A Clinical Trial Assessing the Safety and Efficacy of Taranabant, a CB1R Inverse Agonist, in Obese and Overweight Patients: a High-Dose Study

International Journal of Obesity (2010) 34, 919–935 & 2010 Macmillan Publishers Limited All rights reserved 0307-0565/10 $32.00 www.nature.com/ijo ORIGINAL ARTICLE A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study

LJ Aronne1, S Tonstad2, M Moreno3, I Gantz4, N Erondu4, S Suryawanshi4, C Molony4, S Sieberts4, J Nayee4, AG Meehan4, D Shapiro4, SB Heymsfield4, KD Kaufman4 and JM Amatruda4

1Weill Cornell Medical College, New York, NY, USA; 2Ullevaal University Hospital, Oslo, Norway; 3Pontificia Universidad Cato´lica de Chile, Santiago, Chile and 4Merck Research Laboratories, Rahway, NJ, USA

Objective: To evaluate the efficacy, safety and tolerability of taranabant in obese and overweight patients. Design: Double-blind, randomized, placebo-controlled study. Subjects: Patients were X18 years old, with body mass index of 27–43 kg m–2, and 51% with metabolic syndrome (MS) randomized to placebo (N ¼ 417) or taranabant 2 mg (N ¼ 414), 4 mg (N ¼ 415) or 6 mg (N ¼ 1256) for 104 weeks. Measurements: Key efficacy measurements included body weight, waist circumference (WC), lipid and glycemic end points. Results: On the basis of risk/benefit assessments, the 6-mg dose was discontinued during year 1 (patients on 6 mg were down- dosed to 2 mg or placebo) and the 4-mg dose was discontinued during year 2 (patients on 4 mg were down-dosed to 2 mg). Changes from baseline in body weight at week 52 (all-patients-treated population, last observation carried forward analysis) were À2.6, À6.6 and À8.1 kg, respectively, for placebo and taranabant 2 and 4 mg (both doses Po0.001 vs placebo). For patients who completed year 1, changes from baseline in body weight at week 104 were À1.4, À6.4 and À7.6 kg for placebo and taranabant 2 and 4 mg, respectively (both doses Po0.001 vs placebo). The proportions of patients at weeks 52 and 104 who lost at least 5 and 10% of their baseline body weight were significantly higher and the proportions of patients who met criteria for MS were significantly lower for taranabant 2 and 4 mg vs placebo. The incidence of adverse experiences classified in the gastrointestinal, nervous, psychiatric, cutaneous and vascular organ systems were generally observed to be dose related with taranabant vs placebo. Conclusion: Taranabant at the 2- and 4-mg dose was effective in achieving clinically significant weight loss over 2 years and was associated with dose-related increases in adverse experiences. On the basis of these and other data, an assessment was made that the overall safety and efficacy profile of taranabant did not support its further development for the treatment of obesity. International Journal of Obesity (2010) 34, 919–935; doi:10.1038/ijo.2010.21; published online 16 February 2010

Keywords: randomized clinical trial; cannabinoid-1 receptor; endocannabinoid

Introduction pharmacological therapy as an adjunct to diet and exercise for the treatment of obese and overweight patients would Although the cornerstone for the treatment of obesity and serve an unmet medical need. overweight is dietary restriction and exercise, most rando- In recent years the endocannabinoid pathway has been mized weight loss trials of lifestyle and behavioral interven- the focus of intensive efforts toward antiobesity drug tions report modest weight loss and high recidivism.1–2 development. Endocannabinoids are believed to promote Currently marketed weight loss medications, which target appetite and food intake by activating cannabinoid-1 neurotransmitters or gut lipases, have limited efficacy and a receptors (CB1Rs) expressed in hypothalamic centers that variety of safety and tolerability issues.3 Safe and effective regulate energy balance, the limbic system that regulates reward pathways, and other cortical and subcortical regions.4,5 In addition, CB1R have been detected in several Correspondence: Dr LJ Aronne, Weill Medical College of Cornell University, peripheral tissues,6–9 although the functional significance of 1165 York Avenue, New York, NY 10021-7917, USA. its expression in those tissues remains to be established. E-mail: [email protected] Received 12 July 2009; revised 22 November 2009; accepted 2 January 2010; Taranabant (MK-0364) is a highly specific CB1R inverse 10 published online 16 February 2010 agonist that was being developed for the treatment of High-dose taranabant LJ Aronne et al 920 obesity. Studies in humans indicate that taranabant affects Only 14 patients originally allocated to the 6-mg dose were body weight by reducing appetite and increasing energy down-dosed before the end of year 1; the remainder of this expenditure.11 This manuscript presents data from one of group was down-dosed within the initial 3 months of year 2. the phase III studies that were part of the taranabant During year 2, a decision was made to discontinue the 4-mg development program. Results from this and other studies dose (not depicted in Figure 1) because of a re-assessment of were used to make a composite risk/benefit assessment of the risk/benefit profile of this dose based on accumulating taranabant, which led to its discontinuation from clinical data. All patients originally allocated to the 4 mg dose were development for the treatment of obesity. down-dosed to the 2-mg dose. Only two patients were down- Dose selection for this study was guided by the results of a dosed from taranabant 4 to 2 mg before the end of year 2. 12-week phase II study,11 which explored the efficacy, safety The remainder of this group was to be down-dosed during and tolerability of taranabant at a daily dose of 0.5, 2, 4 or a separate extension study that followed year 2 (not depicted 6 mg. Results of that study suggested that treatment with in Figure 1). doses of 4-mg and 6-mg taranabant (referred to as ‘high-dose The diet regimen used in this study consisted of a recom- taranabant’) led to greater weight loss efficacy compared mended diet, which targeted 25% caloric restriction. The with 2-mg taranabant and was associated with an acceptable exercise regimen was designed according to the patient’s current safety profile. level of physical activity and health status. Details of dietary counseling are presented in Supplementary Information.

Materials and methods Subjects Experimental design Eligible patients were X18 years of age, with a body mass This was a 2-year, double-blind, randomized, placebo-con- index between 30 and 43 kg m–2 (inclusive). Patients with a trolled study (taranabant Protocol 015) that involved 122 body mass index between 27 and 30 kg m–2 (inclusive) were international sites. After a 1-week screening period and a 2- eligible if they had previously been diagnosed with the week single-blind placebo plus diet/exercise run-in period, obesity-related comorbidity of hypertension, dyslipidemia or patients were randomized in a 2:2:2:3:3 ratio to placebo, sleep apnea. In addition, all patients had to meet at least one taranabant 2, 4 and 6 mg (fixed) or 6 mg (up-titrated from of the following four criteria at screening: (1) triglyceride 2 mg at 2-week intervals), respectively, administered once (TG) levels X150 mg per 100 ml; (2) high-density lipoprotein daily for 104 weeks. The objective of the titration scheme cholesterol (HDL-C) levels o40 mg per 100 ml in men and was to assess whether initial up-titration would reduce the o50 mg per 100 ml in women; (3) seated systolic blood occurrence of gastrointestinal-related adverse experiences, pressure (BP) X130 mm Hg or seated diastolic BP X85 mm Hg; which were observed in the phase II study. The study also (4) impaired fasting plasma glucose (X100 mg per 100 ml and included a 28-day post-treatment follow-up period. In o126 mg per 100 ml). These latter criteria, which are elements addition, patients who were discontinued from study drug of the metabolic syndrome (MS), were included to ensure were asked to continue in the study even though they were enrollment of at least 50% of patients with the MS. In the off the study drug. This off-study drug phase of the study was study, patient were classified as having the MS if they had at instituted during year 1 for the purpose of enhancing least three of the following five criteria: (1) waist circum- collection of long-term safety data. The study was monitored ference (WC) X102 cm for men and X88 cm for women by an independent external Data Safety Monitoring (2) TG X150 mg per 100 ml; (3) HDL-C o40 mg per 100 ml for Committee, which reviewed unblinded safety and efficacy men or o50 mg per 100 ml for women; (4) seated systolic data across the taranabant phase III program. BP X130 mm Hg or seated diastolic BP X85 mm Hg; and As initially designed, patients were to remain on their (5) impaired fasting glucose (X100 mg per 100 ml and originally assigned doses throughout the course of the study. o126 mg per 100 ml. However, two changes in the doses of taranabant were made Patients had to be compliant with diet and exercise during the conduct of the study. At a routine meeting in as measured by demonstration of no weight gain during year 1, the Data Safety Monitoring Committee recom- the run-in period. mended discontinuation of the 6-mg dose based on its Patients with a history of a major psychiatric disorder minimal increase in efficacy over 4 mg and a trend toward a were excluded from the study. However, patients with a higher incidence of adverse experiences. The Committee did history of mild depression who were asymptomatic at the not conclude that the 6-mg dose needed to be immediately time of screening/randomization, including those who halted and patients on the 6-mg dose (fixed and titrated were on a single medication for the treatment of their arms) were randomly down-dosed (1:2) to treatment with depression, were allowed to participate. To assist investi- placebo or taranabant 2 mg, respectively (Figure 1). Full gators with assessment of depressive symptomatology, the implementation of the 6 mg down-dosing took approxi- Patient Health Questionnaire-9 (PHQ-9)12 was incorporated mately 6 months because of the time required for regulatory into the study shortly after enrollment had begun. Because agency and ethics board approvals in multiple countries. of this timing, not all patients were screened using the

International Journal of Obesity High-dose taranabant LJ Aronne et al 921

Figure 1 Study design. On the basis of the recommendation of the Data Safety Monitoring Committee, patients on the 6 mg dose (fixed and titrated arms) were randomly down-dosed (1:2) to treatment with placebo or taranabant 2 mg, respectively.

