Effect of SAR153191 (REGN88) With Methotrexate in Patients With Active Rheumatoid Arthritis Who Failed TNF-α Blockers

• Sponsor: Sanofi (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01217814
• Collaborator: Regeneron Pharmaceuticals (Industry)
• Enrollment: 16
• Locations: 14
• Arms: 3
• Duration (Months): 10
• Patients Per Site: 1.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Primary Objective:

• To demonstrate that sarilumab (SAR153191/REGN88) on top of methotrexate (MTX) was superior in efficacy to placebo for the relief of signs and symptoms of rheumatoid arthritis (RA), in participants with active RA who had failed up to 2 tumor necrosis factor-alpha (TNF-α) antagonists.

Secondary Objectives:

• To assess the safety of sarilumab;

• To document the pharmacokinetic profile of sarilumab.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Sarilumab; Drug: Placebo; Drug: Golimumab; Drug: methotrexate (MTX); Drug: Folic/folinic acid	Phase 2

Detailed Description

The duration of the study period for each participant was approximately 22 weeks; including up to 4 weeks screening period, 12-week double-blind treatment period and 6-week safety follow-up period.

Participants who completed the 12-week treatment period were offered enrollment in a separate long-term extension study (LTS11210/NCT01146652).

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Parallel-group, Placebo- and Active Calibrator-controlled Study Assessing the Clinical Benefit of SAR153191 Subcutaneous (SC) on Top of MTX in Patients With Active RA Who Have Failed Previous TNF-α Antagonists
• Study Start Date: Nov 1, 2010
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo 2 mL to match sarilumab once a week (qw) and 0.5 mL to match golimumab every 4 weeks (q4w) on top of MTX (15-25 mg) qw for 12 weeks.	Drug: Placebo; Pharmaceutical form: solution for injection Route of administration: subcutaneous; Drug: methotrexate (MTX); Pharmaceutical form: tablet or solution for injection Route of administration: Oral (tablet) or subcutaneous, intramuscular (solution); Drug: Folic/folinic acid; Pharmaceutical form: tablet Route of administration: oral Folic/folinic acid continued according to local standard.
Active Comparator: Golimumab 50 mg Golimumab 50 mg q4w and placebo (matched to sarilumab) qw on top of MTX (15-25 mg) qw for 12 weeks.	Drug: Placebo; Pharmaceutical form: solution for injection Route of administration: subcutaneous; Drug: Golimumab; Pharmaceutical form: solution for injection Route of administration: subcutaneous; Other Names: Simponi® ; Drug: methotrexate (MTX); Pharmaceutical form: tablet or solution for injection Route of administration: Oral (tablet) or subcutaneous, intramuscular (solution); Drug: Folic/folinic acid; Pharmaceutical form: tablet Route of administration: oral Folic/folinic acid continued according to local standard.
Experimental: Sarilumab 150 mg Sarilumab 150 mg qw and placebo (matched to golimumab) q4w on top of MTX (15-25 mg) qw for 12 weeks.	Drug: Sarilumab; Pharmaceutical form: solution for injection Route of administration: subcutaneous; Other Names: SAR153191 REGN88 ; Drug: Placebo; Pharmaceutical form: solution for injection Route of administration: subcutaneous; Drug: methotrexate (MTX); Pharmaceutical form: tablet or solution for injection Route of administration: Oral (tablet) or subcutaneous, intramuscular (solution); Drug: Folic/folinic acid; Pharmaceutical form: tablet Route of administration: oral Folic/folinic acid continued according to local standard.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Achieved at Least 20% Improvement in American College of Rheumatology (ACR20) Core Set Disease Activity Index at Week 12 [Week 12]

Secondary Outcome Measures

1. Percentage of Participants Who Achieved at Least 50% Improvement in American College of Rheumatology (ACR50) Core Set Disease Activity Index at Week 12 [Week 12]

2. Percentage of Participants Who Achieved at Least 70% Improvement in American College of Rheumatology Core (ACR70) Set Disease Activity Index at Week 12 [Week 12]

3. Disease Activity Score for 28 Joints (DAS28) at Week 12 [Week 12]

4. European League Against Rheumatism (EULAR) Response at Week 12 [Week 12]

5. Percentage of Participants Achieving DAS28 Remission Score < 2.6 at Week 12 [Week 12]

6. Pharmacokinetic (PK) Parameter: Serum Concentration of Functional and Bound Sarilumab [Week 12]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Diagnosis of rheumatoid arthritis ≥6 months duration and American College of Rheumatology (ACR) Class I-III functional status at screening and baseline visits;

