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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Arch Intern Med. Author manuscript; available in PMC Nov 12, 2013.
Published in final edited form as:
PMCID: PMC3753218
NIHMSID: NIHMS489912
Zonisamide for Weight Reduction in Obese Adults A 1-Year Randomized Controlled Trial
Dr. Kishore M. Gadde, MD, Ms. Mariko F. Kopping, MS, RD, Dr. H. Ryan Wagner, II, PhD, Ms. Gretchen M. Yonish, MPH, RD, Dr. David B. Allison, PhD, and Dr. George A. Bray, MD
Obesity Clinical Trials Programme, Duke University Medical Center, Durham, North Carolina (Drs Gadde and Wagner II, and Ms Kopping and Ms Yonish); School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama (Dr Allison); and Pennington Biomedical Research Center, Baton Rouge, Louisiana (Dr Bray)
Corresponding Author: Kishore M. Gadde, MD, Box 3292, Duke University Medical Center, Durham, NC 27710, USA, kishore.gadde/at/duke.edu
Background
Obese individuals who have failed to achieve adequate weight loss with lifestyle changes have limited non-surgical therapeutic options. We evaluated the efficacy and tolerability of zonisamide, an antiepileptic drug, for enhancing weight loss in obese patients receiving diet and lifestyle guidance.
Methods
This was a 1-year randomized, double-blind, placebo-controlled trial conducted between January 2006 and September 2011 at Duke University Medical Center. Patients were 225 obese (mean [SD] body mass index 37.6 [4.9]) women (134 [59.6%]) and men (91 [40.4%]) without diabetes. Interventions were daily dosing with placebo (n=74), zonisamide 200 mg (n=76), orzonisamide 400 mg (n=75), in addition to diet and lifestyle counseling by a dietitian for 1 year. Primary outcome was change in body weight at 1-year.
Results
Of the 225 randomized patients, 218 (97%) provided 1-year follow-up assessments. Change(least-squares mean) in body weight was -4.0 kg (−3.7%; 95% CI, −5.8 kg to −2.3 kg) for placebo, −4.4 kg (−3.9%; −6.1 to −2.6, P=.79vs placebo) for zonisamide 200 mg, and −7.3 kg (−6.8%; −9.0 to −5.6, P=.009vs placebo) for zonisamide 400 mg. In the categorical analysis,23 (31%) on placebo, 26 (34%; P=.71) on zonisamide 200 mg, and 41 (55%; P=.007) onzonisamide 400 mg achieved ≥5% weight loss; for ≥10% weight loss, the corresponding numbers were 6 (8%), 17 (22%; P=.022), and 24 (32%; P=.001). Gastrointestinal, nervous system and psychiatric adverse events occurred at a higher incidence with zonisamide than with placebo.
Conclusion
Zonisamide 400 mg/d moderately enhanced weight loss achieved with diet and lifestyle counseling, but had a high incidence of adverse events.
Keywords: randomized controlled trial, obesity, weight loss, antiobesity drugs, weight loss drugs, zonisamide, antiepileptic drugs
Diet and exercise are often recommended as first-line treatment for obese patients, but long-term results are not impressive.1,2 Although intensive lifestyle interventions of the type tested in the Diabetes Prevention Program3 and Look AHEAD4 trials have demonstrated approximately 6–8% weight loss over a year, these are difficult to implement in primary care settings and third-party payers rarely reimburse.5 Orlistat and lorcaserin, the only monotherapy drugs currently approved for long-term management of obesity achieve about 3 kg weight loss relative to placebo after 1 year.6,7 Thus, for obese patients who fail to achieve adequate benefit from lifestyle therapies, there is a dire need for additional non-surgical therapeutic options. Zonisamide is an antiepileptic drug that demonstrated weight loss efficacy in obese adults(−5.9 kg vs −0.9 kg) in a 16-week trial with further weight loss in the additional 16-week extension phase.8 In that trial, zonisamide dose was titrated to 400 mg/d for all patients by week 7, and to 600 mg/d for patients not losing at least 5% weight. A subsequent review of the data showed that patients with inadequate weight loss at 400 mg had no appreciable additional weight loss at 600 mg. However, since the dose was raised to 400 mg regardless of the degree of weight loss, it was not known whether a lower dose would have been just as effective over longer duration. Furthermore, placebo treatment led to weight loss of only 0.9 kg suggesting that the lifestyle intervention in that trial was not very effective. This trial was designed to answer two questions: 1) Does addition of zonisamide400 mg/d augment weight loss achievable with a fair quality lifestyle intervention that could be administered in a primary care setting? 2) Is a zonisamide lower dose (200 mg/d) also efficacious?
