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Data Supplement

Data Supplement. RIO-Europe RIO-Lipids RIO-Diabetes RIO-North America European labeling. RIO-Europe: Study design. N = 1507 BMI ≥30 kg/m 2 or >27 kg/m 2 with comorbidity* -600 kcal/day + advised to  PA. Placebo Enrolled = 305 Completed = 178. Rimonabant 20 mg Enrolled = 599

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Data Supplement

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  1. Data Supplement RIO-Europe RIO-Lipids RIO-Diabetes RIO-North America European labeling

  2. RIO-Europe: Study design N = 1507 BMI ≥30 kg/m2 or >27 kg/m2 with comorbidity*-600 kcal/day + advised to PA PlaceboEnrolled = 305 Completed = 178 Rimonabant 20 mgEnrolled = 599 Completed = 363 Primary endpoint: Weight change from baseline†Secondary endpoints: Weight loss ≥5% and ≥10%, waist circumference, FG, fasting insulin, total-C, HDL-C, LDL-C, TG, MetS, HOMA-IR Follow-up: 1 year *Hypertension and/or dyslipidemia†Last observation carried forward Van Gaal LF et al. Lancet. 2005;365:1389-97.

  3. RIO-Europe: Treatment effect on weight and waist circumference 0 0 LOCF LOCF -2 -2 ∆ Body weight(kg) -4 -4 ∆ WC(cm) -6 -6 * * -8 -8 -10 -10 0 12 24 36 52 0 12 24 36 52 Weeks (intent-to-treat population) Placebo Rimonabant 20 mg *P ≤ 0.002 vs placeboLOCF = last observation carried forward Van Gaal LF et al. Lancet. 2005;365:1389-97.

  4. RIO-Europe: Treatment effect on lipids 30 15 25 10 * 20 5 ∆ HDL-C(%) ∆ TG(%) 15 0 10 –5 * 5 –10 0 –15 0 12 24 36 52 LOCF 0 12 24 36 52 LOCF Weeks (intent-to-treat population) Placebo Rimonabant 20 mg No significant effect on LDL-C or total-C *P ≤ 0.002 vs placebo Van Gaal LF et al. Lancet. 2005;365:1389-97.

  5. RIO-Europe: Adverse events ≥5% incidence in any group Van Gaal LF et al. Lancet. 2005;365:1389-97.

  6. RIO-Lipids: Study design N = 1033 BMI 27-40 kg/m2 with untreated dyslipidemia*-600 kcal/day + advised to physical activity PlaceboEnrolled = 342 Completed = 214 Rimonabant 20 mgEnrolled = 346 Completed = 221 Primary endpoint: Weight change from baseline†Secondary endpoints: HDL-C, TG, insulin, OGTT, MetS, leptin, adiponectin Follow-up: 1 year *TG 150-700 and/or Total-C/HDL-C >4.5 (women) or >5 (men) †LOCF OGTT = oral glucose tolerance test Després J-P et al. N Engl J Med. 2005;353:2121-34.

  7. RIO-Lipids: Treatment effect on weight and WC Intent-to-treat population 0 0 -2 -2 -4 -4 ∆ Body weight (kg) ∆ WC (cm) -6 -6 -8 -8 * * -10 -10 0 12 24 36 52 0 12 24 36 52 Weeks Placebo Rimonabant 20 mg *P < 0.001 vs placebo Després J-P et al. N Engl J Med. 2005;353:2121-34.

  8. RIO-Lipids: Treatment effect on lipids Intent-to-treat population 30 10 25 5 * 20 0 ∆ TG level(%) ∆ HDL-C (%) 15 -5 10 -10 5 -15 * 0 -20 0 12 24 36 52 0 12 24 36 52 Weeks Placebo Rimonabant 20 mg *P < 0.001 vs placeboNo significant effect on LDL-C and total-C Després J-P et al. N Engl J Med. 2005;353:2121-34.

  9. RIO-Lipids: Rimonabant weight-independent effect on adiponectin 4 3 ∆ Adiponectin level(g/mL) 57% of adiponectin increase was independent of weight loss 2 1 0 Weight gain 0–5 5–10 ≥10 Weight loss (%) Placebo Rimonabant 20 mg Després J-P et al. N Engl J Med. 2005;353:2121-34.

