EFC11072

Sanofi aventis recherche & développement

1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

No

No

No

Final

06 Nov 2013

No

Yes

08 Oct 2013

No

This phase II/III study in subjects with active rheumatoid arthritis used an operationally seamless design. Main objectives were: Phase II - 12 week dose-ranging study (part A): to evaluate efficacy and safety of 5 dose regimens of sarilumab (SAR153191/REGN88) on top of methotrexate (MTX); Phase III - 52-week confirmatory study (part B): to confirm the efficacy and safety of the 2 dose regimens selected from part A.

Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.

22 Mar 2010

No

Yes

Norway: 1

Poland: 154

Portugal: 1

Romania: 45

Spain: 22

Austria: 4

Belgium: 1

Czech Republic: 12

Estonia: 20

Finland: 14

Germany: 22

Greece: 4

Hungary: 55

Lithuania: 10

Argentina: 130

Australia: 27

Belarus: 14

Brazil: 72

Canada: 10

Chile: 133

Colombia: 78

India: 24

Korea, Republic of: 46

Malaysia: 5

Mexico: 175

New Zealand: 9

Philippines: 15

Russian Federation: 213

South Africa: 97

Taiwan: 2

Thailand: 3

Turkey: 3

Ukraine: 67

United States: 187

1675

365

0

0

0

0

0

0

1460

215

0

Overall trial (overall period)

Randomised - controlled

Investigators were blinded with regard to each subject's CRP and IL-6 levels, except at screening and baseline, with the swollen and tender joint counts performed by a separate qualified assessor. Two readers, blinded with regard to treatment assignment, chronologic order of the radiographs, and subject's clinical status, independently reviewed and scored images using the modified Sharp/van der Heijde scoring (SHS) system.

Yes

Sarilumab

SAR153191

REGN88

Solution for injection

Subcutaneous use

Single injection in abdomen.

Sarilumab

SAR153191

REGN88

Solution for injection

Subcutaneous use

Single injection in abdomen.

Sarilumab

SAR153191

REGN88

Solution for injection

Subcutaneous use

Single injection in abdomen.

Placebo (for sarilumab)

Solution for injection

Subcutaneous use

Single injection in abdomen.

Sarilumab

SAR153191

REGN88

Solution for injection

Subcutaneous use

Single injection in abdomen.

Placebo (for sarilumab)

Solution for injection

Subcutaneous use

Single injection in abdomen.

Sarilumab

SAR153191

REGN88

Solution for injection

Subcutaneous use

Single injection in abdomen.

Placebo (for sarilumab)

Solution for injection

Subcutaneous use

Single injection in abdomen.

Placebo (for sarilumab)

Solution for injection

Subcutaneous use

Single injection in abdomen.

Sarilumab

SAR153191

REGN88

Solution for injection

Subcutaneous use

Single injection in abdomen.

Placebo (for sarilumab)

Solution for injection

Subcutaneous use

Single injection in abdomen.

Sarilumab

SAR153191

REGN88

Solution for injection

Subcutaneous use

Single injection in abdomen.

Sarilumab

SAR153191

REGN88

Solution for injection

Subcutaneous use

Single injection in abdomen.

Placebo (for sarilumab)

Solution for injection

Subcutaneous use

Single injection in abdomen.

Part A: SAR 100 mg QW

Part A: SAR 150 mg QW

Part A: SAR 100 mg Q2W

Part A: SAR 150 mg Q2W

Part A: SAR 200 mg Q2W

Part A: Placebo QW

Part B cohort 1: Non-selected doses

Part B: SAR 150 mg Q2W

Part B: SAR 200 mg Q2W

Part B: Placebo Q2W

Part A: SAR 100 mg QW

Part A: SAR 150 mg QW

Part A: SAR 100 mg Q2W

Part A: SAR 150 mg Q2W

Part A: SAR 200 mg Q2W

Part A: Placebo QW

Part B cohort 1: Non-selected doses

Part B: SAR 150 mg Q2W

Part B: SAR 200 mg Q2W

Part B: Placebo Q2W

Part B cohort 2: SAR 150 mg Q2W

Part B subjects randomized to Sarilumab 150 mg q2w after dose selection.

Part B cohort 2: SAR 200 mg Q2W

Part B subjects randomized to Sarilumab 200 mg q2w after dose selection.

Part B cohort 2: Placebo Q2W

Part B subjects randomized to placebo q2w after dose selection.

ACR20 response is defined, based on guidelines set forth by the American College of Rheumatology (ACR), as ≥20 % improvement in tender joint count and swollen joint count as well as ≥20% improvement in at least 3 of 5 following measures: C-Reactive Protein (CRP), subject assessment of pain; subject global assessment of disease activity; physician global assessment of disease activity; and Health Assessment Question-Disability Index (HAQ-DI). Analysis was carried out on Part A Intent-to-treat (ITT) population defined as all randomized subjects who received at least 1 dose of study drug.

Primary

Baseline to Week 12 (missing data imputed by Last Observation Carried Forward [LOCF]).