This report describes a long-term randomized controlled trial testing the efficacy and tolerability of two zonisamide doses (200 mg and 400 mg) in obese adults, also receiving diet and lifestyle counseling.
Study Design and Randomization
This was a randomized, double-blind, parallel-group, three-arm trial, conducted between January 2006 and September 2011 at Duke University Medical Center, Durham, North Carolina. Eligible patients were randomly assigned in a 1:1:1 ratio to receive once-daily treatment with placebo, zonisamide 200 mg, or zonisamide 400 mg for 1-year. Additionally, all patients received diet and lifestyle counseling.
Randomization, facilitated by a pseudo-number generator, with a permuted block size of nine and stratification for gender, was implemented by the medical center’s Investigational Drug Service (IDS). Study drugs were dispensed by IDS as identically appearing capsules, and investigators and patients remained masked to treatment assignment until all patient visits and data entry were completed.
Patients
All patients gave written informed consent. Duke University’s institutional review board approved the protocol.
Eligible patients were 18 to 65 years old with body-mass index (BMI) ranging from 30 to 50 kg/m2. Key exclusion criteria were diabetes mellitus, serious or unstable medical illness; renal calculi history; diabetes mellitus; current major depression, alcohol or drug abuse; score ≥11 on depression subscale of the Hospital Anxiety and Depression Scale (HADS);9 psychosis or bipolar disorder or severe personality disorders; suicidality; antipsychotics or mood stabilizers; other psychotropic medications if taken for less than 3 months; and taking zonisamide or other antiepileptic drugs (see eMethods for details). Patients were recruited via local area advertisements, hospital website listings, and physician referrals. Patients were given a small stipend for travel expenses (maximum $180 for one year).
Study Drugs
Zonisamide 100 mg and placebo capsules were prepared in accordance with Good Manufacturing Practice (GMP) guidelines in Duke Compounding Facility with active pharmaceutical ingredient (Sochinaz SA, Switzerland, distributed by Bachem Americas, King of Prussia, Pennsylvania) plusdextrose as an inactive ingredient. Identical-looking placebo capsules contained dextrose.
Each capsule contained zonisamide 100 mg or placebo, with patients and study staff blinded to contents. Dose was gradually titrated upward as follows: 1 capsule for 15 days, 2 during days 16–30, 3 capsules during days 31–45, and 4 from day 46 onward. The entire dose was taken at night. Blinded dose reduction was allowed and dose increase could be withheld. Patients had the option to discontinue the drug and remain in the study receiving only diet and lifestyle counseling. Compliance was assessed by comparing the number of capsules dispensed and returned.
Diet and Lifestyle Intervention
The study aimed to achieve at least 3% weight loss for all participants. Hence, all patients received diet and lifestyle counseling to promote weight loss. This included an individualized diet plan to reduce daily energy intake by 500 kcal from the energy requirements calculated using Mifflin-St Jeorresting metabolic rate equation.10 Diet compositions were consistent with U.S. Department of Agriculture Guidelines, and patients were advised to consume 50% of their calories from carbohydrates, 20% from protein, and 30% from fat. Complex carbohydrates, whole grains, dietary fiber, and lean proteins were emphasized and subjects were also taught to minimize consumption of saturated and trans fats. Patients were asked to record and monitor their daily caloric intake with a food diary, and at monthly study visits, they met with a registered dietitian for 30 minutes to discuss their progress, any perceived challenges, and receive individualized counseling and educational materials. Topics discussed included goal setting, planning healthy meals, understanding food labels, supermarket shopping, snacking and dining out, and basic guidance to increase aerobic exercise and strength training. All patients in the study were encouraged to exercise and while a specific exercise program was not prescribed, the dietitian discussed strategies for increasing physical activity such as walking at lunch breaks, wearing a pedometer to track steps and setting weekly physical activity goals. Other areas covered were decision-making, managing social situations, barriers to healthy eating, coping strategies, and relapse prevention.