PHQ-9. Other exclusion criteria included diabetes mellitus; LDL-C), measures of glycemic control (fasting serum insulin, significant cardiovascular, hepatic, gastrointestinal, neuro- insulin sensitivity determined by QUICKI (quantitative logical, pulmonary or renal disease; use of nicotine-contain- insulin sensitivity check index) 14 and fasting plasma glucose), ing products; substance abuse; and use of a moderate or and the proportion of patients who met criteria for MS. Other potent CYP3A4 inhibitor.13 On the basis of the occurrence secondary end points assessed at week 52 included change of a few seizures reported during the phase III program, a from baseline in systolic BP and diastolic BP and patient- protocol amendment during year 1 discontinued patients reported outcomes, including the Short Form 36 Health with a history of seizures or those who were at a high risk Survey Version 2 Acute Form (SF-36v2 Acute),15 The Impact of for developing seizures. Weight on Quality of Life (IWQoL)16 and the EuroQoL The study was conducted in accordance with the Declara- (EQ5D) Health State Assessment.17 Measurements of percent tion of Helsinki and Good Clinical Practice guidelines. The body fat (measured by dual-energy X-ray absorptiometry in a study was approved by an institutional review board or sub-population of patients in the United States), high- independent ethics committee and all patients provided sensitivity C-reactive protein and adiponectin were not written informed consent. obtained after week 24 because the subsequent down-dosing would confound the continued longitudinal analysis of these measures. Measurements Safety assessments included collection of adverse The primary efficacy end points were the change in body experiences, physical examinations, vital signs and self- weight from baseline (last measurement before start of administered questionnaires for the evaluation of cognitive/ double-blind study drug) and the proportion of patients neuropsychomotor performance (Digital Symbol Substi- who lost at least 5 or 10% of their baseline body weight at tution Test (DSST)18), mood (Profile of Mood States brief week 52. As a result of the decision to down-dose the 6 mg form (POMSb)19) and depressive symptomatology (PHQ-9). group to 2 mg or placebo during year 1, the statistical If a patient reported a psychiatric adverse experience, a full analysis in the amended protocol did not include the 6 mg Patient Health Questionnaire (FPHQ)20 was administered. dose in the primary efficacy analysis at week 52. As it was Adjudication of possibly suicide-related adverse events was anticipated that only a limited number of patients would performed according to the Food and Drug Administration be down-dosed from taranabant 4 to 2 mg before the end of guidance for exploring suicidality (suicidal ideation and year 2, the statistical analysis plan for the efficacy analysis behavior) in placebo-controlled clinical trials.21 Narratives of the 4-mg dose at week 104 was not altered. for possibly suicide-related adverse events were written and Key secondary end points at week 52 included change from adjudication of these events was performed by an inde- baseline in WC, lipid end points (TG, HDL-C, non-HDL-C and pendent external adjudication committee, which used the

International Journal of Obesity High-dose taranabant LJ Aronne et al 922 Columbia Classification Algorithm of Suicide Assessment assess taranabant for such effects, the weight-independent (C-CASA).22 portion of the total treatment effect was calculated as the ratio of the weight-adjusted treatment effect to the treatment effect in the ANCOVA model without weight change at Laboratory assays week 52 as a covariate. Details of laboratory assays are presented in Supplementary An analysis of year 1 data was performed after the 52-week Information. time point. An analysis of the year 2 data was performed after the 104-week time point.

Statistical methodology The primary analysis population was an all-patients-treated Results population, which included all randomized patients who had a baseline value, had received at least one dose of Baseline characteristics and patient disposition randomized treatment and had at least one post-baseline A total of 2502 patients were randomized, and 1177 (47%) measurement. The primary efficacy end point, mean change completed the study (Supplementary Information, Table S1). from baseline in body weight at week 52, was assessed by Of the total, 41% were male and 51% met criteria for the MS. comparing the placebo group to taranabant 2 and 4 mg A total of 1325 (53%) patients discontinued study drug groups using an analysis of covariance (ANCOVA). The before completion of the 2-year study. The incidence of model included terms for treatment, baseline body weight, discontinuations due to clinical adverse experiences was weight change during run-in and region (US and four ex-US greater in the taranabant groups compared with the placebo geographic regions). The proportion of patients with at least group. The primary reasons for study discontinuation are 5% weight loss from baseline (5% responders) and 10% listed in Supplementary Table S1. In all, 260 (10%) of the weight loss from baseline (10% responders) at week 52 were patients who discontinued from the study agreed to assessed using a logistic model with terms for treatment, continue in the off-study drug phase of the study. The baseline body weight, weight change during run-in and treatment groups were similar with respect to patient region. demographics and baseline characteristics (Table 1). Secondary end points were analyzed using an ANCOVA In the following description of the efficacy and safety model with terms for treatment, baseline value of measure, results, taranabant groups are compared with the placebo weight change during the run-in period, change in the group. There were no formal analyses of differences between measure during run-in, baseline body weight and region. The taranabant groups. In describing results, the terms ‘numeri- proportion of patients who had MS at week 52 was assessed cally higher’ or ‘numerically lower’ are used to denote by comparing taranabant 2 mg and 4 mg with placebo using differences from placebo that are not statistically significant a logistic model. but that might be clinically meaningful. The incidences The primary and secondary end points at week 104 in of adverse experiences in the taranabant fixed and titrated patients who completed week 52 and had at least one efficacy 6 mg groups were similar and, therefore, for simplicity of measurement taken after week 52 were assessed using the presentation, adverse experiences in the 6 mg fixed and above-mentioned ANCOVA models. The comparison of body titrated groups were combined. weight regain from the time of down-dose to 52 weeks after dose change in patients who had been on taranabant 6 mg during year 1 and who had been down-dosed to placebo or Efficacy results 2 mg was performed using ANCOVA, with factors of treat- Treatment with taranabant 2 and 4 mg led to significantly ment, region, body weight change while on 6 mg and body greater weight loss from baseline at weeks 52 and 104 weight at the time of down-dose as covariates. (Table 2 and Figures 2a and 3). Although the taranabant 6 mg All randomized patients who received at least one dose of groups (fixed and titrated) were not included in the active treatment were included in the safety assessment. predefined efficacy analysis, the change in body weight of Inferential P-values were obtained from analyses of prespe- the combined 6 mg fixed and titrated groups is shown in cified clinical adverse experiences. For these analyses, Figure 2b, which plots the weight loss of all treatment groups comparisons based on differences in proportions of patients using all observed data for the within-treatment change in with an event were performed using Fisher’s exact test and body weight at week 52. The mean observed changes from confidence intervals (CIs) for the between-group differences baseline at week 52 in body weight were À4.1, À8.8, À10.3 were computed using Wilson’s score method. Changes from and À11.5 kg in the placebo and in 2-, 4- and 6-mg baseline in questionnaire scores were assessed using ANCOVA (fixed þ titrated) groups, respectively. models with terms for treatment, baseline body weight, Treatment with taranabant 2 and 4 mg also led to weight change during the run-in, baseline score and region. significantly greater reductions from baseline in WC at CB1R antagonists have been reported to have weight- weeks 52 and 104 (Table 2). Consistent with these observa- independent effects on glycemic and lipid parameters. To tions, there were significant reductions from baseline in

International Journal of Obesity High-dose taranabant LJ Aronne et al 923 Table 1 Demographics and baseline characteristics

Placebo Taranabant 2 mg Taranabant 4 mg Taranabant 6 mg (fixed and titrated) Characteristic (N ¼ 417) (N ¼ 414) (N ¼ 415) (N ¼ 1256)

Gender; n (%) Male 184 (44.1%) 168 (40.6%) 156 (37.6%) 515 (41.0%) Female 233 (55.9%) 246 (59.4%) 259 (62.4%) 741 (60.0%) Age; years Mean (s.d.) 48.4 (11.7) 49.2 (10.7) 49.0 (11.6) 49.1 (11.5) Range 19–84 18–76 19–77 18–81 Race; n (%) White 329 (78.9%) 331 (80.0%) 331 (79.8%) 1009 (80.3%) Black 24 (5.8%) 24 (5.8%) 18 (4.3%) 60 (4.8%) Hispanic 31 (7.4%) 27 (6.5%) 32 (7.7%) 93 (7.4%) Other 33 (7.9%) 32 (7.7%) 34 (8.2%) 94 (7.5%) BW; mean (s.d.) (kg) 100.0 (16.1) 100.0 (16.3) 99.2 (15.4) 100.5 (16.7) Run-in BW change; mean (s.d.) (kg) À1.5 (1.3) À1.7 (1.3) À1.8 (1.3) À1.7 (1.3) BMI; mean (s.d.) (kg m–2) 34.8 (3.7) 35.1 (3.9) 35.2 (4.0) 35.1 (4.1) WC; mean (s.d.) (cm) 110.4 (11.8) 111.1 (11.6) 110.8 (11.5) 111.2 (12.0) SBP; mean (s.d.) (mm Hg) 122.0 (14.4) 122.9 (13.2) 123.2 (13.7) 123.6 (13.9) DBP; mean (s.d.) (mm Hg) 78.4 (9.3) 78.8 (9.1) 78.4 (8.8) 78.9 (9.2) TG; median (s.d.) (mg per 100 ml) 139.0 (75.3) 133.0 (69.8) 135.0 (75.3) 136.0 (69.8) HDL-C; mean (s.d.) (mg per 100 ml) 46.9 (11.9) 48.7 (14.7) 48.5 (12.6) 47.9 (13.3) Non-HDL-C; mean (s.d.) (mg per 100 ml) 149.8 (37.2) 147.2 (38.6) 149.3 (38.8) 147.4 (37.8) LDL-C; mean (s.d.) (mg per 100 ml) 118.8 (33.7) 117.1 (34.9) 118.3 (34.0) 117.3 (34.1) TC; mean (s.d.) (mg per 100 ml) 196.7 (38.6) 196.1 (39.9) 197.8 (39.1) 195.2 (38.4) FPG; mean (s.d.) (mg per 100 ml) 96.9 (10.9) 97.3 (10.6) 98.1 (11.2) 97.2 (11.0) FSI; mean (s.d.) (mIU ml–1) 16.6 (8.9) 16.5 (12.3) 16.5 (11.8) 16.2 (9.2) QUICKI; mean (s.d.) 0.319 (0.024) 0.321 (0.027) 0.320 (0.024) 0.321 (0.030) hs-CRP; median (s.d.) (mg per 100 ml) 0.2 (0.4) 0.3 (0.4) 0.3 (0.5) 0.3 (0.4) Adiponectin; mean (s.d.) (mgml–1) 7.2 (3.7) 7.5 (3.6) 7.6 (3.6) 7.8 (3.9)

Abbreviations: BMI, body mass index; BW, body weight; DBP, diastolic blood pressure; FPG, fasting plasma glucose; FSI, fasting serum insulin; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; QUICKI, quantitative insulin sensitivity check index; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides; WC, waist circumference.