• Active disease defined as:

• At least 6 of 68 tender joints and 6 of 66 swollen joints at screening and baseline visits, and

• hs-C-Reactive Protein (hs-CRP) >10 g/L or Erythrocyte Sedimentation Rate (ESR)

28 mm/hr at screening visit;

• Continuous treatment with Methotrexate for at least 12 weeks and on stable dose (minimum 10 mg/week) for at least 6 weeks prior to the screening visit;

• Participant considered as Primary TNF-α blocker nonresponder. i.e.:

• Appropriate for previous TNF-α blocker therapy

• Lack of adequate clinical response after at least 3 months TNF-α blocker therapy with MTX or other synthetic disease modifying anti-rheumatic drug (DMARD) co-therapy.

Exclusion criteria:

• Age <18 years or >75 years;

• Pregnant or breastfeeding woman or woman of childbearing potential, unwilling to utilize adequate contraception or not to become pregnant during the entire study;

• Fever (>38°C), or chronic, persistent, or recurring infection(s);

• History of demyelinating disease;

• Current underlying hepatobiliary disease.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number 840026	Freehold	New Jersey	United States	07728
2	Investigational Site Number 840043	New York	New York	United States	11201
3	Investigational Site Number 840025	Jackson	Tennessee	United States	38305
4	Investigational Site Number 840038	Austin	Texas	United States	78705
5	Investigational Site Number 170004	Barranquilla		Colombia
6	Investigational Site Number 170005	Barranquilla		Colombia
7	Investigational Site Number 170007	Bucaramanga		Colombia
8	Investigational Site Number 203002	Uherske Hradiste		Czechia	68601
9	Investigational Site Number 380002	Firenze		Italy	50141
10	Investigational Site Number 380005	Genova		Italy	16132
11	Investigational Site Number 484008	Durango		Mexico	34270
12	Investigational Site Number 484002	Guadalajara		Mexico	44690
13	Investigational Site Number 724004	Oviedo		Spain	33006
14	Investigational Site Number 724002	Valencia		Spain	46009

Sponsors and Collaborators

• Sanofi
• Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT01217814
• Other Study ID Numbers: ACT11575; 2010-021020-94; U1111-1115-3763
• First Posted: Oct 8, 2010
• Last Update Posted: Sep 1, 2017
• Last Verified: Jul 1, 2017

• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Leucovorin; Folic Acid; Golimumab; Methotrexate; Levoleucovorin

Study Results

Participant Flow

Recruitment Details	The study was conducted at 10 centers in United States and Europe. A total of 41 participants were screened between 15 November 2010 and 18 May 2011 of whom 16 participants were randomized and 25 were screen failures. Screen failures were mainly due to exclusion criteria met.
Pre-assignment Detail	Participants were randomized 2:1:2 (Sarilumab 150 mg : Placebo : Golimumab 50 mg) via a centralized randomization system using an interactive voice response system stratified by region and number of previous anti-tumor necrosis factor-alpha (TNF-α) therapy.

Arm/Group Title	Placebo	Golimumab 50 mg	Sarilumab 150 mg
Arm/Group Description	Subcutaneous (SC) injection of placebo 2 mL once a week (qw) to match sarilumab and 0.5 mL every 4 weeks (q4w) to match golimumab on top of methotrexate (MTX) (15-25 mg) qw for 12 weeks.	Golimumab 50 mg SC injection q4w and placebo (matched to sarilumab) SC injection qw on top of MTX (15-25 mg) qw for 12 weeks.	Sarilumab 150 mg SC injection qw and placebo (matched to golimumab) SC injection q4w on top of MTX (15-25 mg) qw for 12 weeks.
Period Title: Overall Study
STARTED	4	5	7
COMPLETED	3	4	6
NOT COMPLETED	1	1	1

Baseline Characteristics

Arm/Group Title	Placebo	Golimumab 50 mg	Sarilumab 150 mg	Total
Arm/Group Description	SC injection of placebo 2 mL qw to match sarilumab and 0.5 mL q4w to match golimumab on top of MTX (15-25 mg) qw for 12 weeks.	Golimumab 50 mg SC injection q4w and placebo (matched to sarilumab) SC injection qw on top of MTX (15-25 mg) qw for 12 weeks.	Sarilumab 150 mg SC injection qw and placebo (matched to golimumab) SC injection q4w on top of MTX (15-25 mg) qw for 12 weeks.	Total of all reporting groups
Overall Participants	4	5	7	16
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.3 (17.9)	62.6 (7.6)	54.0 (11.1)	54.5 (13.2)
Sex: Female, Male (Count of Participants)
Female	4 100%	3 60%	7 100%	14 87.5%
Male	0 0%	2 40%	0 0%	2 12.5%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Achieved at Least 20% Improvement in American College of Rheumatology (ACR20) Core Set Disease Activity Index at Week 12
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

As the number of participants randomized fell well below target (16 vs. 250), the efficacy data were not systematically collected or cleaned and no datasets have been created to report.

