Rheumatoid Arthritis
Conditions
Brief summary
Primary Objectives: Part A (dose ranging study): To demonstrate that sarilumab (SAR153191/REGN88) on top of MTX was effective on reduction of signs and symptoms of rheumatoid arthritis at 12 weeks. Part B (pivotal study): To demonstrate that sarilumab added to MTX was effective in: * reduction of signs and symptoms of rheumatoid arthritis at 24 weeks * inhibition of progression of structural damage at 52 weeks * improvement in physical function at 16 weeks Secondary Objectives: Part B: To demonstrate that sarilumab added to MTX was effective in induction of a major clinical response at 52 weeks To assess the safety of sarilumab added to MTX To document the pharmacokinetic profile of sarilumab added to MTX in participants with active rheumatoid arthritis who were inadequate responders to MTX therapy.
Detailed description
The total study duration for a participant was 16-22 weeks (Part A) and 56-62 weeks (Part B) broken down as follows: * Screening: Up to 4 weeks * Treatment: 12 weeks (Part A) and 52 weeks (Part B)\* * Follow-up: 6 weeks (for participants who would not continue in the long-term extension study). '\*' Participants successfully completing their treatment period would be offered the opportunity to enter the long term extension study LTS11210 (SARIL-RA-EXTEND) (NCT01146652).
Interventions
DRUGSarilumab
Pharmaceutical form: solution for injection Route of administration: subcutaneous
Pharmaceutical form: solution for injection Route of administration: subcutaneous
DRUGMethotrexate
Same weekly dose as received prior to enrollment
DRUGFolic Acid
According to local standard
Sponsors
Regeneron Pharmaceuticals
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
: * Diagnosis of rheumatoid arthritis ≥3 months duration * Active disease defined as: * at least 8/68 tender joints and 6/66 swollen joints, * high sensitivity C-reactive protein (hs-CRP) \>6 mg/l, * continuous treatment with MTX for at least 12 weeks prior to baseline visit and on stable dose for at least 6 weeks prior to screening visit. Part B only: * Bone erosion based on documented X-ray prior to first study drug intake, or * Cyclic Citrullinated Peptide (CCP) positive, or * Rheumatoid Factor (RF) positive.
Exclusion criteria
* Age \<18 years or \>75 years. * Treatment with disease-modifying antirheumatic drugs (DMARDs) other than MTX within 4 weeks or 12 weeks prior to screening (depending on DMARDs). * Past history of non-response to prior Tumor Necrosis Factor (TNF) or biologic treatment. * Any past or current biologic agents for the treatment of rheumatoid arthritis within 3 months. * Use of parenteral glucocorticoids or intraarticular glucocorticoids within 4 weeks prior to screening visit. * Use of oral glucocorticoid greater than 10mg/day or equivalent/day, or a change in dosage within 4 weeks prior to baseline visit. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | Baseline to Week 12 | ACR20 response was 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), Participant assessment of pain; Participant's global assessment of disease activity; Physician global assessment of disease activity; and Health Assessment Question-Disability Index (HAQ-DI). Missing data imputed by Last Observation Carried Forward (LOCF). |
| Part B: Percentage of Participants Achieving ACR20 Response at Week 24 | Baseline to Week 24 | 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. Responder status was determined if possible. With these rules, participants automatically became non-responders for all time points beyond the time point they started rescue treatment or discontinued study treatment. |
| Part B: Change From Baseline in Health Assessment Question Disability Index (HAQ-DI) at Week 16 | Baseline, Week 16 | HAQ-DI was a participant-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. Data collected after treatment discontinuation was set to missing. |
| Part B: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 52 | Baseline, Week 52 | 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. Missing data were imputed by the linear extrapolation method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B: Percentage of Participants Achieving a Major Clinical Response at Week 52 | Baseline up to Week 52 | 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. In the primary approach, data collected after treatment discontinuation or rescue was set to missing. No imputation of missing post-baseline values was performed. Responder status was determined if possible. With these rules, participants automatically became non-responders for all time points beyond the time point they started rescue treatment or discontinued study treatment. |
Countries
Argentina, Australia, Austria, Belarus, Belgium, Brazil, Canada, Chile, Colombia, Czechia, Egypt, Estonia, Finland, Germany, Greece, Hungary, India, Lithuania, Malaysia, Mexico, Netherlands, New Zealand, Norway, Philippines, Poland, Portugal, Romania, Russia, South Africa, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
The study was conducted at 247 centers in 36 countries. Overall, 3715 participants were screened between March 2010 and July 2012, 2040 of whom were screen failures. Screen failures were mainly due to failure to meet the inclusion criterion for severity of the disease and/or due to meeting the exclusion criterion.