Visits and assessments
Following randomization and drug dispensing, visits occurred twice in the first month, and at monthly intervals thereafter. Assessments included body weight, BP, heart rate, waist circumference, clinical and laboratory evaluations, concomitant medications, treatment compliance, adverse events (AEs), HADS depression subscale, and a suicidal ideation question.
Primary and Secondary Outcomes
The primary outcome, pre-specified in the protocol, was absolute change in body weight in kilograms. Secondary outcomes included proportions of patients achieving 5% and 10% weight loss, and changes in waist circumference, blood pressure, lipids, and other relevant blood tests. Safety outcomes included frequency of adverse events and HADS depression score change.
Statistical analysis
Power analysis, based on the assumption that relative to placebo, zonisamide 400 mg and 200 mg groups would lose 3% and 1.5%, respectively, indicated that 75 patients per treatment group, with primary endpoint data available for 65 patients at one year, would provide over 92% power to detect differences vs placebo at a 0·05 significance level (2-tailed).
Primary analysis was conducted on the intention-to-treat (ITT) sample of all randomized patients. The primary endpoint was weight loss at 1-year, Month-12 weight minus baseline weight, in kilograms. Using ANCOVA, the resulting difference score was regressed on a three-level proxy variable (1 = placebo; 2 = 200 mg; 3 = 400 mg) denoting randomization status; to control for differences in initial body weight. Baseline weight and gender were included as a covariates. Efficacy, testing the overall difference between groups, was evaluated using a 2-degree-of-freedom test. Based on a significant omnibus test, pair-wise contrasts between treatments were subsequently tested using closed (step-down) testing with P values of 0.05 or less indicating significance.
Missing data are a potential source of bias.11 Many past imputation strategies, including last observation carried forward (LOCF) and completer analysis, often provide biased results12 and are no longer favored relative to full likelihood-based and multiple imputation procedures, both of which are less subject to bias and inconsistencies under satisfying assumptions.13 For this study, missing data for the primary analysis were augmented using multiple imputations in a two-step process. Based on available weight data from all randomized subjects, an initial imputation based on a Markov Chain Monte Carlo algorithm was used to establish a monotone missing data pattern. Missing values in the monotone dataset were subsequently multiply imputed (m = 5 imputations) in a second step using regression procedures as described by Rubin and Schenker.14 The primary Month-12 outcome measure was calculated using the imputed datasets and analyzed using ANCOVA regressions as described above; data from the five analyses were subsequently combined into single estimates and tested as described by Schafer.15 Two secondary sensitivity analyses were used: An imputation using traditional LOCF procedures to replace the missing Month-12 data point, and a completers-based approach restricted to full-dose compliant (80%) patients (FDC) with Month-12 data (n=139). The latter two analyses facilitate comparisons with earlier published studies.
For responder analyses, two dichotomous outcome measures were calculated identifying patients with ≥5% and ≥10% weight loss. The latter measures were modeled with logistic regressions that included the three-level group proxy (described above) and a baseline weight covariate, with omnibus testing preceding pairwise tests as before.
Analyses of secondary outcomes were based on intent-to-treat ANCOVAs. Difference scores from baseline to endpoint (Month-12) for each measure were regressed on the three-level proxy denoting group while controlling for the baseline value of the same measure. Contrasts were subsequently estimated in models, which had a significant overall treatment effect.