percent body fat, as assessed using dual-energy X-ray 2-mg group at week 52 or in the 2- and 4-mg groups at week absorptiometry, from baseline at week 24 in the taranabant 104 (Table 2). 2- and 4-mg groups (Table 2). Decreases in fasting serum insulin were observed after The proportions of patients achieving at least 5% and at 52 weeks of treatment with 2- or 4-mg taranabant; however, least 10% of loss of baseline body weight at weeks 52 and 104 the decrease was significant only for the 4-mg dose (Table 2). were significantly greater in the 2- and 4-mg groups (Figure 4). Treatment with taranabant had no significant effects on Patients allocated to treatment with taranabant 6 mg fasting plasma glucose at weeks 52 or 104 or on fasting serum during year 1 and who had been down-dosed to taranabant insulin at weeks 104 (Table 2). Improvements in insulin 2 mg had significantly less weight regain than those down- sensitivity at week 52 were observed in patients treated dosed to placebo (the least-squares mean weight regain in with taranabant 2 and 4 mg with significant improvements patients who were down-dosed to placebo and taranabant in patients treated with 4 mg (Table 2). 2 mg was 5.3 (95% CI 4.8–5.7) and 3.0 (95% CI 2.6–3.3) kg, There was a small mean reduction from baseline in systolic respectively; Figure 5). BP and diastolic BP at weeks 52 and 104 in the 2- and 4-mg The proportion of patients who met criteria for MS at groups (Table 2). There was a reduction at week 24 in high- weeks 52 and 104 was significantly lower in the taranabant sensitivity C-reactive protein and increase in adiponectin in 2- and 4-mg groups (Supplementary Table S2). the 2- and 4-mg groups (Table 2). Treatment with taranabant 2 and 4 mg produced signifi- Secondary end points that were determined to be statisti- cant median percentage reductions from baseline in TG and cally different from placebo were subjected to an exploratory mean percentage increases in HDL-C at weeks 52 and 104 analysis to determine what percentage of the total treatment (Table 2). A small (À3.3%), significant mean percentage effect was due to a weight-independent effect. After adjust- reduction in LDL-C was observed with taranabant 4 mg at ing for change in body weight, there were significant effects week 52, whereas no significant differences in mean on HDL-C and QUICKI with 2- and 4-mg taranabant percentage change in LDL-C were observed in the taranabant compared with placebo (Supplementary Table S3). By this

International Journal of Obesity 924 nentoa ora fObesity of Journal International

Table 2 LS mean change from baseline (95% CI) and difference in LS mean change from placebo (95% CI) for efficacy end points at year 1 (week 52) and year 2 (week 104)

Placebo Taranabant 2 mg Taranabant 4 mg

LS mean change from LS mean change from LS mean difference LS mean change from LS mean difference baseline (95% CI) baseline (95% CI) vs Pbo (95% CI) baseline (95% CI) vs Pbo (95% CI)

Year 1 BW; mean (kg) À2.6 (À3.3 to À1.8) À6.6 (À7.4 to À5.9) À4.1 (À5.0 to À3.2)*** À8.1 (À8.9 to À7.4) À5.6 (À6.5 to À4.7)*** WC; mean (cm) À3.1 (À3.9 to À2.3) À7.0 (À7.8 to À6.1) À3.8 (À4.8 to À2.9)*** À7.5 (À8.3 to À6.7) À4.4 (À5.3 to À3.4)*** Total body fat; mean (%)a À2.3 (À2.9 to À1.7) À3.4 (À4.0 to À2.9) À1.1 (À1.9 to À0.3)** À3.3 (À3.8 to À2.7) À1.0 (À1.8 to À0.1)*

SBP; mean (mm Hg) À1.5 (À2.8 to À0.2) À2.8 (À4.2 to À1.5) À1.3 (À2.9 to 0.2) À2.7 (À4.1 to À1.4) À1.2 (À2.8, 0.3) taranabant High-dose w DBP; mean (mm Hg) À0.2 (À1.1 to 0.7) À1.2 (À2.1 to À0.3) À1.0 (À2.0 to 0.1) À1.6 (À2.5 to À0.8) À1.4 (À2.4, À0.4) TG; median (%) 4.0 (À0.4 to 8.3) À3.1 (À7.2 to 0.9) À9.0 (À13.8 to À4.3)*** À6.2 (À9.9 to À2.5) À10.9 (À15.7 to À6.3)*** HDL-C; mean (%) 7.0 (5.0 to 9.1) 13.2 (11.2 to 15.2) 6.1 (3.8 to 8.5)*** 14.1 (12.1 to 16.1) 7.0 (4.7 to 9.4)*** JAronne LJ Non-HDL-C; mean (%) 4.4 (2.2 to 6.6) 1.1 (À1.1 to 3.3) À3.3 (À5.8, À0.7)** À0.8 (À3.0, 1.3) À5.2 (À7.8, À2.7)*** LDL-C; mean (%) 3.6 (1.0 to 6.3) 2.0 (À0.7 to 4.6) À1.6 (À4.7 to 1.4) 0.3 (À2.3 to 2.9) À3.3 (À6.4 to À0.3)* FPG; mean (mg per 100 ml) 1.2 (0.1 to 2.2) 0.4 (À0.7 to 1.4) À0.8 (À2.1 to 0.5) À0.4 (À1.5 to 0.7) À1.6 (À2.8 to À0.3)* FSI; mean (mIU ml–1 ) 1.9 (À3.1 to 6.9) À0.7 (À5.6 to 4.2) À2.6 (À7.0 to 1.9) À2.7 (À7.5 to 2.1) À4.6 (À9.2 to À0.0)* w al et QUICKI; mean À0.013 (À0.024 to À0.002) 0.001 (À0.010 to 0.012) 0.014 (0.004 to 0.024) 0.002 (À0.008 to 0.013) 0.015 (0.005 to 0.026)** w w hs-CRP; median (%)b À0.63 (À8.87 to 7.62) À21.25 (À27.59 to À14.91) À20.78 (À29.13 to À12.70) À30.56 (À36.07 to À25.04) À26.99 (À35.13 to À19.05) w w Adiponectin; mean (%)b 1.7 (À2.2 to 5.6) 8.6 (4.7 to 12.5) 6.9 (2.4 to 11.4) 6.8 (3.0 to 10.6) 5.1 (0.6 to 9.6)

Year 2 c BW; mean (kg) À1.4 (À2.5 to À0.3) À6.4 (À7.4 to À5.3) À5.0 (À6.3 to À3.6)*** À7.6 (À8.7 to À6.5) À6.2 (À7.5 to À4.9)*** w WC; mean (cm) À2.7 (À3.8 to À1.5) À6.3 (À7.4 to À5.2) À3.6 (À5.0 to À2.3) À7.0 (À8.1 to À5.9) À4.4 (À5.7 to À3.0)** SBP; mean (mm Hg) À1.9 (À3.8 to À0.0) À2.3 (À4.1 to À0.5) À0.4 (À2.6 to 1.8) À1.9 (À3.6 to À0.1) 0.0 (À2.2 to 2.3) DBP; mean (mm Hg) À0.2 (À1.5 to 1.0) À1.3 (À2.5 to À0.0) À1.0 (À2.6 to 0.5) À0.8 (À2.0 to 0.5) À0.5 (À2.1 to 1.0) w w TG; median (%) 5.8 (1.0 to 10.5) À7.5 (À12.4 to À2.5) À10.4 (À16.2 to À4.5) À1.7 (À6.7 to 3.4) À8.5 (À14.4 to À2.6) w w HDL-C; mean (%) 7.8 (4.8 to 10.8) 18.3 (15.4 to 21.1) 10.4 (7.0 to 13.9) 17.2 (14.4 to 20.1) 9.4 (5.9 to 12.9) Non-HDL-C; mean (%) 3.7 (0.7 to 6.6) 1.1 (À1.7 to 4.0) À2.5 (À6.0 to 0.9) 2.0 (À0.8 to 4.8) À1.7 (À5.1 to 1.8) LDL-C; mean (%) 1.6 (À1.8 to 5.1) 2.1 (À1.3 to 5.4) 0.4 (À3.7 to 4.5) 3.5 (0.2 to 6.8) 1.9 (À2.2 to 5.9) FPG; mean (mg per 100 ml) 0.1 (À1.6 to 1.8) À0.5 (À2.2 to 1.1) À0.6 (À2.6 to 1.4) À0.3 (À2.0 to 1.3) À0.4 (À2.4 to 1.6) FSI; mean (mIU ml–1 ) 1.2 (À3.7 to 6.1) 0.1 (À4.8 to 4.9) À1.2 (À6.1 to 3.7) À1.1 (À6.3 to 4.1) À2.3 (À7.7 to 3.1) QUICKI; mean À0.008 (À0.022 to 0.006) À0.004 (À0.018 to 0.011) 0.004 (À0.010 to 0.018) À0.006 (À0.021 to 0.009) 0.002 (À0.013 to 0.017)

Abbreviations: BMI, body mass index; BW, body weight; CI, confidence interval; DBP, diastolic blood pressure; FPG, fasting plasma glucose; FSI, fasting serum insulin; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; LS, least squares; QUICKI, quantitative insulin sensitivity check index; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides; WC, waist circumference. aTotal body fat was assessed using MRI in a subset of patients (91, 94 and 88 patients in the Pbo, taranabant 2-mg and taranabant 4-mg groups, respectively) at baseline and week 24. bAdiponectin and hs-CRP were assessed at baseline and week 24. cIncludes patients who completed year 1 and entered year 2 on the same treatment. *Pp0.050 vs w placebo; **Pp0.010 vs placebo; ***Pp0.001 vs placebo; nominally significant Pp0.050 vs placebo not adjusted for multiplicity. High-dose taranabant LJ Aronne et al 925