Pre-assignment details
Randomization was performed centrally with allocation generated by Interactive Voice/Web Response System, stratified by geographical region and prior biological use. 306 participants were randomized in Part A. 1369 participants were randomized in part B, 172 before dose selection (cohort 1) and 1197 after dose selection (cohort 2).
Participants by arm
| Arm | Count |
|---|---|
| Part A: SAR 100 mg qw Sarilumab 100 mg SC injection qw on top of MTX for 12 weeks. | 50 |
| Part A: SAR 150 mg qw Sarilumab 150 mg SC injection qw on top of MTX for 12 weeks. | 50 |
| Part A: SAR 100 mg q2w Sarilumab 100 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks. | 51 |
| Part A: SAR 150 mg q2w Sarilumab 150 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks. | 51 |
| Part A: SAR 200 mg q2w Sarilumab 200 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks. | 52 |
| Part A: Placebo qw Placebo (for sarilumab) qw on top of MTX for 12 weeks. | 52 |
| Part B Cohort 1: Non-selected Doses Sarilumab 100 mg qw, 150 mg qw or 100 mg q2w SC injections on top of MTX up to dose selection. After dose selection, participants were not continued but were allowed to participate in the open-label, long-term, extension study SARIL-RA-EXTEND (LTS11210). | 84 |
| Part B: SAR 150 mg q2w (Cohort 1[Selected Dose]+Cohort 2) Sarilumab 150 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with high dose of sarilumab (SAR 200 mg q2w). | 430 |
| Part B: SAR 200 mg q2w (Cohort 1[Selected Dose]+Cohort 2) Sarilumab 200 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with high dose of sarilumab (SAR 200 mg q2w). | 427 |
| Part B: Placebo q2w (Cohort 1[Selected Dose]+Cohort 2) Placebo (for sarilumab) q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with high dose of sarilumab (SAR 200 mg q2w). | 428 |
| Total | 1,675 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 13 | 1 | 3 | 2 | 4 | 1 | 4 | 63 | 67 | 34 |
| Overall Study | Dose regimen not selected | 0 | 0 | 0 | 0 | 0 | 0 | 79 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 0 | 2 | 1 | 1 | 1 | 2 | 1 | 9 | 9 | 10 |
| Overall Study | Not treated | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 2 | 1 | 0 |
| Overall Study | Other than specified above | 0 | 1 | 2 | 0 | 1 | 0 | 0 | 18 | 15 | 21 |
| Overall Study | Poor compliance to protocol | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 5 | 9 |
Baseline characteristics
| Characteristic | 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 (Cohort 1[Selected Dose]+Cohort 2) | Part B: SAR 200 mg q2w (Cohort 1[Selected Dose]+Cohort 2) | Part B: Placebo q2w (Cohort 1[Selected Dose]+Cohort 2) | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 53.9 years STANDARD_DEVIATION 12.3 | 50.9 years STANDARD_DEVIATION 11.1 | 53.5 years STANDARD_DEVIATION 11.8 | 51.2 years STANDARD_DEVIATION 12.9 | 48.7 years STANDARD_DEVIATION 12.4 | 55.2 years STANDARD_DEVIATION 12.5 | 51.1 years STANDARD_DEVIATION 11.5 | 50.3 years STANDARD_DEVIATION 11.9 | 50.8 years STANDARD_DEVIATION 12 | 51.1 years STANDARD_DEVIATION 11.2 | 51.04 years STANDARD_DEVIATION 11.79 |
| Sex: Female, Male Female | 41 Participants | 42 Participants | 38 Participants | 42 Participants | 42 Participants | 38 Participants | 69 Participants | 345 Participants | 359 Participants | 346 Participants | 1362 Participants |
| Sex: Female, Male Male | 9 Participants | 8 Participants | 13 Participants | 9 Participants | 10 Participants | 14 Participants | 15 Participants | 85 Participants | 68 Participants | 82 Participants | 313 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 16 / 50 | 16 / 50 | 7 / 51 | 12 / 52 | 19 / 51 | 11 / 51 | 6 / 29 | 8 / 26 | 6 / 29 | 163 / 370 | 194 / 369 | 95 / 259 | 83 / 284 |
| serious Total, serious adverse events | 3 / 50 | 0 / 50 | 3 / 51 | 0 / 52 | 0 / 51 | 2 / 51 | 2 / 29 | 2 / 26 | 0 / 29 | 35 / 370 | 46 / 369 | 21 / 259 | 7 / 284 |
Outcome results
Primary
Part A: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12
ACR20 response was 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), Participant assessment of pain; Participant's global assessment of disease activity; Physician global assessment of disease activity; and Health Assessment Question-Disability Index (HAQ-DI). Missing data imputed by Last Observation Carried Forward (LOCF).