  10. RIO-Lipids: Adverse events ≥5% incidence in any group Després J-P et al. N Engl J Med. 2005;353:2121-34.

  11. RIO-Diabetes: Study design N = 1047 T2DM, BMI 27–40 kg/m2, A1C 6.5%–10%, and FG 100–271 mg/dL-600 kcal/day + advised to PA PlaceboEnrolled = 348 Completed = 231 Rimonabant 20 mgEnrolled = 339 Completed = 229 Primary endpoint: Weight change from baseline*Secondary endpoints: A1C, HDL-C, TG, FG, fasting insulin, hsCRP, leptin, MetS, waist circumference, BP Follow-up: 1 year *LOCF Scheen AJ et al. Lancet. 2006;368:1660-72.

  12. RIO-Diabetes: Treatment effect on weight and waist circumference Intent-to-treat population Weight Waist circumference 0 0 -5 -1 Δ Body weight (lb) ΔWC(in) P < 0.0001 P < 0.0001 -10 -2 -15 -3 0 12 24 36 52 0 12 24 36 52 Week Week Placebo Rimonabant 20 mg/day Scheen AJ et al. Lancet. 2006;368:1660-72.

  13. RIO-Diabetes: Treatment effect on lipids HDL-C Triglycerides 20 10 5 15 0 P < 0.0001 Δfrom baseline (%) Δ from baseline (%) P < 0.0001 10 -5 -10 5 -15 0 -20 0 12 24 36 52 0 12 24 36 52 Week Week Placebo Rimonabant 20 mg No significant effect on LDL-C and total-C Scheen AJ et al. Lancet. 2006;368:1660-72.

  14. RIO-Diabetes: Treatment effect on glucose metabolism A1C HOMA-IR Δ from baseline(%) Δ from baseline P < 0.0001 P = 0.03 Placebo Rimonabant 20 mg Scheen AJ et al. Lancet. 2006;368:1660-72.

  15. RIO-Diabetes: Adverse events ≥5% incidence in any group Scheen AJ et al. Lancet. 2006;368:1660-72.

  16. RIO-North America: Study design N = 3045 BMI ≥30 kg/m2 or >27 kg/m2 with comorbidity Year 1Rimonabant 20 mgEnrolled = 1222Completed = 673 Year 1PlaceboEnrolled = 607Completed = 309 Year 2PlaceboEnrolled = 327 Completed = 225 Year 2PlaceboEnrolled = 299Completed = 214 Year 2Rimonabant 20 mgEnrolled = 333 Completed = 257 Primary endpoints: Weight change from baseline; prevention of weight regain*Secondary endpoints: Weight loss ≥5% or ≥10%, waist circumference, lipids, MetS, BP, FG, fasting insulin, HOMA-IR *LOCF Pi-Sunyer FX et al. JAMA. 2006;295:761-75.

  17. RIO-North America: Weight change by treatment assignment Intent-to-treat population Year 1 Year 2 0 0 -2 -2 -4 -4 Δ Body weight(kg) -6 -6 -8 -8 -10 -10 0 12 24 36 52 52 64 76 88 104 Weeks Placebo Rimonabant 20 mg Placebo/Placebo Rimonabant 20 mg/Placebo Rimonabant 20 mg/Rimonabant 20 mg Pi-Sunyer FX et al. JAMA. 2006;295:761-75.

  18. RIO-North America: Waist circumference by treatment assignment Year 1 Year 2 0 0 -2 -2 -4 -4 Δ WC (cm) -6 -6 -8 -8 -10 -10 0 12 24 36 52 52 64 76 88 104 Weeks Placebo Rimonabant 20 mg Placebo/Placebo Rimonabant 20 mg/Placebo Rimonabant 20 mg/Rimonabant 20 mg Pi-Sunyer FX et al. JAMA. 2006;295:761-75.

  19. RIO-North America: Treatment effect on lipids at 1 year 10 5 0 8 -5 6 -10 ∆ HDL-C(mg/dL) ∆ TG (mg/dL) 4 -15 2 -20 0 -25 -2 -30 0 12 24 36 52 0 12 24 36 52 Weeks Placebo Rimonabant 20 mg No significant effect on LDL-C or total-C Pi-Sunyer FX et al. JAMA. 2006;295:761-75.

