Arthritis, Rheumatoid
Conditions
Keywords
Arthritis, Rheumatoid, Active rheumatoid arthritis despite anti-TNF-alpha therapy, Sirukumab, Human Anti-IL-6 monoclonal antibody
Brief summary
The purpose of this study is to assess the efficacy of sirukumab as measured by the reduction of the signs and symptoms of rheumatoid arthritis (RA) in patients with active RA who are unresponsive or intolerant to treatment with anti-TNF-alpha agents.
Detailed description
Patients will be randomly assigned to treatment groups, and they and study personnel will not know the identity of the treatments given. Some patients will receive a placebo, which resembles a medication, but does not contain an active substance. This helps to determine if the study agent is effective. Patients will receive placebo or sirukumab by injection under the skin. The expected duration of the study is 68 weeks, which includes 52 weeks of treatment. Participants who complete participation in the study will be eligible for inclusion into the long term extension study if enrollment at a participating site is available to them. If they do not participate in the long-term study, they will continue into the safety follow-up for approximately 16 weeks. The placebo-controlled portion of the study is through Week 24, when placebo patients will cross over to one of two sirukumab dose regimens. Patient safety will be monitored throughout the study.
Interventions
DRUGPlacebo
Form=solution for injection, route=subcutaneous use; every 2 weeks from Week 0 through Week 22.
DRUGSirukumab
Type=exact, unit=mg, number=50 or 100, form=solution for injection, route=subcutaneous use; every 2 weeks for 100 mg and every 4 weeks for 50 mg, Week 23 through Week 52.
Sponsors
GlaxoSmithKline
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have a diagnosis of rheumatoid arthritis (RA) for at least 3 months before screening * Have moderately to severely active RA with at least 4 of 68 tender joints and 4 of 66 swollen joints, at screening and at baseline * Have had anti-tumor necrosis factor (TNF)-alpha therapy and were unresponsive by 1 of the following 2 reasons: Lack of benefit to at least 1 anti-TNF-alpha biologic therapy, as assessed by the treating physician, after at least 12 weeks of etanercept, yisaipu, adalimumab, golimumab, or certolizumab pegol therapy and/or at least a 14-week dosage regimen (ie, at least 4 doses) of infliximab; Intolerance to at least 2 anti-TNF-alpha biologic therapies, as assessed by the treating physician, to etanercept, yisaipu, adalimumab, golimumab, certolizumab pegol, or infliximab or have documented intolerance to an anti-TNF-alpha agent as described above that precludes further administration of anti-TNF-alpha agents * If using oral corticosteroids, must be on a stable dose equivalent to less than or equal to 10 mg/day of prednisone for at least 2 weeks prior to the first administration of study agent. If currently not using corticosteroids, must not have received oral corticosteroids for at least 2 weeks prior to the first administration of study agent * If using non nonsteroidal anti-inflammatory drug (NSAIDs) or other analgesics for RA, must be on a stable dose for at least 2 weeks prior to the first administration of study agent * If using non-biologic disease modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine, chloroquine, or bucillamine, must be on a stable dose for at least 4 weeks prior to the first administration of study agent and should have no serious toxic side effects attributable to the DMARD * C-reactive protein (CRP) 8.00 mg/L or more or erythrocyte sedimentation rate (ESR) 28 mm/hr or more at screening
Exclusion criteria
* Has received infliximab, infliximab biosimilar, or golimumab intravenous (IV) within 8 weeks of the first study agent administration * Has received subcutaneously (SC) golimumab, adalimumab, or certolizumab pegol within 6 weeks of the first study agent administration * Has received etanercept or yisaipu within 4 weeks of the first study agent administration * Has a history of intolerance to tocilizumab that precluded further treatment with it, or inadequate response to 3 months of tocilizumab (anti-IL-6 receptor) therapy. Has used tocilizumab within 8 weeks of the first study agent administration * Has used B-cell-depleting therapy (eg, rituximab) within 7 months of first study agent administration or have evidence during screening of abnormally low B-cell level caused by previous B-cell depletion therapy * Has used anakinra within 1 week of first study agent administration * Has used abatacept or any other biologic therapy for the treatment of RA within 8 weeks of the first study agent administration * Has received intra-articular (IA), intramuscular (IM), or IV corticosteroids for RA, including adrenocorticotrophic hormone during the 4 weeks prior to first study agent administration * Has received leflunomide within 24 months before the first study agent administration and has not undergone a drug elimination procedure, unless the M1 metabolite is measured and is undetectable * Has a history of cyclophosphamide or cytotoxic agent use * Has received cyclosporine A, azathioprine, tacrolimus, mycophenolate