Patients
Two-hundred sixty patients signed consent forms and 225 patients were randomly assigned to 3 treatment groups – 74 to placebo, 76 to 200 mg, and 75 to 400 mg. Reasons for not randomizing 35 screed patients, and subsequent flow are depicted in Figure 1. Twenty patients discontinued placebo, 25 discontinued 200 mg, and 13 discontinued 400 mg. However, some patients who discontinued the drug remained in the study and completed all visits, and 41 patients that discontinued the drug returned for their 1-year visit to complete final assessments. Thus, primary endpoint assessment was available for 71 assigned to placebo, 73 assigned to 200 mg, and 74 assigned to 400 mg, leaving only 7 of 225 lost to follow-up.
Figure 1
Figure 1
Flow of Patient Screening, Randomization, and Disposition
Patient characteristics at baseline, shown in Table 1, were similar among the 3 groups. We enrolled 40% men and 37% ethnic minorities. Mean age and BMI were43 years, and 37.6 kg/m2, respectively. Approximately 21% had depression history and 9% were on antidepressants.
Table 1
Table 1
Patient Characteristics by Treatment Group
Weight loss
Patients assigned to zonisamide 400 mg lost more weight than those assigned to placebo whereas 200 mg dose was not superior to placebo. In the primary MI analysis, weight changes (least-squares [LS] mean) were −4.0 kg (95% CI −5·8% to −2.3)for placebo, −4.4 kg (−6.1 to −2.6, P=.79) for 200 mg, and −7.3 kg (−9.0 to −5.6, P=.009) for 400 mg; corresponding %weight changes were −3.7%, −3.9%, and −6.8%, respectively. LOCF analysis showed similar weight change (Table 2), and full-dose compliant (FDC) patients showed greater weight loss with similar between-group differences.
Table 2
Table 2
Changes in Weight and Secondary Parameters
In the categorical MI analyses, 23 (31.1%) patients assigned to placebo achieved ≥5% weight loss compared with 26 (34.2%, P=.72vs placebo)and 41 (54.7%, P=.007 vs placebo) assigned to 200 mg and 400 mg, respectively; for ≥10% weight loss, the corresponding figures were 6 (8.1%), 17 (22.4% [P=.023]), and 24 (32.0% [P<.001]), respectively.
Weight Changes for Patients Who Dropped Out and Returned
Table 4 shows weight changes for the 41 patients (placebo = 15, 200 mg = 15, 400 mg = 11) who dropped out, but returned at 1-year. Weight gain was observed in all treatment groups, most notably for the 400 mg group. Mean (SD) weight changes were 1.4% (3.1) for placebo patients, 0.7% (3.5) for 200 mg (P vs placebo = 0.35), and 4.9% (3.4) for 400 mg (P vs placebo = 0.008).
Table 4
Table 4
Weight Change of Patients Who Withdrew Early and Returned for 1-Year Visit
Secondary Outcomes
Waist circumference decreased in all treatment groups; there was a greater decrease with 400 mg than with placebo. Changes in blood pressure, heart rate, fasting glucose, and lipids were favorable with all treatments without significant between-group differences. Although 400 mg led to a statistically significant (P=.007) greater reduction in glycated hemoglobin, the change was not clinically significant. There were no significant changes in hepatic enzymes and serum bicarbonate.
Adverse Events
This trial was not powered to detect differences in adverse events. Given the relatively small sample, we combined adverse events of similar nature into broader categories (e.g., terms such as sadness, crying, depression, depressed mood were combined as ‘depression-related’). As shown in Table 3, altered taste, constipation, diarrhea, dry mouth, headache, fatigue, nausea/vomiting, somnolence, fatigue, headache, language/speech problems, impaired attention/concentration, memory problems, and anxiety-related and depression-related adverse events were more frequent with one or both of the zonisamide doses. HADS depression scores were <3 (within normal) at all time points in all treatment groups. No patients developed major depressive disorder and none had suicidal ideation or panic attacks. Most neuropsychiatric adverse events were mild in severity and all events resolved quickly upon dose reduction or drug discontinuation.