Figure 2 (a) Mean change in body weight (kg) from baseline (week 0) over time to week 52 for the all-patients-treated (APT) population using the last observation carried forward (LOCF) method. Estimates and 84% confidence intervals (CIs) of change in body weight from baseline at week 52 using least- Figure 4 Percentage of patients achieving X5andX10% body weight loss squares (LS) means from an ANCOVA model with LOCF and a repeated relative to baseline. measure analysis (RMA) model are shown after the line break at the primary end point (week 52). (b) Absolute (non-modeled) mean change from baseline (week 0) in body weight (kg) (84% CI) plotted as data observed not using the LOCF method. analysis, approximately 50% of the HDL-C changes and approximately 70% of the QUICKI changes were estimated to be weight independent. At week 52, treatment with taranabant 4 mg led to a worsening from baseline in four components of the SF36v2 questionnaire: standardized mental component, social functioning, role emotional and mental health (Supplementary Table S4). No changes in the SF36v2 component scores from baseline at week 52 were observed in the taranabant 2 mg group. At week 52, treatment with taranabant 4 mg led to an improvement from baseline in the physical function score and total score of the IWQoL (Supplementary Table S5). At week 52, the treatment with taranabant 2 and 4 mg led to an improvement from baseline in the self-esteem score. At week 52, the EQ5D showed improvements in all treatment groups Figure 3 Mean change in body weight (kg) from baseline to week 104 for (Supplementary Table S6). patients in the placebo, taranabant 2 and 4 mg groups who completed year 1 No difference in patient-reported outcomes between and entered year 2 using the last observation carried forward (LOCF) method patients treated with taranabant 2 mg and those treated in the second year. Estimates and 84% confidence intervals (CIs) of change in with placebo were observed after 104 weeks of treatment; body weight for baseline at week 104 using least squares (LS) means from an analysis of covariance model with LOCF in the second year are shown after the however, a worsening was observed between the 4 mg and line break at week 104. placebo groups in the Standardized Mental Component,

International Journal of Obesity High-dose taranabant LJ Aronne et al 926 Vitality, Social Functioning, Mental Health and Work Clinical adverse experiences classified according to the component of the IWQOL. Medical Dictionary for Regulatory Activities (MedDRA, version 10.1) system organ classes (SOC) are presented in Table 4. The specific clinical adverse experiences listed that Safety results were prespecified as clinical adverse experiences related to The overall incidences of clinical adverse experiences were the mechanism of action and previously observed safety comparable across the treatment groups in both years 1 and profile of taranabant are discussed below. Discontinuations 2, although discontinuations due to overall and drug-related due to drug-related clinical adverse experiences reported clinical adverse experiences were numerically higher in the by at least two patients in any treatment group in years 1 or taranabant groups in both years (Table 3). 2 are presented in Supplementary Table S7. Analyses of the prespecified clinical adverse experiences in year 1 for the entire study population and in year 2 for those patients who completed year 1 and entered year 2 on the same treatment are provided in Table 5. During year 1, the incidences of nausea and diarrhea were significantly higher in all taranabant groups; the incidences of frequent bowel movements were numerically higher in the 2 and 6-mg groups and significantly higher in the 4-mg group and the incidence of vomiting was numerically higher in the 2-mg group and significantly higher in the 4- and 6-mg groups. There were no clinically meaningful differences between the taranabant fixed and titrated 6-mg groups (data not shown) in the incidences of overall adverse experiences in the Gastrointestinal Disorders SOC or of prespecified, selected gastrointestinal-related adverse experiences, indicat- ing that dose titration at initiation of treatment did not Figure 5 Mean change in body weight from baseline over 52 weeks after reduce the incidences of these adverse experiences. switching from 6 to 2 mg taranabant or placebo or placebo to placebo for patients who completed year 1 and entered year 2 using the last observation In the Nervous System Disorders SOC the incidences of carried forward method in year 2. adverse experiences in the dizziness, sedation and syncope

Table 3 Overall summary of clinical and laboratory adverse experiences at year 1 (week 52) and year 2 (weeks 52 to 104)

Adverse event category Year 1 Year 2 a

Placebo Taranabant Taranabant Taranabant 6 mg (fixed and Placebo Taranabant Taranabant N ¼ 417 2mg N ¼ 414 4mg N ¼ 415 titrated) b N ¼ 1256 N ¼ 244 2mg N ¼ 264 4mg N ¼ 260

One or more clinical AE 361 (86.6%) 353 (85.3%) 377 (90.8%) 1110 (88.4%) 192 (78.7%) 189 (71.6%) 193 (74.2%) Drug-relatedc clinical AE 152 (36.5%) 185 (44.7%) 236 (56.9%) 689 (54.9%) 18 (7.4%) 25 (9.5%) 38 (14.6%) Serious clinical AE 25 (6.0%) 33 (8.0%) 29 (7.0%) 91 (7.2%) 11 (4.5%) 16 (6.1%) 17 (6.5%) Drug-relatedc serious clinical AE 0 0 1 (0.2%) 11 (0.9%) 0 1 (0.4%) 0 Discontinued due to clinical AE 40 (9.6%) 53 (12.8%) 82 (19.8%) 263 (20.9%) 3 (1.2%) 11 (4.2%) 11 (4.2%) Discontinued due to drug-relatedc 29 (7.0%) 42 (10.1%) 66 (15.9%) 216 (17.2%) 2 (0.8%) 9 (3.4%) 7 (2.7%) clinical AE Discontinued due to serious clinical AE 4 (1.0%) 3 (0.7%) 6 (1.4%) 18 (1.4%) 0 1 (0.4%) 2 (0.8%) Discontinued due to drug-related c 0 0 1 (0.2%) 10 (0.8%) 0 1 (0.4%) 0 serious clinical AE Deathsd 1 (0.2%) 1 (0.2%) 0 0 0 0 0 One or more laboratory AE 16 (3.9%) 12 (2.9%) 16 (3.9%) 51 (4.1%) 8 (3.3%) 7 (2.7%) 11 (4.2%) Drug-relatedc laboratory AE 4 (1.0%) 3 (0.8%) 5 (1.2%) 20 (1.6%) 1 (0.4%) 2 (0.8%) 2 (0.8%) Serious laboratory AE 0 0 0 0 0 0 0 Discontinued due to laboratory AE 2 (0.5%) 0 1 (0.2%) 0 0 1 (0.4%) 0 Discontinued due to drug-related 2 (0.5%) 0 1 (0.2%) 0 0 0 0 laboratory AE

Abbreviation: AE, adverse experience. aIncludes AEs reported from weeks 52 to 104 in patients who completed year 1 and entered year 2 on the same treatment. bIncludes AEs reported while on taranabant 6 mg (fixed or titrated) plus 28 days after switching to placebo or 2 mg. cDetermined by the study investigator to be possibly, probably or definitely treatment related. dA 66-year-old man (placebo group) who died of metastatic lung cancer (investigator assessment as probably not drug related). A 56-year-old man (2-mg group) who died of septic shock secondary to necrotizing fasciitis (investigator assessment as probably not drug related). In addition, a 65-year-old female (6/2-mg group), who had been participating in the off-drug phase of the study for 167 days, died of a sudden cardiac death (investigator assessment as definitely not drug related).

International Journal of Obesity Table 4 Clinical adverse experiences classified by MedDRA system organ classes

Year 1 Year 2a

Placebo Taranabant 2 mg Taranabant 4 mg Taranabant 6 mg (fixed and titrated)b Placebo Taranabant 2 mg Taranabant 4 mg N ¼ 417 N ¼ 414 N ¼ 415 N ¼ 1256 N ¼ 244 N ¼ 264 N ¼ 260

SOCs and specific clinical AEs with incidences X5%c Eye disorders 23 (5.5%) 14 (3.4%) 8 (1.9%) 57 (4.5%) 7 (2.9%) 12 (4.5%) 13 (5.0%) Gastrointestinal disorders 119 (28.5%) 173 (41.8%) 194 (46.7%) 578 (46.0%) 52 (21.3%) 43 (16.3%) 54 (20.8%) Diarrhea 30 (7.2%) 51 (12.3%) 57 (13.7%) 174 (13.9%) 16 (6.6%) 9 (3.4%) 15 (5.8%) Nausea 27 (6.5%) 69 (16.7%) 89 (21.4%) 301 (24.0%) 5 (2.0%) 6 (2.3%) 11 (4.2%) Vomiting 14 (3.4%) 23 (5.6%) 35 (8.4%) 91 (7.2%) 3 (1.2%) 3 (1.1%) 5 (1.9%) General disorders and administrative site 58 (13.9%) 65 (15.7%) 90 (21.7%) 242 (19.3%) 20 (8.2%) 20 (7.6%) 23 (8.8%) conditions Irritability 7 (1.7%) 22 (5.3%) 36 (8.7%) 85 (6.8%) 1 (0.4%) 0 3 (1.2%) Infections and Infestations 225 (54.0%) 206 (49.8%) 221 (53.3%) 623 (49.6%) 122 (50.0%) 109 (41.3%) 119 (45.8%) Influenza 19 (4.6%) 34 (8.2%) 25 (6.0%) 81 (6.4%) 10 (4.1%) 9 (3.4%) 15 (5.8%) Nasopharyngitis 67 (16.1%) 49 (11.8%) 74 (17.8%) 198 (15.8%) 34 (13.9%) 36 (13.6%) 33 (12.7%) Sinusitis 23 (5.5%) 22 (5.3%) 22 (5.3%) 66 (5.3%) 13 (5.3%) 11 (4.2%) 13 (5.0%) Upper respiratory tract infection 50 (12.0%) 59 (14.3%) 48 (11.6%) 140 (11.1%) 32 (13.1%) 39 (14.8%) 31 (11.9%) Injury, poisoning and procedural complications 66 (15.8%) 63 (15.2%) 70 (16.9%) 177 (14.1%) 37 (15.2%) 31 (11.7%) 30 (11.5%) Metabolism and nutrition disorders 15 (3.6%) 23 (5.6%) 22 (5.3%) 72 (5.7%) 6 (2.5%) 7 (2.7%) 9 (3.5%) Musculoskeletal and connective tissue disorders 122 (29.3%) 117 (28.3%) 121 (29.2%) 333 (26.5%) 58 (23.8%) 70 (26.5%) 65 (25.0%) Arthralgia 29 (6.7%) 25 (6.0%) 24 (5.8%) 83 (6.6%) 12 (4.9%) 16 (6.1%) 16 (6.2%) Back pain 35 (8.4%) 30 (7.2%) 41 (9.9%) 84 (6.7%) 15 (6.1%) 14 (5.3%) 14 (5.4%) Pain in extremity 23 (5.5%) 20 (4.8%) 14 (3.4%) 46 (3.7%) 12 (4.9%) 13 (4.9%) 9 (3.5%) Nervous system disorders 102 (24.5%) 94 (22.7%) 138 (33.3%) 356 (28.3%) 29 (11.9%) 33 (12.5%) 42 (16.2%) Dizziness 24 (5.8%) 23 (5.6%) 43 (10.4%) 109 (8.7%) 7 (2.9%) 8 (3.0%) 6 (2.3%) Headache 52 (12.5%) 38 (9.2%) 48 (11.6%) 117 (9.3%) 15 (6.1%) 15 (5.7%) 18 (6.9%) Aronne LJ taranabant High-dose Psychiatric disorders 80 (19.2%) 108 (26.1%) 149 (35.9%) 444 (35.4%) 14 (5.7%) 16 (6.1%) 25 (9.6%) Anxiety 14 (3.4%) 16 (3.9%) 41 (9.9%) 105 (8.4%) 2 (0.8%) 2 (0.8%) 6 (2.3%) Depressed mood 12 (2.9%) 21 (5.1%) 21 (4.8%) 65 (5.2%) 3 (1.2%) 4 (1.5%) 4 (1.5%) Insomnia 25 (6.0%) 27 (6.5%) 40 (9.6%) 91 (7.3%) 5 (2.0%) 3 (1.1%) 11 (4.2%) al et Renal and urinary disorders 11 (2.6%) 11 (2.7%) 32 (7.7%) 67 (5.3%) 4 (1.6%) 1 (0.4%) 6 (2.3%) Reproductive system and breast disorders 22 (5.3%) 29 (7.0%) 28 (6.7%) 88 (7.0%) 4 (1.6%) 8 (3.0%) 13 (5.0%) Respiratory, thoracic and mediastinal disorders 56 (13.4%) 62 (15.0%) 69 (16.6%) 211 (16.8%) 25 (10.2%) 19 (7.2%) 29 (11.2%) Skin and subcutaneous tissue disorders 62 (14.9%) 72 (17.4%) 72 (17.3%) 269 (21.4%) 15 (6.1%) 14 (5.3%) 22 (8.5%) Pruritus 12 (2.9%) 19 (4.6%) 24 (5.8%) 95 (7.6%) 0 2 (0.8%) 2 (0.8%) Vascular disorders 22 (5.3%) 28 (6.8%) 49 (11.8%) 129 (10.3%) 16 (6.6%) 6 (2.3%) 17 (6.5%) Hypertension 15 (3.6%) 9 (2.2%) 22 (5.3%) 49 (3.9%) 9 (3.7%) 5 (1.9%) 9 (3.5%)