Time frame: Baseline to Week 12
Population: Part A Intent-to-treat (ITT) population defined as all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: SAR 100 mg qw | Part A: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 62 Percentage of participants |
| Part A: SAR 150 mg qw | Part A: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 72 Percentage of participants |
| Part A: SAR 100 mg q2w | Part A: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 49 Percentage of participants |
| Part A: SAR 150 mg q2w | Part A: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 66.7 Percentage of participants |
| Part A: SAR 200 mg q2w | Part A: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 65.4 Percentage of participants |
| Part A: Placebo qw | Part A: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 46.2 Percentage of participants |
Comparison: 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.p-value: 0.115595% CI: [0.85, 4.64]Cochran-Mantel-Haenszel
p-value: 0.004195% CI: [1.53, 9.63]Cochran-Mantel-Haenszel
p-value: 0.711995% CI: [0.52, 2.61]Cochran-Mantel-Haenszel
p-value: 0.036395% CI: [1.06, 5.35]Cochran-Mantel-Haenszel
p-value: 0.042695% CI: [1.03, 5.29]Cochran-Mantel-Haenszel
Primary
Part B: Change From Baseline in Health Assessment Question Disability Index (HAQ-DI) at Week 16
HAQ-DI was a participant-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. Data collected after treatment discontinuation was set to missing.
Time frame: Baseline, Week 16
Population: Cohort 2 ITT population only and included participants with available data of HAQ-DI at baseline and on or before Week 16.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: SAR 100 mg qw | Part B: Change From Baseline in Health Assessment Question Disability Index (HAQ-DI) at Week 16 | Week 16 | 1.08 units on a scale | Standard Deviation 0.67 |
| Part A: SAR 100 mg qw | Part B: Change From Baseline in Health Assessment Question Disability Index (HAQ-DI) at Week 16 | Baseline | 1.63 units on a scale | Standard Deviation 0.63 |
| Part A: SAR 100 mg qw | Part B: Change From Baseline in Health Assessment Question Disability Index (HAQ-DI) at Week 16 | Change from baseline at Week 16 | -0.54 units on a scale | Standard Deviation 0.55 |
| Part A: SAR 150 mg qw | Part B: Change From Baseline in Health Assessment Question Disability Index (HAQ-DI) at Week 16 | Week 16 | 1.11 units on a scale | Standard Deviation 0.7 |
| Part A: SAR 150 mg qw | Part B: Change From Baseline in Health Assessment Question Disability Index (HAQ-DI) at Week 16 | Baseline | 1.69 units on a scale | Standard Deviation 0.63 |
| Part A: SAR 150 mg qw | Part B: Change From Baseline in Health Assessment Question Disability Index (HAQ-DI) at Week 16 | Change from baseline at Week 16 | -0.58 units on a scale | Standard Deviation 0.63 |
| Part A: SAR 100 mg q2w | Part B: Change From Baseline in Health Assessment Question Disability Index (HAQ-DI) at Week 16 | Baseline | 1.61 units on a scale | Standard Deviation 0.65 |
| Part A: SAR 100 mg q2w | Part B: Change From Baseline in Health Assessment Question Disability Index (HAQ-DI) at Week 16 | Change from baseline at Week 16 | -0.3 units on a scale | Standard Deviation 0.58 |
| Part A: SAR 100 mg q2w | Part B: Change From Baseline in Health Assessment Question Disability Index (HAQ-DI) at Week 16 | Week 16 | 1.31 units on a scale | Standard Deviation 0.67 |
Comparison: Analysis was performed using a mixed model for repeated measures (MMRM). Differences in least square (LS) mean between each dose of sarilumab and placebo were derived. Testing was performed according to the hierarchical testing procedure (performed only when the previous endpoint was statistically significant).p-value: <0.000195% CI: [-0.312, -0.157]Mixed Models Analysis
p-value: <0.000195% CI: [-0.336, -0.181]Mixed Models Analysis
Primary
Part B: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 52
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. Missing data were imputed by the linear extrapolation method.