Table 3
Table 3
Adverse events
A total of 14 patients discontinued study drug due to adverse events – 4 on placebo (1 patient each for mental slowing, memory impairment, tactile hallucinations, and stomach ache), 6 on 200 mg (2 headache, 1 memory impairment, 1 muscle weakness, 1 irritability, 1 depressed mood), and 4 on 400 mg (1 headache, 1 somnolence, 1 memory impairment, 1 depressed mood). Drug (400 mg) was stopped for one patient who became pregnant; she delivered a normal healthy baby at full-term. A total of 12 patients completed the study on reduced dose (1 on placebo, 2 on 200 mg, and 9 on 400 mg).
To our knowledge, this is the first RCT examining the long-term efficacy of zonisamide for weight reduction. Zonisamide 400 mg/d led to 3.3 kg greater weight loss than diet and lifestyle intervention alone. Zonisamide 200 mg/d was not efficacious.
A unique feature of this trial is the high retention. Of 48 patients who dropped out, 41 returned at 1-year time-point, leaving only 7 of 225 randomized patients lost to follow-up. Not surprisingly, MI and LOCF imputation procedures showed almost identical results as few data were missing. Historically, dropout rates have generally been in the range of 30–50% in pharmaceutical weight loss trials, including recent long-term trials.1619 Interestingly, in the COR-BD trial that tested the addition of naltrexone + bupropion or placebo to intensive behavior modification, 42% withdrew early in the behavior modification (plus placebo) group and 12% cited an adverse event for discontinuation,20 Simons-Morton et al21 criticized obesity trials with the argument that high attrition introduces a bias, and randomization does not serve its purpose when data from patients who have not adhered to treatment are not analyzed. A counter argument is that physicians are interested in treatment effects among patients that adhere to it and not the effect of being assigned to a treatment.
Various statistical models are employed in obesity RCTs to make up missing data, the most common being LOCF. Food and Drug Administration (FDA), in its guidance to industry,22 recommends LOCF, which implicitly assumes that patients who withdraw early in a trial would have maintained the same weight at study exit as at the time of withdrawal. Other statistical imputation procedures make less restrictive assumptions for the individual patient or the assigned group based on patterns of weight change prior to dropout. Although some imputation procedures are superior to others, it is important to recognize that all imputation approaches make assumptions, some of which are inherently untestable (e.g., that data are missing at random).15
Observations of weight change among the 41 patients in this trial, who dropped out early, but returned for final assessment at 1-year, demonstrate that most obese patients gain weight or regain their lost weight after they drop out from a clinical trial, calling into question the results from trials with high dropout rates and the validity of commonly used imputation procedures in obesity RCTs. As seen in Table 4, many patients who lost substantial weight prior to drop out regained considerable weight by 1-year visit. The 11 dropouts in the 400 mg group gained almost 5% weight on the average when they returned at 1-year.
There were no extraordinary efforts in this trial that could explain the high retention. There were no extended screening visits to ensure patients were serious about participation. Patients were educated about time and commitment required for participation, and that they needed to make changes to their diet and lifestyle without which drug therapy would not help. They were counseled to have realistic expectations about what could be achieved over a year. Very few patients were excluded during screening. They were told that if they withdrew early, they would be requested to return for 1-year visit to complete final assessments, which would be valuable for the study’s success. There was no coercion and the stipend offered was minimal.
Historically, most obesity RCTs enrolled primarily white women. This trial enrolled a fair number of men (40%) and ethnic minorities (37%).
A notable limitation of this trial is that most patients did not have significant weight-related comorbidities. At baseline, patients had normal blood pressure, lipids, and glycemic measures. Reduction in risks associated with obesity is most demonstrable when patients with risk factors are enrolled. This is a consideration for future investigation.