Drug-relatedd SOCs and clinical AEs with incidences X2%c Gastrointestinal disorders 54 (12.9%) 93 (22.5%) 110 (26.5%) 339 (27.0%) 4 (1.6%) 7 (2.7%) 12 (4.6%) Diarrhea 11 (2.6%) 20 (4.8%) 29 (7.0%) 87 (6.9%) 2 (0.8%) 2 (0.8%) 1(0.4%) Frequent bowel movements 1 (0.2%) 3 (0.7%) 11 (2.7%) 14 (1.1%) 0 0 0 Nausea 16 (3.8%) 49 (11.8%) 68 (16.4%) 224 (17.8%) 0 3 (1.1%) 5 (1.9%) Vomiting 3 (0.7%) 5 (1.2%) 17 (4.1%) 39 (3.1%) 0 2 (0.8%) 2 (0.8%) General Disorders and administrative site 22 (5.3%) 28 (6.8%) 47 (11.3%) 133 (10.6%) 3 (1.2%) 2 (0.8%) 3 (1.2%) nentoa ora fObesity of Journal International conditions Fatigue 6 (1.4%) 7 (1.7%) 7 (1.7) 31 (2.5%) 1 (0.4%) 2 (0.8%) 0 Irritability 7 (1.7%) 16 (3.9%) 27 (6.5%) 60 (4.8%) 1 (0.4%) 0 2 (0.8%) Metabolism and nutrition disorders 2 (0.5%) 10 (2.4%) 8 (1.9%) 38 (3.0%) 0 2 (0.8%) 1 (0.4%) Nervous system disorders 38 (9.1%) 34 (8.2%) 60 (14.5%) 154 (12.3%) 4 (1.6%) 1 (0.4%) 9 (3.5%) Dizziness 11 (2.6%) 10 (2.4%) 21 (5.1%) 49 (3.9%) 2 (0.8%) 0 0 Headache 17 (4.1%) 6 (1.4%) 15 (3.6%) 47 (3.7%) 0 1 (0.4%) 3 (1.2%) 927 High-dose taranabant LJ Aronne et al 928 groupings in the taranabant 4-mg group and in the dizziness and motor disorder groupings in the 6-mg group were Includes 260 b significantly higher during year 1. No significant differences ¼

N in the incidences of adverse experiences in Nervous System Disorders SOC groupings were observed during year 2. Two seizures occurred in the study: one in a

a patient in the 2-mg group who was found to have a newly

264 diagnosed brain tumor and one in a patient in the 6 mg Year 2 ¼ group who had a history of brain surgery as a child for a N neuroma. The incidences of adverse experiences within the Psychia- tric Disorders SOC plus irritability were significantly higher

244 in year 1 and numerically higher in year 2 in all taranabant ¼

Placebo Taranabant 2 mg Taranabant 4 mg groups. The incidences of adverse experiences in the altered N affect grouping and depression grouping and the adverse

b experience of anxiety were numerically higher in the 2 mg assessed causality) reaching an incidence of at least 5% and group and significantly higher in the 4- and 6-mg groups in year 1. The incidence of the combined adverse experiences of depressed mood and depressive symptoms were numerically higher in the 2- and 4-mg groups and significantly higher

1256 in the 6-mg groups compared with the placebo group in ¼

N year 1. The incidence of the combined adverse experiences of aggression and anger were numerically higher in the taranabant groups in years 1 and 2. Suicidal ideation was reported in three patients in the One patient may have reported more than one event within an SOC or between SOCs. c taranabant 6-mg group in year 1 and in one patient in the 4-mg group in year 2. There was one suicide attempt reported in a patient with a previous history of suicide attempts in the

415 6/2-mg group while the patient was receiving 2-mg, and one Year 1 ¼ episode of suicidal behavior reported in a patient in the N 6/2-mg group while the patient was receiving 6-mg. There were no completed suicides. The adjudication of possibly suicide-related adverse experiences during years 1 and 2 indicated an increased 414

¼ incidence of suicidality in the taranabant groups (13/417

N (3.1%), 22/414 (5.3%), 27/415 (6.5%), 55/1256 (4.4%) of patients in the placebo, 2-, 4- and 6-mg groups, respectively). The odds ratios for suicidality among taranabant groups were Includes AEs reported from week 52 up to week 104 in patients who completed year 1 and entered year 2 on the same treatment. a 1.74 (95% CI 0.87–3.51), 2.16 (95% CI 1.10–4.25) and 2.34 417

¼ (95% CI 1.11–4.96) for the 2-, 4- and 6-mg (fixed and Placebo Taranabant 2 mg Taranabant 4 mg Taranabant 6 mg (fixed and titrated) N titrated) groups, respectively. This increase in suicidality in the taranabant groups primarily reflects patient-positive responses to PHQ-9 question 9 and FPHQ question 2i, which were adjudicated as representing suicidal ideation. Each question asks the patient whether they have been bothered by ‘Thoughts that you would be better off dead or of hurting yourself in some way’. The incidences of adverse experiences in the Skin and Subcutaneous Disorders SOC minus hypoesthesia facial were numerically higher in the taranabant 2- and 4-mg groups and significantly higher in the 6-mg group compared with

adverse experiences reaching an incidence of at least 2% in any treatment groupthe in year 1 (week 52) and yearplacebo 2 (weeks 52 to 104) group in year 1, which reflected the increased d incidences of the adverse experiences of hyperhidrosis and (continued) pruritus.

Affect labilityAnxietyDepressed moodDepressionInsomniaMood alteredHiccupsHyperhidrosisPruritusHot flush 2 (0.5%) 9 (2.2%) 11 (2.6%) 3 9 14 (0.7%) (2.2%) (3.4%) 10 5 (2.4%) (1.2%) 10 (2.4%) 7 12 (1.7%) 15 (2.9%) (3.6%) 15 (3.6%) 4 (1.0%)The 26 (6.3%) 2 (0.5%) 0incidences 9 (2.2%) 25 (6.0%) 5 (1.2%) 7 (1.7%) 6 (1.4%) 31 48 (2.5%) 1 (3.8%) (0.2%) 2 13 (0.5%) 77 (3.1%)of (6.1%) 6 (1.4%) adverse 9 33 (2.2%) (2.6%) 60 (4.8%) 16 21 6 (3.9%) (1.7%) (1.4%) 2 (0.8%)experiences 11 (2.7%) 0 0 36 (2.9%) 2 (0.8%) 2 (0.8%) 0 67 28 (5.3%) (2.2%) in 0 0 1 26 1 2the (0.4%) (2.1%) (0.4%) (0.8%) 1Vascular (0.4%) 0 4 6 (1.5%) (2.3%) 0 1 (0.4) 0 0 2 (0.8%) 1 (0.4%) 0 1 (0.4%) 0 0 0 0 0 1 (0.4%) 0 Psychiatric disordersReproductive system and breastRespiratory, disorders thoracic and mediastinal disordersSkin and subcutaneous tissue disorders 51 2 (12.2%) (0.5%) 3 (0.7%)Vascular disorders 75 (18.1%) 7 (1.7%) 6 22 (1.4%) (5.3%) 105 (25.3%) 10 29 (2.4%) (7.0%) 4 (1.0%) 34 (8.2%) 331 (26.4%) 44 4 (3.5%) (1.0%) 26 (2.1%) 13 140 (3.1%) (11.1%) 5 (2.0%) 19 (4.6%) 8 (3.0%) 0 0 14 0 (5.4% 1 (0.4%) 49 (3.9%) 0 1 (0.4%) 0 3 (1.2%) 3 (1.2%) 0 1 (0.4%) 1 (0.4%) Determined by the study investigator to be possibly, probably or definitely treatment related. Adverse experiences (irrespective of investigator drug-related Table 4 d AEs reported while on taranabant 6 mg (fixed or titrated) plus 28 days after switching to placebo or 2 mg. Abbreviations: AE, adverse experience; SOC, system organ class. Disorders SOC were numerically higher in the 2-mg group