Time frame: Baseline, Week 52
Population: Cohort 2 ITT population and included participants with available data of mTSS at baseline and on or before Week 52.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: SAR 100 mg qw | Part B: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 52 | Week 52 | 55.57 units on a scale | Standard Deviation 63.73 |
| Part A: SAR 100 mg qw | Part B: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 52 | Baseline | 54.67 units on a scale | Standard Deviation 63.42 |
| Part A: SAR 100 mg qw | Part B: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 52 | Change from baseline at Week 52 | 0.90 units on a scale | Standard Deviation 4.66 |
| Part A: SAR 150 mg qw | Part B: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 52 | Week 52 | 46.59 units on a scale | Standard Deviation 57.63 |
| Part A: SAR 150 mg qw | Part B: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 52 | Baseline | 46.34 units on a scale | Standard Deviation 57.43 |
| Part A: SAR 150 mg qw | Part B: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 52 | Change from baseline at Week 52 | 0.25 units on a scale | Standard Deviation 4.61 |
| Part A: SAR 100 mg q2w | Part B: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 52 | Baseline | 48.01 units on a scale | Standard Deviation 65.23 |
| Part A: SAR 100 mg q2w | Part B: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 52 | Change from baseline at Week 52 | 2.78 units on a scale | Standard Deviation 7.73 |
| Part A: SAR 100 mg q2w | Part B: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 52 | Week 52 | 50.79 units on a scale | Standard Deviation 65.82 |
Comparison: Analysis was performed using two-sided rank-based ANCOVA model. Testing was performed according to the hierarchical testing procedure (performed only when the previous endpoints were statistically significant).p-value: <0.0001Rank ANCOVA
p-value: <0.0001Rank ANCOVA
Primary
Part B: Percentage of Participants Achieving ACR20 Response at Week 24
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. Responder status was determined if possible. With these rules, participants automatically became non-responders for all time points beyond the time point they started rescue treatment or discontinued study treatment.
Time frame: Baseline to Week 24
Population: ITT population which included all participants randomized after dose selection (cohort 2).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: SAR 100 mg qw | Part B: Percentage of Participants Achieving ACR20 Response at Week 24 | 58 Percentage of participants |
| Part A: SAR 150 mg qw | Part B: Percentage of Participants Achieving ACR20 Response at Week 24 | 66.4 Percentage of participants |
| Part A: SAR 100 mg q2w | Part B: Percentage of Participants Achieving ACR20 Response at Week 24 | 33.4 Percentage of participants |
Comparison: 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.p-value: <0.000195% CI: [2.077, 3.703]Cochran-Mantel-Haenszel
p-value: <0.000195% CI: [2.957, 5.344]Cochran-Mantel-Haenszel
Secondary
Part B: Percentage of Participants Achieving a Major Clinical Response at Week 52
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. In the primary approach, data collected after treatment discontinuation or rescue was set to missing. No imputation of missing post-baseline values was performed. Responder status was determined if possible. With these rules, participants automatically became non-responders for all time points beyond the time point they started rescue treatment or discontinued study treatment.
Time frame: Baseline up to Week 52
Population: ITT population which included all participants randomized after dose selection (cohort 2).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: SAR 100 mg qw | Part B: Percentage of Participants Achieving a Major Clinical Response at Week 52 | 12.8 Percentage of participants |
| Part A: SAR 150 mg qw | Part B: Percentage of Participants Achieving a Major Clinical Response at Week 52 | 14.8 Percentage of participants |
| Part A: SAR 100 mg q2w | Part B: Percentage of Participants Achieving a Major Clinical Response at Week 52 | 3 Percentage of participants |
Comparison: 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 (performed only when the previous endpoints were statistically significant).p-value: <0.000195% CI: [2.451, 8.863]Cochran-Mantel-Haenszel
p-value: <0.000195% CI: [2.946, 10.515]Cochran-Mantel-Haenszel