In a preliminary trial by Gadde et al.,8 zonisamide achieved 5 kg greater weight loss than placebo (5.9 kg vs 0.9 kg) over 16 weeks. The current RCT examined whether zonisamide, could enhance long-term weight loss achievable with a good quality diet and lifestyle intervention that is implementable in a primary care clinical setting. In contrast to the previous trial, placebo group in the current RCT achieved an impressive 4 kg weight loss. Our lifestyle intervention was not as intensive as the ones administered in DPP,3 Look AHEAD,4 and COR-BMOD20 trials, and could be easily incorporated into primary care practices.
Although, zonisamide 400 mg/d demonstrated moderate efficacy of a magnitude similar to orlistat6 and lorcaserin,7 neuropsychiatric adverse events (mood changes and memory problems) occurred at a higher frequency relative to placebo. Hence, for treatment of obesity, the drug’s benefit-to-risk ratio needs thoughtful and cautious assessment. The results of our trial must be considered in the context of our follow-up procedures, which were markedly different from those of typical weight loss trials.
Figure 2
Figure 2
Abbreviations: ZNS, zonisamide. Depicted as least-square means (SE). For one patient who was found to be pregnant at Month 5, data collected between Month 6 and Month 12 are not included.
Acknowledgments
Funding/Support: This study was supported by grant 5R01 DK67352 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to Dr. Gadde.
Role of the Sponsors: The sponsor had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Footnotes
Trial Registration Clinicaltrials.gov identifier: NCT00275834
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. DrGadde reported receiving grants from Bristol Myers Squibb, Forest Laboratories, National Institute of Diabetes and Digestive and Kidney Diseases, Pfizer and Vivus in the past 36 months. He has been awarded several patents in the name of his institution for use of zonisamide as monotherapy and in combination with other drugs for treatment of obesity as well as weight gain associated with psychotropic drugs; these patents have been licensed to Orexigen Therapeutics by his institution. Consequent to the licensing agreement, Dr Gadde owns equity in Orexigen, which is developing zonisamide and bupropion combination therapy for obesity, based on his patents. However, to the best of DrGadde’s knowledge, no commercial entity has announced plans to develop zonisamide monotherapy for obesity or other applications claimed in his patents. Dr Allison has had financial interests with Arena Pharmaceuticals, EnteroMedics, Frontiers Foundation, Federal Trade Commission, Jason Pharmaceuticals, Kraft Foods, Mead Johnson Nutrition, Mead Johnson & Company, Medifast, Orexigen Therapeutics, Sage Publications, University of Arizona, University of Wisconsin, Vivus, Wolters Kluwer Pharma Solutions, and Paul, Pfizer, Weiss, Wharton and Garrison LLP. Dr Bray reported that he has been a consultant to Abbott Laboratories and Takeda Global Research Institute; is an advisor to Medifast, Herbalife, and Global Direction in Medicine; and has received royalties for the Handbook of Obesity. No other authors provided any financial disclosures.
Disclaimer: The views expressed in this article are those of the authors and do not necessarily represent the official views of the NIDDK, the National Institutes of Health, or the Department of Health and Human Services.
Additional Contributions: We thank all of the patients who participated in this trial. We are grateful to Catherine Gang, MPH, RD (Duke University Medical Center), for data collection and dietary counseling, Jonathan R. Davidson, MD (Professor Emeritus, Duke University), for monitoring data safety on a periodic basis for the entire duration of patient participation, and Andrew W. Brown, PhD (University of Alabama at Birmingham) for valuable comments during critical revision of the manuscript. Ms Gang and Dr Davidson were compensated for their services from the grant. Dr Brown received no compensation.
Author Contributions: Dr Gadde had full access to all of the data in the study and takes full responsibility for the integrity of the data. Dr Wagner II takes responsibility for the accuracy of the data analysis.
Study concept and design: Gadde, Wagner II, Allison, Bray.
Acquisition of data: Gadde, Kopping, Yonish, Gang.
Analysis and interpretation of data: Wagner II, Gadde.
Drafting of the manuscript: Gadde, Kopping.
