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
*Hypertension and/or dyslipidemia†Last observation carried forward
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
Van Gaal LF et al. Lancet. 2005;365:1389-97.
Van Gaal LF et al. Lancet. 2005;365:1389-97.
RIO-Europe: Treatment effect on weight and waist circumference
Weeks (intent-to-treat population)
LOCF
*P ≤ 0.002 vs placeboLOCF = last observation carried forward
∆ WC(cm)
Placebo Rimonabant 20 mg
0
-2
-4
-6
-8
-10
0
-2
-4
-6
-8
-100 12 24 36 52 0 12 24 36 52
LOCF
∆ Body weight
(kg)*
*
Placebo
RIO-Europe: Treatment effect on lipids
Van Gaal LF et al. Lancet. 2005;365:1389-97.
No significant effect on LDL-C or total-C
*P ≤ 0.002 vs placebo
0 12 24
Weeks (intent-to-treat population)
LOCF36 52 5236 LOCF0 12 24
–10
–5
0
5
10
15
–15
30
25
20
15
10
5
0
*
*
∆ HDL-C(%)
∆ TG(%)
Rimonabant 20 mg
RIO-Europe: Adverse events
Placebo (%)(n = 305)
Rimonabant 20 mg (%)(n = 599)
Nasopharyngitis 15.7 15.5
Influenza 10.5 9.0
Gastroenteritis 7.9 8.5
Upper respiratory tract infection (URTI)
7.5 5.5
Bronchitis 5.2 5.7
Sinusitis 5.6 4.3
Headache 13.4 9.8
Dizziness 4.9 8.7
Nausea 4.3 12.9
Diarrhea 3.0 7.2
Arthralgia 6.9 7.8
Back pain 8.5 9.2
Fatigue 5.6 4.2
Van Gaal LF et al. Lancet. 2005;365:1389-97.
≥5% incidence in any group
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
*TG 150-700 and/or Total-C/HDL-C >4.5 (women) or >5 (men)†LOCFOGTT = oral glucose tolerance test
Primary endpoint: Weight change from baseline†
Secondary endpoints: HDL-C, TG, insulin, OGTT, MetS, leptin, adiponectin
Follow-up: 1 year
Després J-P et al. N Engl J Med. 2005;353:2121-34.
RIO-Lipids: Treatment effect on weight and WC
Després J-P et al. N Engl J Med. 2005;353:2121-34.
Intent-to-treat population
∆ Body weight
(kg)
Weeks
52
Placebo
-100
-1024 36 520 1224 3612
Rimonabant 20 mg
*P < 0.001 vs placebo
∆ WC (cm)
0
-2
-4
-8
-6
0
-2
-4
-8
-6
**
RIO-Lipids: Treatment effect on lipids
Després J-P et al. N Engl J Med. 2005;353:2121-34.
Intent-to-treat population
*P < 0.001 vs placeboNo significant effect on LDL-C and total-C
Placebo Rimonabant 20 mg
∆ HDL-C (%)
Weeks
0 -20
∆ TG level(%)
30
25
20
15
5
10
5
0
-5
-15
10 -10
24 36 520 1224 36 520 12
*
*
RIO-Lipids: Rimonabant weight-independent effect on adiponectin
Després J-P et al. N Engl J Med. 2005;353:2121-34.
57% of adiponectin increase was independent of weight loss
Placebo Rimonabant 20 mg
∆ Adiponectin
level(g/mL)
0
4
3
1
2
0–5 5–10 ≥10Weight gain
Weight loss (%)
RIO-Lipids: Adverse events
Placebo (%)(n = 342)
Rimonabant 20 mg (%)(n = 346)
Nasopharyngitis 21.6 19.4
Headache 15.8 15.3
Nausea 3.2 12.7
Dizziness 6.7 10.4
Influenza 5.3 9.5
URTI 9.9 8.7
Anxiety 3.8 8.7
Back pain 10.2 7.2
Diarrhea 4.1 7.2
Gastroenteritis 6.4 6.6
Insomnia 2.6 6.4
Arthralgia 9.6 5.5
≥5% incidence in any group
Després J-P et al. N Engl J Med. 2005;353:2121-34.
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
Scheen AJ et al. Lancet. 2006;368:1660-72.*LOCF
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
0
-5
-10
-15
0
-1
-3
RIO-Diabetes: Treatment effect on weight and waist circumference
Weight Waist circumference
P < 0.0001 P < 0.0001
Scheen AJ et al. Lancet. 2006;368:1660-72.
Δ Body weight
(lb)
Δ WC(in)
0 12 24 36 52
Week
0 12 24 36 52
Week
-2
Intent-to-treat population
Placebo Rimonabant 20 mg/day
Δ from baseline
(%)
RIO-Diabetes: Treatment effect on lipids
No significant effect on LDL-C and total-C Scheen AJ et al. Lancet. 2006;368:1660-72.
20
15
10
5
0
10
0
-5
-15
-20
HDL-C Triglycerides
P < 0.0001P < 0.0001
Δ from baseline
(%)
0 12 24 36 52
Week
0 12 24 36 52
Week
5
-10
Placebo Rimonabant 20 mg
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
RIO-Diabetes: Treatment effect on glucose metabolism
A1C
Δ from baseline
(%)
Δ from baseline
HOMA-IR
P < 0.0001
P = 0.03
Placebo Rimonabant 20 mg
Scheen AJ et al. Lancet. 2006;368:1660-72.