International Journal of Obesity Table 5 Number (%) of patients with pre-specified clinical adverse experiences and groupings of interest at year 1 (week 52) and year 2 (week 104)

Clinical adverse event Year 1 Year 2a

Placebo Taranabant 2 mg Taranabant 4 mg Taranabant 6 mg (fixed and titrated) Placebo Taranabant 2 mg Taranabant 4 mg N ¼ 417 N ¼ 414 N ¼ 415 N ¼ 1256 N ¼ 254 N ¼ 270 N ¼ 264

Gastrointestinal disorders SOC 119 (28.5%) 173 (41.8%)*** 193 (46.5%)*** 578 (46.0%)*** 62 (24.4%) 45 (16.7%)* 58 (22.0%) Diarrhea 30 (7.2%) 51 (12.3%)* 57 (13.7%)** 174 (13.9%)*** 18 (7.1%) 9 (3.3%) 14 (5.3%) Frequent bowel movements 2 (0.5%) 6 (1.4%) 12 (2.9%)** 20 (1.6%) 0 0 1 (0.4%) Nausea 27 (6.5%) 69 (16.7%)*** 89 (21.4%)*** 301 (24.0%)*** 5 (2.0%) 6 (2.2%) 12 (4.5%) Vomiting 14 (3.4%) 23 (5.6%) 35 (8.4%)** 91 (7.3%)** 3 (1.2%) 4 (1.5%) 6 (2.3%) Expanded nervous system disorders SOCb 105 (25.2%) 94 (22.7%) 138 (33.3%)* 358 (28.5%) 30 (11.8%) 35 (13.0%) 45 (17.0%) Dizziness groupingc 24 (5.8%) 23 (5.6%) 43 (10.4%)* 111 (8.8%)* 8 (3.1%) 10 (3.7%) 8 (3.0%) Cognition groupingd 6 (1.4%) 5 (1.2%) 9 (2.2%) 23 (1.8%) 1 (0.4%) 1 (0.4%) 4 (1.5%) Sedation groupinge 4 (1.0%) 7 (1.7%) 12 (2.9%)* 27 (2.2%) 0 2 (0.7%) 1 (0.4%) Epilepsy, convulsion 0 0 0 1 (0.1%) 0 0 0 Stroke groupingf 0 0 1 (0.2%) 7 (0.6%) 0 0 1 (0.4%) Syncope groupingg 4 (1.0%) 3 (0.7%) 14 (3.4%)* 26 (2.1%) 0 1 (0.4%) 2 (0.8%) Vertigo groupingh 0 2 (0.5%) 0 3 (0.2%) 1 (0.4%) 0 0 Sensory disorder groupingi 11 (2.6%) 4 (1.0%) 20 (4.8%) 53 (4.2%) 3 (1.2%) 5 (1.9%) 9 (3.4%) Motor disorder groupingj 0 3 (0.7%) 3 (0.7%) 12 (1.0%)* 2 (0.8%) 0 0 Vision groupingk 4 (1.0%) 0 0 4 (0.3%) 1 (0.4%) 1 (0.4%) 0 Headache groupingl 59 (14.1%) 43 (10.4%) 57 (13.7%) 137 (10.9%) 17 (6.7%) 16 (5.9%) 20 (7.6%) Psychiatric disorders SOC plus irritability 85 (20.4%) 117 (28.3%)** 167 (40.2%)*** 478 (38.1%)*** 17 (6.7%) 23 (8.5%) 27 (10.2%) Altered affect groupingm 11 (2.6%) 19 (4.6%) 28 (6.7%)** 91 (7.3%)*** 0 0 2 (0.8%) Depression groupingn 27 (6.5%) 37 (8.9%) 44 (10.6%)* 141 (11.2%)** 7 (2.8%) 8 (3.0%) 9 (3.4%) Depression, major depression 12 (2.9%) 13 (3.1%) 20 (4.8%) 57 (4.5%) 2 (0.8%) 2 (0.7%) 5 (1.9%) Depressed mood, depressive symptom 15 (3.6%) 24 (5.8%) 27 (6.5%) 84 (6.7%)* 4 (1.4%) 6 (2.2%) 3 (1.1%) Irritability 7 (1.7%) 22 (5.3%)** 36 (8.7%)*** 85 (6.8%)*** 1 (0.4%) 1 (0.4%) 3 (1.1%) Nervousness 3 (0.7%) 3 (0.7%) 8 (1.9%) 24 (1.9%) 0 2 (0.7%) 0 Aronne LJ taranabant High-dose Anxiety groupingo 14 (3.4%) 20 (4.8%) 46 (11.1%)*** 117 (9.3%)*** 3 (1.2%) 2 (0.7%) 8 (3.0%) Anxiety 14 (3.4%) 16 (3.9%) 41 (9.9%)*** 105 (8.4%)*** 3 (1.2%) 2 (0.7%) 8 (3.0%) Anxiety disorder 0 0 2 (0.5%) 4 (0.3%) 0 0 0

Panic disorder, panic attack 0 4 (1.0%) 4 (1.0%) 11 (0.9%) 0 0 0 al et Insomnia groupingp 25 (6.0%) 27 (6.5%) 40 (9.6%) 93 (7.4%) 5 (2.0%) 4 (1.5%) 12 (4.5%) Aggression, anger 3 (0.7%) 9 (2.2%) 7 (1.7%) 22 (1.8%) 0 1 (0.4%) 4 (1.5%) Disorientation, confusional state 0 1 (0.2%) 0 5 (0.4%) 0 0 0 Suicidal groupingq 0 0 0 3 (0.2%) 0 0 1 (0.4%) Suicidal ideationr 0 0 0 3 (0.2%) 0 0 1 (0.4%) Skin and Subcutaneous disorders SOC minus 62 (14.9%) 71 (17.1%) 72 (17.3%) 268 (21.3%)** 17 (6.7%) 17 (6.3%) 31 (11.7%)* hypoesthesia facial Hyperhidrosis 2 (0.5%) 8 (1.9%) 9 (2.2%)* 46 (3.8%)*** 1 (0.4%) 0 1 (0.4%) Pruritus groupings 12 (2.9%) 19 (4.6%) 27 (6.5%)* 105 (8.4%)*** 1 (0.4%) 3 (1.1%) 5 (1.9%) Vascular disorders SOC 22 (5.3%) 28 (6.8%) 49 (11.8%)*** 129 (10.3%)** 16 (6.3%) 7 (2.6%) 19 (7.2%) Flushing, hot flush 4 (1.0%) 11 (2.7%) 19 (4.6%)*** 56 (4.5%)*** 5 (2.0%) 1 (0.4%) 4 (1.5%)

Abbreviation: SOC, system order class according to the Medical Dictionary for Regulatory Activities (MedDRA) version 10.1. aIncludes AEs reported from week 52 up to week 104 in patients who completed year 1 and entered year 2 on the same treatment. bNervous system disorders SOC plus hypoesthesia facial, amaurosis fugax, vision blurred, scotoma, blindness, altered visual depth perception, photopsia and diplopia. cDizziness and dizziness postural. dAmnesia, memory impairment, dementia, mental impairment and cognitive disorder. eSedation, lethargy, depressed level of consciousness, somnolence, disturbance in attention. fCerebral hemorrhage, hemorrhagic stroke, thrombotic stroke, embolic stroke, ischemic stroke, thromboembolic stroke, cerebral infarction, transient ischemic attack, hemiparesis, nentoa ora fObesity of Journal International hemiplegia, amaurosis fugax and cerebrovascular accident. gSyncope vasovagal, loss of consciousness and syncope. hVertigo CNS origin, cerebellar ataxia, nystagmus, coordination abnormal, clumsiness and balance disorder. iHypoesthesia, hyperesthesia, paresthesia, dysesthesia, formication, dysgeusia, hypogeusia, ageusia, anosmia, parosmia, burning sensation, neuritis, meralgia paresthetica, hypoesthesia facial, neuropathy, neuropathy peripheral, neuralgia, sensory loss and sensory disturbance. jMotor dysfunction, Tinel’s sign, clonus, hyperreflexia, tremor and facial palsy. kVision blurred, scotoma, blindness, altered visual depth perception, photopsia and diplopia. lHeadache, tension headache, head discomfort, migraine and migraine with aura. mAffect lability, inappropriate affect, crying, tearfulness, mood altered and mood swings. nDepression, major depression, depressed mood, depressive symptom, dysthymic disorder and anhedonia. oAnxiety, anxiety disorder, panic disorder and panic attack. pCompleted suicide, suicide attempt, suicidal behavior, suicidal ideation and depression suicidal. qInsomnia, initial insomnia and middle insomnia. rSpontaneously reported by the patient to the study investigator. sPruritus and pruritus generalized. *Pp0.050 vs placebo; **Pp0.010 vs placebo; ***Pp0.001 vs placebo. 929 High-dose taranabant LJ Aronne et al 930 and significantly higher in the 4- and 6-mg groups compared Although head-to-head studies would be required for with the placebo group in year 1, which reflected the accurate comparison, it is nonetheless worthwhile to place increased incidences of the combined adverse experiences the magnitude of weight loss associated with treatment with of flushing and hot flush. taranabant into context along with other centrally acting All treatment groups experienced improvements in DSST weight loss medications that have been studied in large scores from baseline at weeks 52 and 104. The increases in clinical trials. The magnitude and time course of the weight the taranabant groups were smaller compared with the loss observed with taranabant 2 mg at 1 year was comparable placebo group at week 52. No significant changes from to the 1-year weight loss efficacy that was reported in clinical baseline were observed in cognitive/neuropsychomotor trials with 20 mg of the CB1R inverse agonist, rimonabant,23–26 performance (DSST) at weeks 52 and 104 in any taranabant and 10–20 mg of the serotonin and noradrenaline reuptake group (Supplementary Table S8). inhibitor, sibutramine.27–31 For example, in the meta-analyses No significant changes from baseline at week 52 were of weight loss studies,31 compared with placebo, 10–20-mg observed in overall total mood disturbance scores of the sibutramine reduces body weight from baseline by 4.2 kg POMSb in the taranabant 2- and 4-mg groups (Supplementary (3.6 to 4.7 kg) and 20-mg rimonabant reduces weight body Table S9). However, the changes in the Confusion–Bewilder- weight from baseline by 4.7 kg (4.1 to 5.3 kg). On the basis of ment domain scores in the 4-mg group reflected a deteriora- the data presented in this paper and this meta-analysis of tion from baseline at week 52. There were no differences rimonabant, it might be concluded that the CB1R mechanism, between taranabant groups and placebo in total mood although capable of producing clinically meaningful weight disturbance scores or any of the domains from weeks 52 to loss, is not capable of producing double-digit weight loss as a 104 in patients who completed year 1 and entered year 2. monotherapy. All treatment groups had deterioration from baseline in The observed weight regain of patients who were down- PHQ-9 scores at week 52, with the 4-mg group experiencing dosed from taranabant 6 mg to placebo compared with the a greatest worsening (Supplementary Table S10). There weight regain observed in those down-dosed to taranabant were no differences from weeks 52 to 104 in patients who 2 mg or those maintained on a stable dose of taranabant completed year 1 and entered year 2 on the same treatment. showed that, as expected, continued therapy with tarana- The incidences of laboratory adverse experiences were bant was necessary to maintain weight loss. The tendency for low and generally comparable among the treatment groups weight regain and the requirement for continued drug in years 1 and 2 (Table 3). No serious laboratory adverse treatment to maintain weight loss has been observed in experiences were reported in this study. There were no clinical trials with other drugs used for weight loss with clinically relevant changes in heart rate or QTc interval in similar (rimonabant)23–26 and different (sibutramine and the any of the treatment groups (data not shown). intestinal lipase inhibitor orlistat)27,32 mechanisms of action. The observed improvements in metabolic measures (WC, TG, HDL-C, fasting serum insulin and insulin sensitivity) and the decrease in the percentage of patients who meet Discussion criteria for the MS are consistent with the decrease in body weight and body fat observed with taranabant and are also This study in obese and overweight patients showed that consistent with the effects reported in clinical studies with treatment with taranabant 2- and 4-mg resulted in statistically rimonabant.23–26 These changes suggest that treatment with significant and clinically meaningful weight loss relative to taranabant 2 and 4 mg might be associated with improve- placebo, which was sustained for 2 years. ments in cardiometabolic risk.33–36 A modest incremental weight loss efficacy was observed It has been hypothesized that CB1R inverse agonists exert with taranabant at doses 42 mg. The placebo-subtracted an effect directly on adipocytes, hepatocytes, pancreatic weight loss observed with taranabant 4 mg was approximately islets and skeletal muscle to mediate metabolic effects.37 23 and 24% greater than that observed with taranabant 2 mg Using a regression modeling approach, it has been reported at the 1- and 2-year time points, respectively (percentages that as much as 57% of the placebo-subtracted effects of based on placebo-subtracted least-squares mean weight loss). 20-mg rimonabant on HDL-C and HbA1c were independent Similarly, the weight loss efficacy of taranabant 6 mg was of weight loss and consistent with direct peripheral meta- approximately 19% greater than that observed with 4 mg bolic effects of rimonabant.38 Using a similar regression taranabant at 1 year. The modest increase in efficacy observed modeling approach in this study, weight loss-independent with the 4- and 6-mg doses in this study compared with effects of taranabant on HDL-C and QUICKI were observed. the 2 mg dose, in conjunction with increased incidences However, conclusive evidence for the contribution of of adverse experiences with the 4- and 6-mg doses relative peripherally located CB1R to in vivo efficacy of CB1R inverse to the 2-mg dose, led to the discontinuation of the antagonists is lacking,39 and statistical analysis alone is not 4- and 6-mg doses. These data also suggest that the higher conclusive evidence of a weight-independent effect.40 To doses had approached the maximum weight loss effect of show a weight-independent effect, a study design that taranabant. included a treatment group that avoided weight loss by

