet in
Arne Astrup,* Ian Caterson,† Pierre Zelissen,‡ Bernard Guy-Grand,§ Michele Carruba,¶ Brian Levy,**
Xiang Sun,** and Martin Fitchet** for the OBES-004 Study Group
ASTRUP, ARNE, IAN CATERSON, PIERRE ZELISSEN,
BRIAN LEVY, XIANG SUN, AND MARTIN FITCHET.
Topiramate: long-term maintenance of weight loss induced
by a low-calorie diet in obese subjects. Obes Res. 2004;12:
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 con-
trolled-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 pre-
mature termination of the study. Subjects receiving TPM
lost 15.4% (96 mg/d) and 16.5% (192 mg/d) of their enroll-
ment weight by week 44, compared with 8.9% in the pla-
cebo 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 be-
yond that achieved by a low-calorie diet.
Key words: topiramate, weight loss, diet, drug therapy,
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)1survey 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 docu-
mented, 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 (8–10), dyslipidemia (8,9), coronary artery
Received for review December 1, 2003.
Accepted in final form July 28, 2004.
The costs of publication of this article were defrayed, in part, by the payment of page
charges. This article must, therefore, be hereby marked “advertisement” in accordance with
18 U.S.C. Section 1734 solely to indicate this fact.
*Royal Veterinary and Agricultural University, Frederiksberg, Denmark; †School of Mo-
lecular and Microbial Biosciences, University of Sydney, Sydney, Australia; ‡Department of
Internal Medicine/Endocrinology, University Medical Center, Utrecht, The Netherlands;
§University Pierre et Marie Curie, Paris, France; ¶Department of Preclinical Sciences,
University of Milan, Milan, Italy; and **Johnson and Johnson Pharmaceutical Research and
Development, LLC, Raritan, New Jersey.
Address correspondence to Arne Astrup, The Department of Human Nutrition and LMC,
The Royal Veterinary and Agricultural University, 30 Rolighedsvej, 1958 Frederiksberg C,
Copyright © 2004 NAASO
1Nonstandard 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.
1658OBESITY RESEARCH Vol. 12 No. 10 October 2004
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 exer-
cise 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 dis-
appointing. Those who lose weight through dietary restric-
tion 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
(17–21). 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
Research Methods and Procedures
Subjects were eligible for enrollment if they were be-
tween 18 and 75 years of age and had a BMI ?30 to ?50
kg/m2. Subjects with a BMI of ?30 kg/m2to ?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 diag-
nosed 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 eligi-
ble, 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 Austra-
lia. 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 Pharmaceu-
ticals for Human Use (ICH) Good Clinical Practice and
approved by Ethics Committees at all sites. All subjects
provided written informed consent before enrollment.
Medications that were not allowed during the study pe-
riod 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 hor-
mone (except as part of a stable treatment regimen).
The study was a randomized, double-blind, placebo-con-
trolled, parallel-group multicenter trial. It was originally
designed to last a total of 74 weeks: an 8-week nonpharma-
cological low-calorie (800 to 1000 kcal/d) weight-loss
run-in phase, an 8-week titration phase, a 52-week mainte-
nance 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 pre-
defined (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 med-
ication (8-week titration phase and 36-week maintenance
phase) before the sponsor’s announcement of study termi-
nation. The rationale for the MITT analysis is provided in
the statistical analysis section. The safety population con-
sisted of all individuals who had at least one dose of study
medication and who provided any postbaseline safety infor-
mation while on medication.
Enrollment and Run-in Phase
At the initial enrollment visit (week ?8), subjects were
evaluated with a medical examination including history,
(weight, height, waist and hip circumferences), an oral
glucose tolerance test, and a 12-lead electrocardiogram.
Blood and urine samples were collected for laboratory anal-
TPM for Maintenance of Weight Loss, Astrup et al.
OBESITY RESEARCH Vol. 12 No. 10 October 20041659
hances 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
?-aminobutyric acid receptor and the ?-amino-3-hydroxy-
5-methyl-4-isoxazolepropionic acid/kainite subtype of glu-
tamate 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 di-
abetes 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
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 sig-
nificant 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 effi-
cacy and safety in obesity is warranted.
This trial was supported by Johnson & Johnson Pharma-
ceutical Research and Development, LLP. The members of
the OBES-004 Study Group are: Norbert Balarac (St. Lau-
rent 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 (Amster-
dam, The Netherlands), Ottavio Bosello (Verona, Italy),
Carlo Maria Rotella (Firenze, Italy), Jacques Bringer
(Montpellier, France), Soeren Toubro (Frederiksberg, Den-
mark), 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,
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Placebo [n (%)]
All TPM [n (%)]96 mg/d [n (%)]192 mg/d [n (%)]
Adverse events leading to discontinuation in which any TPM-treated group had a higher percentage of discontinuations than placebo. One
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* p ? 0.05 vs. placebo.
† p ? 0.001 vs. placebo.
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