mofetil, oral or parenteral gold, or D-penicillamine within 4 weeks of the first study agent administration * Has received an investigational drug (including investigational vaccines) or used an investigational medical device within 3 months or 5 half-lives, whichever is longer, before the first study agent administration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving American College of Rheumatology (ACR) 20 Response at Week 16 | Week 16 | The ACR 20 Response is defined as greater than or equal to (\>=) 20 percent improvement in swollen joint count (66 joints) and tender joint count (68 joints) and \>=20 percent improvement in 3 of following 5 assessments: patient's assessment of pain using Visual Analog Scale (VAS; 0-10 scale, 0 =no pain and 10 =worst possible pain), patient's global assessment of disease activity by using VAS (the scale ranges from 0 to 10, \[0 =no pain to 10 =worst possible pain\]), physician's global assessment of disease activity using VAS, participant's assessment of physical function measured by Health Assessment Questionnaire-Disability Index (HAQ-DI, defined as a 20-question instrument assessing 8 functional areas. The derived HAQ-DI ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and serum C-Reactive Protein (CRP). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 24 | Baseline and Week 24 | The HAQ-DI is a 20-question instrument that assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping and activities of daily living). Responses in each functional area are scored from 0 to 3 (0=no difficulty and 3=inability to perform a task in that area). Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. |
| Percentage of Participants Achieving American College of Rheumatology (ACR) 50 Response at Week 24 | Week 24 | The ACR 50 Response is defined as \>= 50 percent improvement in swollen joint count (66 joints) and tender joint count (68 joints) and \>=50 percent improvement in 3 of following 5 assessments: patient's assessment of pain using VAS ( 0-10 scale, 0 =no pain and 10 =worst possible pain), patient's global assessment of disease activity by using VAS (the scale ranges from 0 to 10, \[0 =no pain to 10 =worst possible pain\]), physician's global assessment of disease activity using VAS, participant's assessment of physical function measured by HAQ-DI (defined as a 20-question instrument assessing 8 functional areas. The derived HAQ-DI ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and serum C-Reactive Protein (CRP). |
| Percentage of Participants With Disease Activity Index Score 28 (CRP) Remission at Week 24 | Week 24 | The Disease Activity Index Score 28 (DAS28) based on C-Reactive Protein (CRP) is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP and patient's global assessment of disease activity. The set of 28 joint count is based on evaluation of the shoulder, elbow, wrist, metacarpophalangeal (MCP) MCP1 to MCP5, proximal interphalangeal (PIP) PIP1 to PIP5 joints of both the upper right extremity and the upper left extremity as well as the knee joints of lower right and lower left extremities. The values are 0=best to 10=worst. DAS28 (CRP) remission is defined as a DAS28 (CRP) value of less than (\<) 2.6 at any study visit. |
Countries
Argentina, Australia, Austria, Belgium, Canada, Croatia, France, Germany, Japan, Lithuania, Mexico, Netherlands, New Zealand, Poland, Portugal, Puerto Rico, Russia, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 878 participants (placebo \[n=294\], sirukumab 50 mg every 4 week (q4w) \[n=292\], and sirukumab 100 milligram (mg) every 2 week (q2w) \[n=292\]) were randomized and included in the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received matching placebo every 2 week (q2w) until either early escape (EE) at Week 18, or crossed over (CO) at Week 24. Participants who met EE criteria at Week 18 or crossover (CO) at Week 24 re-randomized and received subcutaneous (SC) sirukumab 50 mg dose regimen q4w up to Week 52. Participants who discontinued or completed study agent administration before and up to Week 52 entered the safety follow-up period as well as those who completed through Week 52 were followed up for safety. | 294 |
| Sirukumab 50 mg q4w All participants received Sirukumab 50 mg SC at Week 0, 4 and q4w up to Week 52. Participants who discontinued or completed study agent administration up to Week 52 and decided to enter the safety follow-up period were followed up for safety from Week 52 to Week 68. | 292 |
| Sirukumab 100 mg q2w All participants received Sirukumab 100 mg SC at Week 0, 2 and q2w up to Week 24. Participants who received matching placebo in the placebo controlled period and met EE criteria at Week 18 or crossover (CO) at Week 24 re-randomized and received subcutaneous (SC) sirukumab 100 mg dose regimen q2w up to Week 52. Participants who discontinued or completed study agent administration up to Week 52 and decided to enter the safety follow-up period were followed up for safety from Week 52 to Week 68. | 292 |
| Total | 878 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Prior to Week 24 | Adverse Event | 11 | 18 | 22 | 0 | 0 |
| Prior to Week 24 | Lack of Efficacy | 15 | 14 | 8 | 0 | 0 |