International Journal of Obesity High-dose taranabant LJ Aronne et al 931 adjusting energy intake or that involved comparison to a example, Wellbutrin) to a CB1R inverse agonist would drug that had no effects beyond weight reduction would mitigate the risk of psychiatric adverse experiences to an be required. extent that would significantly change the risk–benefit The safety profile of taranabant was characterized by the assessment of these compounds. Nor are there preclinical increased incidences of adverse experiences classified in or clinical data to support a physiological rationale for the the gastrointestinal, psychiatric, nervous, cutaneous and notion that a drug, such as phentermine, would mitigate the vascular organ systems compared with placebo. In general, psychiatric adverse event profile of a CB1R inverse antago- adverse experiences observed with taranabant were mild to nist. On the other hand, some preclinical studies suggest that moderate in intensity. sub-therapeutic doses of CB1R inverse agonists in combina- Gastrointestinal-related adverse experiences, including tion with other agents might prove to be a viable therapeutic nausea, vomiting and diarrhea, were very common, espe- strategy.47–49 cially in the first 2–3 months of treatment, but led to The clinical effect of the adverse experiences of hyperhi- relatively few discontinuations. Gastrointestinal-related drosis, pruritus, flushing and hot flush were also dose related adverse experiences are consistent with the localization of but more prominent in the 6-mg group. The clinical CB1R on enteric neurons and in the hindbrain.41 implications of these adverse experiences were, in general, CB1Rs are highly expressed in the central nervous system modest based on their relatively low incidence, limited and adverse experiences in this organ system were prespeci- duration and infrequent need for patient discontinuation. fied for analysis. Adverse experiences in the dizziness, seda- Expression of CB1Rs in human skin50 may be related to tion and syncope groupings were generally higher in the the adverse experiences of hyperhidrosis and pruritus. The taranabant 4- and 6-mg groups compared with the placebo adverse experiences of flushing and hot flush occurred group. In general, nervous system-related adverse experi- predominantly in perimenopausal women and were reported ences did not lead to discontinuation from study drug, and less frequently by men. The mechanism underlying the sensory grouping nervous system adverse experiences did flushing and hot flush adverse experiences is unclear. not notably increase over time. The incidences of clinical adverse experiences in the Psychiatric-related adverse experiences observed in this taranabant 2- and 4-mg groups in year 2 were numerically study included a range of reports of dysphoric states, lower when compared with year 1. These data are consistent including an increased incidence of affect lability, depres- with a ‘survivor’ effect in which patients who tolerated 52 sion, anxiety, aggression, anger and suicidal ideation. CB1Rs weeks of taranabant therapy were less likely to experience are widely expressed in brain pathways involved in mood adverse experiences during year 2. In general, the safety regulation, including the limbic system and prefrontal profile of taranabant 2 and 4 mg did not change mean- cortex.10,42–44 Alterations in CB1R signaling in those ingfully between years 1 and 2. anatomic regions that may be associated with the treatment Despite the results reported in this study, suspension of with taranabant provide a plausible mechanism for the rimonabant marketing in 2008 and the subsequent disconti- observed increase in reports of adverse experiences related to nuation of several other CB1R inverse antagonist develop- dysphoric states in this study. Psychiatric-related adverse ment programs, it may be premature to abandon all efforts at experiences were dose related and none of the doses used in antiobesity drug development that targets the CB1R. Several this study was devoid of psychiatric-related adverse experi- methods have been suggested that might circumvent the ences when incidences were compared with placebo. It is psychiatric side effects of CB1R antagonists.51 Both tarana- noteworthy that increased incidences of these adverse bant and rimonabant52 can exert an effect as CB1R inverse experiences were also observed in studies with lower doses agonists and it is possible that neutral antagonists might not of taranabant (0.5- and 1.0-mg doses).45,46 The observed have the same behavioral liabilities. Similarly, it has been dose–response relationship between weight loss and inci- suggested that peripherally acting CB1R neutral antagonists dence of psychiatric adverse experiences is consistent with or inverse agonists might provide another means of these adverse experiences being mechanism based. More- circumventing those side effects.53,54 Identification of over, the increased incidence of psychiatric adverse experi- CB1R antagonists with an improved side-effect profile, ences reported in the published rimonabant studies23–26 which could be used as monotherapy or combination further supports the hypothesis that these adverse experi- therapy, still remains a relevant therapeutic goal. ences are mechanism based. A strategy that has been used to augment the modest weight lose efficacy of existing antiobesity monotherapies is Conflict of interest that of combination therapy. However, because of the lack of an adequate therapeutic window and concern for patient The study was funded by Merck & Co. The authors IG, NE, safety outside of the clinical trial setting, there does not seem SS, CM, SS, JN, AGM, DS, SBH, KDK and JMA are or were to be a clear path forward for combining taranabant with employees of Merck & Co., Inc. and may hold stock in that other agents. For example, it is unlikely that addition of an company. LA and ST are members of a Merck Diabetes and antidepressant that itself is associated with weight loss (for Obesity Advisory Committee.

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Appendix Central Texas Clinical Research, Austin, TX; Mary E Bartz, Central Texas Clinical Research, Austin, TX; Richard O Study sites Butcher, Careview Medical Group, Inc., San Diego, CA; Louis J Aronne, Comprehensive Weight Control Program, Rodney G Hood, Careview Medical Group, Inc., San Diego, New York, NY; Stephen Louis Aronoff, Research Institute of CA; Robert S Call, Commonwealth Clinical Research Specia- Dallas, Dallas, TX; Harold E Bays, Louisville Metabolic and lists, Richmond, VA; Antonio Caos, Central Florida Clinical Atherosclerosis Research Center, Louisville, KY; Robert J Studies, Ocoee, FL; Christopher M Chappel, FPA Clinical Bielski, Summit Research Network, Farmington Hills, MI; Research, Kissimmee, FL; Harry Collins, Anderson and Bruce Taylor Bowling, Regional Clinical Research, Inc., Collins Clinical Research, Inc., Edison, NJ; Martin J Conway, Endwell, NY; George August Bray, Pennington Biomedical Lovelace Scientific Resources, Inc., Albuquerque, NM; Research Center, Baton Rouge, LA; Cynthia C Brinson, Michael H Davidson, Radiant Research, Chicago, IL; Mark