Arm/Group Title	Placebo	Golimumab 50 mg	Sarilumab 150 mg
Arm/Group Description	SC injection of placebo 2 mL qw to match sarilumab and 0.5 mL q4w to match golimumab on top of MTX (15-25 mg) qw for 12 weeks.	Golimumab 50 mg SC injection q4w and placebo (matched to sarilumab) SC injection qw on top of MTX (15-25 mg) qw for 12 weeks.	Sarilumab 150 mg SC injection qw and placebo (matched to golimumab) SC injection q4w on top of MTX (15-25 mg) qw for 12 weeks.
Measure Participants	0	0	0

2. Secondary Outcome

Title	Percentage of Participants Who Achieved at Least 50% Improvement in American College of Rheumatology (ACR50) Core Set Disease Activity Index at Week 12
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

As the number of participants randomized fell well below target (16 vs. 250), the efficacy data were not systematically collected or cleaned and no datasets have been created to report.

Arm/Group Title	Placebo	Golimumab 50 mg	Sarilumab 150 mg
Arm/Group Description	SC injection of placebo 2 mL qw to match sarilumab and 0.5 mL q4w to match golimumab on top of MTX (15-25 mg) qw for 12 weeks.	Golimumab 50 mg SC injection q4w and placebo (matched to sarilumab) SC injection qw on top of MTX (15-25 mg) qw for 12 weeks.	Sarilumab 150 mg SC injection qw and placebo (matched to golimumab) SC injection q4w on top of MTX (15-25 mg) qw for 12 weeks.
Measure Participants	0	0	0

3. Secondary Outcome

Title	Percentage of Participants Who Achieved at Least 70% Improvement in American College of Rheumatology Core (ACR70) Set Disease Activity Index at Week 12
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

As the number of participants randomized fell well below target (16 vs. 250), the efficacy data were not systematically collected or cleaned and no datasets have been created to report.

Arm/Group Title	Placebo	Golimumab 50 mg	Sarilumab 150 mg
Arm/Group Description	SC injection of placebo 2 mL qw to match sarilumab and 0.5 mL q4w to match golimumab on top of MTX (15-25 mg) qw for 12 weeks.	Golimumab 50 mg SC injection q4w and placebo (matched to sarilumab) SC injection qw on top of MTX (15-25 mg) qw for 12 weeks.	Sarilumab 150 mg SC injection qw and placebo (matched to golimumab) SC injection q4w on top of MTX (15-25 mg) qw for 12 weeks.
Measure Participants	0	0	0

4. Secondary Outcome

Title	Disease Activity Score for 28 Joints (DAS28) at Week 12
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

As the number of participants randomized fell well below target (16 vs. 250), the efficacy data were not systematically collected or cleaned and no datasets have been created to report.

Arm/Group Title	Placebo	Golimumab 50 mg	Sarilumab 150 mg
Arm/Group Description	SC injection of placebo 2 mL qw to match sarilumab and 0.5 mL q4w to match golimumab on top of MTX (15-25 mg) qw for 12 weeks.	Golimumab 50 mg SC injection q4w and placebo (matched to sarilumab) SC injection qw on top of MTX (15-25 mg) qw for 12 weeks.	Sarilumab 150 mg SC injection qw and placebo (matched to golimumab) SC injection q4w on top of MTX (15-25 mg) qw for 12 weeks.
Measure Participants	0	0	0

5. Secondary Outcome

Title	European League Against Rheumatism (EULAR) Response at Week 12
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

As the number of participants randomized fell well below target (16 vs. 250), the efficacy data were not systematically collected or cleaned and no datasets have been created to report.

