data supplement rio-europe rio-lipids rio-diabetes rio-north america european labeling

Data Supplement

RIO-EuropeRIO-LipidsRIO-DiabetesRIO-North AmericaEuropean labeling

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.


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


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


≥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


Completed = 214


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


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



*P < 0.001 vs placeboNo significant effect on LDL-C and total-C


∆ 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


57% of adiponectin increase was independent of weight loss


∆ Adiponectin

level(g/mL)

0

4

3

1

2

0–5 5–10 ≥10Weight gain

Weight loss (%)

RIO-Lipids: Adverse events




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



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


Completed = 231


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


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


-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



RIO-Diabetes: Adverse events



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



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


Pi-Sunyer FX et al. JAMA. 2006;295:761-75.

Year 2Placebo

Enrolled = 327 Completed = 225

Year 2Rimonabant 20 mg


Year 2Placebo


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



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


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


∆ 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


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


Rimonabant 20 mg vs placebo

ANCOVA

RIO-North America: Adverse events

Placebo (%) (n = 498)


URTI 15.2 18.5


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



RIO-North America: Adverse events, cont’d



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



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.

data supplement rio-europe rio-lipids rio-diabetes rio-north america european labeling

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