  20. RIO-North America: Weight-independent and weight-dependent effects on lipids 10 5 0 Change (%) -5 -10 -15 Rimonabant 20 mg vs placebo 58% Weight-independent effect TG 42% Weight-dependent effect HDL-C 47% Weight-independent effect 53% Weight-dependent effect ANCOVA Pi-Sunyer FX et al. JAMA. 2006;295:761-75.

  21. RIO-North America: Weight-independent and weight-dependent effects on insulin and IR Rimonabant 20 mg vs placebo 49%Weight-dependent 50%Weight-dependent Δ Δ 51%Weight-independent (U/mL) 50%Weight-independent ANCOVA Pi-Sunyer FX et al. JAMA. 2006;295:761-75.

  22. RIO-North America: Adverse events ≥5% incidence in any group Pi-Sunyer FX et al. JAMA. 2006;295:761-75.

  23. RIO-North America: Adverse events, cont’d ≥5% incidence in any group Pi-Sunyer FX et al. JAMA. 2006;295:761-75.

  24. Obesity program* depression-related events: Overall incidences Rimonabant Depressed mood disorders and disturbances Mood alterations with depressive symptoms Depressive disorders PlaceboN = 2472(%) 5 mgN = 2520(%) 20 mgN = 2742(%) 4.5 2.81.7 6.3 3.62.8 8.4 4.73.9 *Obesity program (RIO-Europe, RIO-North America, RIO-Lipids, RIO-Diabetes, REBA, EFC5745 and ACT3801)Taking into account any patient exposure Data on file from sanofi-aventis.

  25. Completed phase 2 and 3 studies* as of March 2007: All suicidality-related events Rimonabant PlaceboN = 3411N (%) 5 mgN = 5254N (%) 10 mgN = 198N (%) 20 mgN = 7851N (%) 40 mgN = 206N (%) Definitely suicidal(suicidal behavior/ideation) Possibly suicidal 21 2 (0.62) (0.06) 11 1† (0.21) (0.02) 0 0 (0) (0) 48 5 (0.61) (0.06) 0 0 (0) (0) *Phase 2 studies: ACT4389, DRI3388, ACT4855, Metatrial study (DFI3077, DFI3024, DFI3067, DFI3138), PDY3796, DRI5747 and Phase 3 studies: RIO-Europe, RIO-North America, RIO-Lipids, RIO-Diabetes, REBA, SERENADE, EFC5745, ACT3801 and EFC4474, EFC4796, EFC4964, EFC5794, EFC4798†Originally reported as a completed suicide but adjudicated as not enough information, fatalUsing first randomized treatment Data on file from sanofi-aventis.

  26. Rimonabant clinical safety: Summary • Safety assessment based on extensive exposure up to 2 years • The most frequent adverse events that led to drug discontinuation were depression, mood alteration, nausea and anxiety • Psychiatric events: • Increased incidence of depression-related events and anxiety with rimonabant vs placebo, overall incidence remained relatively low • Most adverse events were mild to moderate intensity • Similar qualitative characteristics between rimonabant 20 mg vs placebo • No clinical changes in laboratory test, electrocardiogram, or vital signs • Long-term exposure did not identify new or increased risks and supports its long term administration in overweight/obese patients with at least one cardiometabolic risk factor Data on file from sanofi-aventis.

  27. ACOMPLIA: European product information Therapeutic indication • As an adjunct to diet and exercise for treatment of patients with BMI ≥30 kg/m2 or >27 kg/m2 with associated risk factors such as T2DM or dyslipidemia Adult dosing • 20 mg daily, to be taken in the morning before breakfast • No dosage adjustment in elderly, mild/moderate hepatic insufficiency, or mild/moderate renal impairment European Medicines Agency (EMEA). http://emea.europa.eu.

  28. Contraindicated/Not recommended Pregnant or breast-feeding women Children below age 18 years Uncontrolled serious psychiatric illness such as major depression Taking antidepressant medication Severe renal or hepatic impairment Use with caution Receiving potent CYP3A4 inhibitors Ketoconazole Itraconazole Ritonavir Telithromycin Clarithromycin Nefazodone Treated for epilepsy Moderate hepatic impairment Age >75 years ACOMPLIA: European product information, cont’d EMEA. http://emea.europa.eu.

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