RIO-Diabetes: Adverse events
Placebo (%)(n = 348)
Rimonabant 20 mg (%)(n = 339)
Nausea 6 12
Nasopharyngitis 21 12
Dizziness 5 9
Arthralgia 8 9
Headache 9 8
Diarrhea 7 7
Back pain 7 7
URTI 9 7
Vomiting 2 6
Hypoglycemia 2 5
Fatigue 4 5
Anxiety 3 5
≥5% incidence in any group
Scheen AJ et al. Lancet. 2006;368:1660-72.
RIO-North America: Study design
N = 3045BMI ≥30 kg/m2 or >27 kg/m2 with comorbidity
Year 1Rimonabant 20 mg
Enrolled = 1222Completed = 673
Year 1Placebo
Enrolled = 607Completed = 309
Pi-Sunyer FX et al. JAMA. 2006;295:761-75.
Year 2Placebo
Enrolled = 327 Completed = 225
Year 2Rimonabant 20 mg
Enrolled = 333Completed = 257
Year 2Placebo
Enrolled = 299Completed = 214
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
RIO-North America: Weight change by treatment assignment
Pi-Sunyer FX et al. JAMA. 2006;295:761-75.
Intent-to-treat population
Δ Body weight
(kg)
Weeks
52
0
-2
-4
-8
-6
-100 24 3612
Year 1 Year 2
104
0
-2
-4
-8
-6
-1052 76 8864
Placebo Rimonabant 20 mgRimonabant 20 mg/Placebo Rimonabant 20 mg/Rimonabant 20 mg
Placebo/Placebo
RIO-North America: Waist circumference by treatment assignment
Pi-Sunyer FX et al. JAMA. 2006;295:761-75.
Δ WC (cm)
Weeks
52
0
-2
-4
-8
-6
-100 24 3612
Year 1 Year 2
104
0
-2
-4
-8
-6
-1052 76 8864
Placebo Rimonabant 20 mgRimonabant 20 mg/Placebo Rimonabant 20 mg/Rimonabant 20 mg
Placebo/Placebo
RIO-North America: Treatment effect on lipids at 1 year
Pi-Sunyer FX et al. JAMA. 2006;295:761-75.No significant effect on LDL-C or total-C
Placebo Rimonabant 20 mg
∆ HDL-C(mg/dL)
Weeks
-2 -30
∆ TG (mg/dL)
10
8
6
4
0
5
0
-5
-10
-202
-15
24 36 520 1224 36 520 12
-25
-15
-10
-5
0
5
10
Change (%)
RIO-North America: Weight-independent and weight-dependent effects on lipids
Pi-Sunyer FX et al. JAMA. 2006;295:761-75.
HDL-C
TG42% Weight-dependent effect
58% Weight-independent effect
53% Weight-dependent effect
47% Weight-independent effect
Rimonabant 20 mg vs placebo
ANCOVA
RIO-North America: Weight-independent and weight-dependent effects on insulin and IR
-3
-2.5
-2
-1.5
-1
-0.5
0
Fasting insulin
-1
-0.8
-0.6
-0.4
-0.2
0
HOMA-IR
Δ
(U/mL)
50%Weight-
dependent
50%Weight-
independent
Δ
49%Weight-
dependent
51%Weight-
independent
Pi-Sunyer FX et al. JAMA. 2006;295:761-75.
Rimonabant 20 mg vs placebo
ANCOVA
RIO-North America: Adverse events
Placebo (%) (n = 498)
Rimonabant 20 mg (%)(n = 1042)
URTI 15.2 18.5
Nasopharyngitis 14.0 17.0
Nausea 5.8 11.2
Arthralgia 8.2 8.8
Sinusitis 11.7 8.7
Headache 10.2 7.8
Back pain 6.1 5.9
Influenza 7.7 8.8
Diarrhea 5.1 5.3
Viral gastroenteritis 4.8 5.7
≥5% incidence in any group
Pi-Sunyer FX et al. JAMA. 2006;295:761-75.
RIO-North America: Adverse events, cont’d
Placebo (%)(n = 498)
Rimonabant 20 mg (%)(n = 1042)
Dizziness 4.0 5.6
Anxiety 2.1 6.1
Bronchitis 5.1 4.3
Depressed mood 3.1 5.2
Fatigue 3.6 5.2
Insomnia 4.4 5.8
≥5% incidence in any group
Pi-Sunyer FX et al. JAMA. 2006;295:761-75.
Obesity program* depression-related events: Overall incidences
Depressed mood disordersand disturbances
Mood alterations with depressive symptoms
Depressive disorders
4.5
2.8
1.7
6.3
3.6
2.8
8.4
4.7
3.9
PlaceboN = 2472
(%)
5 mgN = 2520
(%)
20 mgN = 2742
(%)
Rimonabant
*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.
Completed phase 2 and 3 studies* as of March 2007: All suicidality-related events
Definitely suicidal(suicidal behavior/ideation)
Possibly suicidal
Rimonabant
*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
21
2
PlaceboN = 3411
N (%)
11
1†
5 mgN = 5254
N (%)
0
0
10 mgN = 198N (%)
48
5
20 mgN = 7851
N (%)
0
0
40 mgN = 206N (%)
(0.62)
(0.06)
(0.21)
(0.02)
(0)
(0)
(0.61)
(0.06)
(0)
(0)
Data on file from sanofi-aventis.
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.
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.
ACOMPLIA: European product information, cont’d
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
EMEA. http://emea.europa.eu.