Critical revision of the manuscript for important intellectual content: Gadde, Kopping, Wagner II, Yonish, Gang, Allison, Bray.
Statistical analysis: Wagner II.
Obtained funding: Gadde.
Administrative, technical, or material support: Gadde, Kopping.
Study supervision: Gadde
1. Douketis JD, Macie C, Thabane L, et al. Systematic review of long-term weight loss studies in obese adults: clinical significance and applicability to clinical practice. Int J Obes. 2005;29:1153–1167. [PubMed]
2. Franz MJ, VanWormer JJ, Crain AL, et al. Weight-loss outcomes: A systematic review and meta-analysis of weight-loss clinical trials with a minimum 1-year follow-up. J Am Diet Assoc. 2007;107:1755–1767. [PubMed]
3. Diabetes Prevention Program (DPP) Research Group. The Diabetes Prevention Program (DPP): description of lifestyle intervention. Diabetes Care. 2002;25:2165–2171. [PMC free article] [PubMed]
4. Wadden TA, West DS, Delahanty L, et al. for the Look AHEAD Research Group. The Look AHEAD study: a description of the lifestyle intervention and the evidence supporting it. Obesity. 2006;14:737–752. [PMC free article] [PubMed]
5. Ryan DH, Kushner R. The state of obesity and obesity research. JAMA. 2010;304:1835–1836. [PubMed]
6. LeBlanc ES, O’Connor E, Whitlock EP, et al. Effectiveness of primary care-relevant treatments for obesity in adults: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155:434–447. [PubMed]
7. Food and Drug Administration. FDA briefing document: NDA 22529. Lorqess (lorcaserin hydrochloride) tablets, 10 mg. Endocrinologic and Metabolic Drugs Advisory Committee Meeting; May 10, 2012; [Accessed 13July 2012]. Accessible at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM303198.pdf.
8. Gadde KM, Franciscy DM, Wagner HR, et al. Zonisamide for weight loss in obese adults: a randomized controlled trial. JAMA. 2003;289:1820–1825. [PubMed]
9. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67:361–370. [PubMed]
10. Mifflin MD, St Jeor ST, Hill LA, et al. A new predictive equation for resting energy expenditure in healthy individuals. Am J Clin Nutr. 1990;51:241–247. [PubMed]
11. Rubin D. Inference and missing data. Biometrika. 1976;63:581–592.
12. Gadbury GL, Coffey CS, Allison DB. Modern statistical methods for handling missing repeated measurements in obesity trial data: beyond LOCF. Obes Rev. 2003;4:174–184. [PubMed]
13. Elobeid MA, Padilla MA, McVie T, et al. Missing data in randomized clinical trials for weight loss: scope of the problem, state of the field, and performance of statistical methods. PLoS One. 2009;4(8):e6624. [PMC free article] [PubMed]
14. Rubin DB, Schenker N. Multiple imputation in health-care databases: an overview and some implications. Stat Med. 1991;10:585–598. [PubMed]
15. Schafer JL. Analysis of incomplete multivariate data. New York, NY: Chapman & Hall; 1997.
16. Pi-Sunyer FX, Aronne LJ, Heshmati HM, et al. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight/obese patients: RIO North America: a randomized controlled trial. JAMA. 2006;295:761–775. [PubMed]
17. Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363:245–56. 50. [PubMed]
18. Greenway FL, Fujioka K, Plodkowski RA, et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2010;376:595–605. [PubMed]
19. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP) Obesity. 2012;20:330–342. [PMC free article] [PubMed]
20. Wadden TA, Foreyt JP, Foster GD, et al. Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial. Obesity. 2011;19:110–120. [PubMed]
21. Simons-Morton DG, Obarzanek E, Cutler JA. Obesity research – limitations of methods, measurements, and medications. JAMA. 2006;295:826–828. [PubMed]
22. Food and Drug Administration. Guidance for industry developing products for weight management. [Accessed 13 July 2012];Draft guidance. Revision 1, Feb 2007. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071612.pdf.