| Prior to Week 24 | Lost to Follow-up | 0 | 3 | 2 | 0 | 0 |
| Prior to Week 24 | Other | 4 | 7 | 5 | 0 | 0 |
| Prior to Week 24 | Physician Decision | 0 | 3 | 1 | 0 | 0 |
| Prior to Week 24 | Withdrawal by Subject | 12 | 10 | 9 | 0 | 0 |
| Safety Follow-up Period (Week 52-68) | Death | 0 | 0 | 0 | 0 | 1 |
| Safety Follow-up Period (Week 52-68) | Lost to Follow-up | 0 | 1 | 2 | 0 | 1 |
| Safety Follow-up Period (Week 52-68) | Other | 0 | 3 | 9 | 1 | 3 |
| Safety Follow-up Period (Week 52-68) | Withdrawal by Subject | 4 | 6 | 6 | 1 | 3 |
| Week 24 to Week 52 | Adverse Event | 0 | 11 | 14 | 3 | 15 |
| Week 24 to Week 52 | Death | 0 | 0 | 2 | 1 | 0 |
| Week 24 to Week 52 | Lack of Efficacy | 0 | 13 | 7 | 10 | 3 |
| Week 24 to Week 52 | Lost to Follow-up | 0 | 1 | 1 | 1 | 0 |
| Week 24 to Week 52 | Other | 0 | 1 | 5 | 2 | 2 |
| Week 24 to Week 52 | Physician Decision | 0 | 1 | 1 | 0 | 0 |
| Week 24 to Week 52 | Withdrawal by Subject | 0 | 6 | 3 | 0 | 0 |
Baseline characteristics
| Characteristic | Sirukumab 100 mg q2w | Total | Placebo | Sirukumab 50 mg q4w |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants 12.28 | 0 Participants | 0 Participants 12.19 | 0 Participants 11.89 |
| Age, Categorical >=65 years | 62 Participants | 195 Participants | 66 Participants | 67 Participants |
| Age, Categorical Between 18 and 65 years | 230 Participants | 683 Participants | 228 Participants | 225 Participants |
| Age, Continuous | 55 years STANDARD_DEVIATION 12.28 | 55.4 years STANDARD_DEVIATION 12.11 | 55.4 years STANDARD_DEVIATION 12.19 | 55.8 years STANDARD_DEVIATION 11.89 |
| Region of Enrollment Argentina | 3 Participants | 19 Participants | 10 Participants | 6 Participants |
| Region of Enrollment Australia | 0 Participants | 3 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Austria | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Region of Enrollment Belgium | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Canada | 1 Participants | 10 Participants | 2 Participants | 7 Participants |
| Region of Enrollment France | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Germany | 7 Participants | 27 Participants | 7 Participants | 13 Participants |
| Region of Enrollment Italy | 4 Participants | 9 Participants | 5 Participants | 0 Participants |
| Region of Enrollment Japan | 44 Participants | 116 Participants | 37 Participants | 35 Participants |
| Region of Enrollment Lithuania | 5 Participants | 16 Participants | 4 Participants | 7 Participants |
| Region of Enrollment Mexico | 6 Participants | 17 Participants | 7 Participants | 4 Participants |
| Region of Enrollment Netherlands | 1 Participants | 6 Participants | 4 Participants | 1 Participants |
| Region of Enrollment Poland | 26 Participants | 76 Participants | 21 Participants | 29 Participants |
| Region of Enrollment Portugal | 4 Participants | 11 Participants | 3 Participants | 4 Participants |
| Region of Enrollment Puerto Rico | 1 Participants | 8 Participants | 1 Participants | 6 Participants |
| Region of Enrollment Republic of Korea | 5 Participants | 17 Participants | 5 Participants | 7 Participants |
| Region of Enrollment Russian Federation | 21 Participants | 50 Participants | 18 Participants | 11 Participants |
| Region of Enrollment Spain | 7 Participants | 23 Participants | 8 Participants | 8 Participants |
| Region of Enrollment Taiwan, Province of China | 2 Participants | 12 Participants | 8 Participants | 2 Participants |
| Region of Enrollment United Kingdom | 3 Participants | 9 Participants | 2 Participants | 4 Participants |
| Region of Enrollment United States | 152 Participants | 445 Participants | 148 Participants | 145 Participants |
| Sex: Female, Male Female | 240 Participants | 712 Participants | 240 Participants | 232 Participants |
| Sex: Female, Male Male | 52 Participants | 166 Participants | 54 Participants | 60 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 |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 106 / 294 | 50 / 124 | 152 / 292 | 63 / 126 | 169 / 292 | 0 / 28 | 1 / 7 | 2 / 65 | 3 / 19 | 4 / 62 |
| serious Total, serious adverse events | 15 / 294 | 8 / 124 | 51 / 292 | 18 / 126 | 37 / 292 | 0 / 28 | 0 / 7 | 1 / 65 | 2 / 19 | 0 / 62 |
Outcome results
Primary
Percentage of Participants Achieving American College of Rheumatology (ACR) 20 Response at Week 16
The ACR 20 Response is defined as greater than or equal to (\>=) 20 percent improvement in swollen joint count (66 joints) and tender joint count (68 joints) and \>=20 percent improvement in 3 of following 5 assessments: patient's assessment of pain using Visual Analog Scale (VAS; 0-10 scale, 0 =no pain and 10 =worst possible pain), patient's global assessment of disease activity by using VAS (the scale ranges from 0 to 10, \[0 =no pain to 10 =worst possible pain\]), physician's global assessment of disease activity using VAS, participant's assessment of physical function measured by Health Assessment Questionnaire-Disability Index (HAQ-DI, defined as a 20-question instrument assessing 8 functional areas. The derived HAQ-DI ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and serum C-Reactive Protein (CRP).