Analysis was performed using two-sided Cochran-Mantel-Haenszel test. Pairwise comparisons of the response rates between each dose of sarilumab and placebo were derived. The multiplicity issues were addressed by using the Hommel-procedure.

Part A: SAR 100 mg QW v Part A: Placebo QW

102

Pre-specified

1.99

2-sided

Part A: SAR 150 mg QW v Part A: Placebo QW

102

Pre-specified

3.84

2-sided

Part A: Placebo QW v Part A: SAR 100 mg Q2W

103

Pre-specified

1.17

2-sided

Part A: SAR 150 mg Q2W v Part A: Placebo QW

103

Pre-specified

2.38

2-sided

Part A: SAR 200 mg Q2W v Part A: Placebo QW

104

Pre-specified

2.34

2-sided

ACR20 improvement responses were determined without imputation of missing post-baseline values. In addition data collected after treatment discontinuation or rescue was set to missing. Analysis was carried out on the ITT population, which included all subjects randomized after dose selection (cohort 2).

Primary

Baseline to Week 24

Analysis was performed using two-sided Cochran-Mantel-Haenszel test. Pairwise comparisons of the response rates between each dose of sarilumab and placebo was derived. The multiplicity issues for part B were addressed by using a Bonferroni correction for each dose together with a hierarchical testing procedure across the 3 co-primary and the main secondary endpoints.The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.025 level.

Part B cohort 2: SAR 150 mg Q2W v Part B cohort 2: Placebo Q2W

798

Pre-specified

2.773

2-sided

Part B cohort 2: SAR 200 mg Q2W v Part B cohort 2: Placebo Q2W

797

Pre-specified

3.975

2-sided

HAQ-DI is a subject-reported questionnaire that assesses the difficulty of performing daily activities: dress/groom, arise, eat, walk, reach, grip, hygiene and common activities. Overall score range from 0=least difficulty to 3=extreme difficulty. An increase in the score indicates a worsening of physical function while a decrease in the score represents improvement. Analysis was carried out on the Cohort 2 ITT population only and included subjects with available data of HAQ-DI at baseline and Week 16.

Primary

Baseline, Week 16

Analysis was performed using a mixed model for repeated measures (MMRM). Differences in LS means between each dose of sarilumab and placebo were derived. Testing was performed according to the hierarchical testing procedure (previous endpoint was statistically significant).

Part B cohort 2: SAR 150 mg Q2W v Part B cohort 2: Placebo Q2W

740

Pre-specified

-0.235

2-sided

Part B cohort 2: SAR 200 mg Q2W v Part B cohort 2: Placebo Q2W

743

Pre-specified

-0.258

2-sided

The Sharp method modified by D. van der Heijde involves separate scores for erosions and joint space narrowing based on radiographs to assess the degree of structural damage. Total score range from 0 (normal) to 448 (worst possible total score). An increase in total score represents progression of structural damage. Analysis was carried out on the Cohort 2 ITT population and included subjects with available data of mTSS at baseline and Week 52.

Primary

Baseline, Week 52 (missing data imputed by the linear extrapolation method).

Analysis was performed using two-sided rank-based ANCOVA model. Testing was performed according to the hierarchical testing procedure (previous endpoints were statistically significant).

Part B cohort 2: Placebo Q2W v Part B cohort 2: SAR 150 mg Q2W

704

Pre-specified

Part B cohort 2: Placebo Q2W v Part B cohort 2: SAR 200 mg Q2W

711

Pre-specified

Major clinical response was defined as an ACR70 response maintained for at least 24 consecutive weeks. ACR70 response uses the same criteria as for ACR20 but requires 70% improvement. Analysis was carried out on Part B Cohort 2 ITT population.

Secondary

Baseline up to Week 52

Analysis was performed using two-sided Cochran-Mantel-Haenszel test. Pairwise comparisons of the response rates between each dose of sarilumab and placebo were derived. Testing was performed according to the hierarchical testing procedure (previous endpoints were statistically significant).

Part B cohort 2: SAR 150 mg Q2W v Part B cohort 2: Placebo Q2W

798

Pre-specified

4.661

2-sided

Part B cohort 2: SAR 200 mg Q2W v Part B cohort 2: Placebo Q2W

797

Pre-specified

5.565

2-sided

All Adverse Events (AE) were collected from signature of the informed consent form up to study completion regardless of seriousness or relationship to investigational product.

Reported AEs and deaths are treatment-emergent that is AEs that developed/worsened and deaths that occurred during the ‘treatment-emergent period’ (from the first IMP injection up to the end of the study).

16.0

Part A: Placebo QW

Part A: SAR 100mg Q2W

Part A: SAR 150mg Q2W

Part A: SAR 100mg QW

Part A: SAR 200mg Q2W

Part A: SAR 150mg QW

Part B: Placebo Q2W until rescue

Part B: SAR 150mg Q2W until rescue

Part B: SAR 200mg Q2W until rescue

Part B: Rescue SAR 200mg Q2W