Arm/Group Title	Placebo	Golimumab 50 mg	Sarilumab 150 mg
Arm/Group Description	SC injection of placebo 2 mL qw to match sarilumab and 0.5 mL q4w to match golimumab on top of MTX (15-25 mg) qw for 12 weeks.	Golimumab 50 mg SC injection q4w and placebo (matched to sarilumab) SC injection qw on top of MTX (15-25 mg) qw for 12 weeks.	Sarilumab 150 mg SC injection qw and placebo (matched to golimumab) SC injection q4w on top of MTX (15-25 mg) qw for 12 weeks.
Measure Participants	0	0	0

6. Secondary Outcome

Title	Percentage of Participants Achieving DAS28 Remission Score < 2.6 at Week 12
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

As the number of participants randomized fell well below target (16 vs. 250), the efficacy data were not systematically collected or cleaned and no datasets have been created to report.

Arm/Group Title	Placebo	Golimumab 50 mg	Sarilumab 150 mg
Arm/Group Description	SC injection of placebo 2 mL qw to match sarilumab and 0.5 mL q4w to match golimumab on top of MTX (15-25 mg) qw for 12 weeks.	Golimumab 50 mg SC injection q4w and placebo (matched to sarilumab) SC injection qw on top of MTX (15-25 mg) qw for 12 weeks.	Sarilumab 150 mg SC injection qw and placebo (matched to golimumab) SC injection q4w on top of MTX (15-25 mg) qw for 12 weeks.
Measure Participants	0	0	0

7. Secondary Outcome

Title	Pharmacokinetic (PK) Parameter: Serum Concentration of Functional and Bound Sarilumab
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Analysis was performed in PK population of all participants with at least one non-missing serum concentration data.

Arm/Group Title	Sarilumab 150 mg qw
Arm/Group Description	Sarilumab 150 mg SC injection qw and placebo (matched to golimumab) SC injection q4w on top of MTX (15-25 mg) qw for 12 weeks.
Measure Participants	7
Bound Concentration	4271.43 (1328.86)
Functional Concentration	42391.43 (26168.68)

Adverse Events

Time Frame	All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (week 18) regardless of seriousness or relationship to investigational product.
Adverse Event Reporting Description	Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first dose injection of the double-blind investigational product to the end of the follow-up period).
Arm/Group Title	Placebo		Golimumab 50 mg		Sarilumab 150 mg
Arm/Group Description	SC injection of placebo 2 mL qw to match sarilumab and 0.5 mL q4w to match golimumab on top of MTX (15-25 mg) qw for 12 weeks.		Golimumab 50 mg SC injection q4w and placebo (matched to sarilumab) SC injection qw on top of MTX (15-25 mg) qw for 12 weeks.		Sarilumab 150 mg SC injection qw and placebo (matched to golimumab) SC injection q4w on top of MTX (15-25 mg) qw for 12 weeks.
All Cause Mortality
	Placebo		Golimumab 50 mg		Sarilumab 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Golimumab 50 mg		Sarilumab 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/5 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Golimumab 50 mg		Sarilumab 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/4 (75%)		1/5 (20%)		3/7 (42.9%)
Gastrointestinal disorders
Diarrhoea	0/4 (0%)		1/5 (20%)		0/7 (0%)
Vomiting	0/4 (0%)		1/5 (20%)		0/7 (0%)
General disorders
Application site reaction	0/4 (0%)		0/5 (0%)		1/7 (14.3%)
Chills	0/4 (0%)		0/5 (0%)		1/7 (14.3%)
Infections and infestations
Influenza	0/4 (0%)		0/5 (0%)		1/7 (14.3%)
Nasopharyngitis	1/4 (25%)		0/5 (0%)		0/7 (0%)
Sinusitis	1/4 (25%)		0/5 (0%)		0/7 (0%)
Urinary tract infection	1/4 (25%)		0/5 (0%)		0/7 (0%)
Injury, poisoning and procedural complications
Accidental overdose	1/4 (25%)		0/5 (0%)		1/7 (14.3%)
Investigations
Transaminases increased	0/4 (0%)		0/5 (0%)		1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Muscle spasms	0/4 (0%)		0/5 (0%)		1/7 (14.3%)
Respiratory, thoracic and mediastinal disorders
Cough	0/4 (0%)		0/5 (0%)		1/7 (14.3%)
Skin and subcutaneous tissue disorders
Dermatitis	0/4 (0%)		1/5 (20%)		0/7 (0%)
Urticaria	1/4 (25%)		0/5 (0%)		0/7 (0%)
Vascular disorders
Hypertension	0/4 (0%)		0/5 (0%)		1/7 (14.3%)

Limitations/Caveats

The study was prematurely terminated due to small number of participants entering randomization.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.