International Journal of Obesity High-dose taranabant LJ Aronne et al 934 A Deeg, Richard L Roudebush Veterans Affairs Medical Soufer, Chase Medical Research, Waterbury, CT; Mark Allen Center, Indianapolis, IN; Marian Sue Kirkman, Richard L Stich, Jacksonville Center for Clinical Research, Jacksonville, Roudebush Veterans Affairs Medical Center, Indianapolis, FL; Phillip D Toth, Midwest Institute for Clinical Research, IN; John Howard Pratt, Richard L Roudebush Veterans Affairs Indianapolis, IN; David J Turk, Madrona Medical Group, Medical Center, Indianapolis, IN; Eleuterio P Delfin, Jr., Bellingham, WA; Thomas A Wadden, University of Pennsyl- Center for Clinical Trials, LLC; Paramount, CA; Samuel S vania, Weight & Eating Disorder Program, Philadelphia, PA; Engel, Soundview Research Associates; Norwalk, CT; Mindy J Mervyn Upali Weerasinghe, Rochester Clinical Research, Sotsky, Soundview Research Associates, Norwalk, CT; James Inc., Rochester, NY; Frederick C Whittier, Clinical Research Mecham Ferguson, Radiant Research; Salt Lake City, UT; Limited, Canton, OH; Michael Paul Wiggins, Big Thompson Fares J Arguello, Radiant Research, Salt Lake City, UT; Harold Medical Group, PC, Loveland, CO; Troy Williams, Pivotal J Fields, Village Family Practice Clinic, Houston, TX; Chester Research Centers, Peoria, AZ; Louise A Taber, Pivotal L Fisher, Jr., Health Research of Hampton Roads; Newport Research Centers, Peoria, AZ; James H Zavoral, Radiant News, VA; Alan Duane Forker, Saint Luke’s Hospital, Lipid Research, Edina, MN; Karl-Michael Derwahl, St Hedwig- and Diabetes Research Center, Kansas City, MO; Neil J Fraser, Krankenhaus, Institut fur Klinische Foschung und Entwick- Troy Internal Medicine Research; Troy, MI; Ken Fujioka, lung GmbH, Berlin, Germany; Hans-Michael Foerster,- Scripps Clinic and Research Foundation; San Diego, CA; Grafschafter Str., Baerl/Ndrhn, Germany; Andreas Hamann, Geoffrey S Gladstein, Stamford Therapeutics Consortium, Diabetes Klinik Bad Nauheim GmbH, FA fur Innere Medizin, Stamford, CT; David M Radin, Stamford Therapeutics Bad Nauheim, Germany; Alberto Allemant, Hospital Consortium; Stamford, CT; Forrest Anthony Hanke, Trover Nacional ‘Hipolito Unanue’, Lima, Peru; Cesar Butron Clinic, Madisonville, KY; Lisa M Harris, Chase Wellness Delgado, Centro Endocrionologico, Arequipa, Peru; Luis H Center; Virginia Beach, VA; David R Hassman, Comprehen- Zapata-Rincon, Casa De Diabetes Y Nutricion, Lima, Peru; sive Clinical Research, Berlin, NJ; David Keith Helton, Soren Toubro, Hvidovre Hospital, Hvidovre, Denmark; Arya Southeastern Clinical Research, Chattanooga, TN; Priscilla Sharma, Hamilton Hospital General Division, Hamilton, L Hollander, Baylor University Medical Center, Baylor Ontario, Canada; Paul F Whitsitt, Paradigm Clinical Trials, Endocrine Center, Dallas, TX; William P Jennings, Radiant Inc., Oshawa, Ontario, Canada; Michelle Tolszczuk, Q et Research, San Antonio, TX; Norman J Kakos, QUEST T Recherche Inc., Sherbrooke, Quebec, Canada; Ronald Research Institute, Bingham Farms, MI; Adam D Karns, Girard, Q et T Recherche Inc., Sherbrooke, Quebec, Canada; Lovelace Scientific Resources, Inc., Beverly Hills, CA; Alan J. Markolf Hanefeld, Gesellschaft fur Wissens-und Techno- Kivitz, Altoona Center for Clinical Research, Duncansville, logietransfer der TU Dresden GmbH, Zentrum fur PA; Eric J Klein, Capital Clinical Research Center, Olympia, Klinische Studien Forschungsbereich Endokrinologie und WA; Samuel Klein, Washington University School of Medi- Stoffwechsel, Dresden, Germany; Peter Kindermann, Inter- cine, Center for Human Nutrition, Saint Louis, MO; Dominic nistische Praxis, Riesa, Germany; Peter Marcinowski, H-Arzt Reeds, Washington University School of Medicine, Center Torenstr. Meersburg, Germany; Erik-Delf Schulze, Hauptstr. for Human Nutrition, Saint Louis, MO; Diane Rachel Krieger, Berlin, Germany; Thomas Zoeller, Klinische Forschung Miami Research Associates, Inc., Miami, FL; Wayne E Larson, Berlin, Berlin, Germany; Francis CC Chow, Prince of Wales Radiant Research, Lakewood, WA; Frank P Maggiacomo, Hospital, Shatin, Hong Kong; Karen Siu Ling Lam, Queen New England Center for Clinical Research, Cranston, RI; Mary Hospital, Hong Kong, Hong Kong; Eduardo Garcia Dennis C McCluskey, Radiant Research, Mogadore, OH; Garcia, Instituto Nacional de Ciencias Medicas y Nutricion Harris Hugh McIlwain, Tampa Medical Group, Tampa, Salvador Zubiran, Mexico City, Mexico; Jose Geraldo Gonza- FL; James McKenney, National Clinical Research, Inc., lez, Hospital Universitario de Monterrey, Mexico City, Nuevo Richmond, VA; Alan Brad Miller, Atlanta Pharmaceutical Leon, Mexico; Bernhard Paulweber, St Johanns-Spital, Land- Research Center, Inc., Dunwoody, GA; Richard E Mills, esklinik fur Innere Medizin I, Salzburg, Austria; Hermann Palmetto Medical Research, Mount Pleasant, SC; Leslie Toplak, University of Graz, Medical University Clinic, Penny Moldauer, Radiant Research, Denver, CO; Arthur J Ambulanz fur Diabetes und Stoffwechsel, Graz, Austria; Mollen, Mollen Clinic, Phoenix, AZ; David J Morin, Tri-Cities Christa Firbas, Allgemeines Krankenhaus (AKH) Wien, Medical Research, Bristol, TN; Bryan C Pogue, Radiant Klinische Pharmakologie, Wien, Austria; Gerfried Hans Karl Research, Boise, ID; Terry L Poling, Heartland Research Nell, ClinPharm International GmbH & Co KG, Vienna, Associates, LLC, Wichita, KS; Jane L Rohlf, Premier Research, Austria; Rudolf Prager, Krankenhaus Lainz, Wein, Austria; Trenton, NJ; Domenica Marie Rubino, Weight Management Miguel Angel Rubio Herrara, Hospital Clinico San Carlos, Program, Washington DC; Richard D Wasnich, Covance, Madrid, Spain; Xavier Formiguera Sala, Hospital Universitari Inc., Honolulu, HI; Jon Leslie Ruckle, Covance, Inc., Germans Trias i Pujol, Barcelona, Spain; Olga Gonzalez- Honolulu, HI; Gary E. Ruoff, Westside Family Medical Albarran, Hospital Ramon y Cajal, Madrid, Spain; Barbara Center, Kalamazoo, MI; Randall J Severance, Radiant C Biedermann, Kantonsspital Bruderholz, Bruderholz, Research, Chandler, AZ; Stephan C Sharp, Clinical Research Switzerland; Bernhard H Lauterberg, Inselspital, Bern, Associates, Inc., Nashville, TN; Norman G Soler, Springfield Switzerland; Roger Darioli, CHUV Policlinique Medicale Diabetes and Endocrine Center, Springfield, IL; Joseph Universitaire, Lausanne, Switzerland; Alain Golay, Hopitaux

International Journal of Obesity High-dose taranabant LJ Aronne et al 935 Universitaires de Geneve, Division d’Enseignement/Therapeu- Australia; Milan Kvapil, ResTrial Outpatient Office of Diabe- tique pour Maladies Chroniques, Geneva, Switzerland; Joce- tology, Prague, Czech Republic; Vojtech Hainer, Institute of lyne Rachelle Benatar, Green Lane Hospital, Green Lane Endocrinology, Prague, Czech Republic; Pavol Hlubik, Uni- Clinical Centre Cardiovascular Research Unit, Auckland, New versity of Defence, Faculty of Military Health Sciences, Zealand; Ajith Munasinghe Dissanayake, Middlemore Hospi- Department of Preventive Medicine, Hradec Kralova, Czech tal, Centre for Clinical Research and Effective Practice, Republic; Gerrit H de Groot, Nederlandse Obesitas Kliniek, Auckland, New Zealand; Siew Pheng Chan, University Malaya Hilversum, Netherlands; Elisabeth M Mathuss-Vliegen, Medical Centre, Jalan University, Kuala Lumpur, Malaysia; Academisch Medisch Centrum, Amsterdam, Netherlands; Chii-Min Hwu, Taipei Veterans General Hospital, Taipei, Manuel Ignacio Moreno, Av. Portugal, Santiago, Chile; Victor Taiwan; Wayne Huey-Herng Sheu, Taichung Veterans General Saavedra, NovAdilap Servicios Medicos Ltda, Santiago, Chile; Hospital, Taichung, Taiwan; Wei-Shiung Yang, National Verner Codoceo, FACH Hospital, Tratamiento Intermedio Taiwan University, University Hospital, Taipei, Taiwan; Jeff Medico (TIM), Santiago, Chile; Aila Marjatta Rissanen, Karrasch, Peninsula Specialist Centre, Kipparing, Queensland, Lihavuustutkimusyksikko, Helsinki, Finland; Markku Savolai- Australia; Robert Moses, Clinical Trials and Research Unit, nen, Oulun Yliopisto, Sairaala Sisatautien Kilinkka, Oulu, Wollongong, New South Wales, Australia; Boyd Strauss, Finland; Manuel Borrell Munoz, Centres d’Assistencia Primer- Monash Medical Centre, Body Composition Laboratory, ia Sarria, Barcelona, Spain; Albert Ledesma-Castelltort, CAP Clayton, Victoria, Australia; Joseph Proietto, Austin & Remei, Barcelona, Spain; Serena Tonstad, Ullevaal Hospital, Repatriation Medical Centre, Heidelberg, Victoria, Australia; Ulleval universitetssykehus HF, Oslo, Norway; Hans Olav Ian Caterson, Royal Prince Alfred Hospital, Metabolish & Hoivik, Hedmark Medisinske Senter AS, Hamar, Norway; Bard Obesity Research Group, Camperdon, New South Wales, Eirik Kulseng, Sankt Olavs Hospital, Trondheim, Norway.

International Journal of Obesity