Time frame: Week 16
Population: Efficacy full analysis set included all participants who were randomized into the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Achieving American College of Rheumatology (ACR) 20 Response at Week 16 | 24.1 Percentage of Participants |
| Sirukumab 50 mg | Percentage of Participants Achieving American College of Rheumatology (ACR) 20 Response at Week 16 | 40.1 Percentage of Participants |
| Sirukumab 100 mg | Percentage of Participants Achieving American College of Rheumatology (ACR) 20 Response at Week 16 | 45.2 Percentage of Participants |
p-value: <0.00195% CI: [8.5, 23.2]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [13.6, 28.5]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 24
The HAQ-DI is a 20-question instrument that assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping and activities of daily living). Responses in each functional area are scored from 0 to 3 (0=no difficulty and 3=inability to perform a task in that area). Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty.
Time frame: Baseline and Week 24
Population: Efficacy full analysis set included all participants who were randomized into the study. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 24 | Baseline | 1.5663 Units on a scale | Standard Deviation 0.65223 |
| Placebo | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 24 | Change at Week 24 | -0.12 Units on a scale | Standard Deviation 0.491 |
| Sirukumab 50 mg | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 24 | Baseline | 1.6499 Units on a scale | Standard Deviation 0.59743 |
| Sirukumab 50 mg | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 24 | Change at Week 24 | -0.31 Units on a scale | Standard Deviation 0.543 |
| Sirukumab 100 mg | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 24 | Baseline | 1.6122 Units on a scale | Standard Deviation 0.6132 |
| Sirukumab 100 mg | Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 24 | Change at Week 24 | -0.33 Units on a scale | Standard Deviation 0.526 |
p-value: <0.00195% CI: [-0.251, -0.088]ANCOVA
p-value: <0.00195% CI: [-0.275, -0.112]ANCOVA
Secondary
Percentage of Participants Achieving American College of Rheumatology (ACR) 50 Response at Week 24
The ACR 50 Response is defined as \>= 50 percent improvement in swollen joint count (66 joints) and tender joint count (68 joints) and \>=50 percent improvement in 3 of following 5 assessments: patient's assessment of pain using VAS ( 0-10 scale, 0 =no pain and 10 =worst possible pain), patient's global assessment of disease activity by using VAS (the scale ranges from 0 to 10, \[0 =no pain to 10 =worst possible pain\]), physician's global assessment of disease activity using VAS, participant's assessment of physical function measured by HAQ-DI (defined as a 20-question instrument assessing 8 functional areas. The derived HAQ-DI ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and serum C-Reactive Protein (CRP).
Time frame: Week 24
Population: Efficacy full analysis set included all participants who were randomized into the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Achieving American College of Rheumatology (ACR) 50 Response at Week 24 | 8.8 Percentage of Participants |
| Sirukumab 50 mg | Percentage of Participants Achieving American College of Rheumatology (ACR) 50 Response at Week 24 | 20.9 Percentage of Participants |
| Sirukumab 100 mg | Percentage of Participants Achieving American College of Rheumatology (ACR) 50 Response at Week 24 | 21.6 Percentage of Participants |
p-value: <0.00195% CI: [6.4, 17.7]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [7, 18.4]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Disease Activity Index Score 28 (CRP) Remission at Week 24
The Disease Activity Index Score 28 (DAS28) based on C-Reactive Protein (CRP) is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP and patient's global assessment of disease activity. The set of 28 joint count is based on evaluation of the shoulder, elbow, wrist, metacarpophalangeal (MCP) MCP1 to MCP5, proximal interphalangeal (PIP) PIP1 to PIP5 joints of both the upper right extremity and the upper left extremity as well as the knee joints of lower right and lower left extremities. The values are 0=best to 10=worst. DAS28 (CRP) remission is defined as a DAS28 (CRP) value of less than (\<) 2.6 at any study visit.
Time frame: Week 24
Population: Efficacy full analysis set included all participants who were randomized into the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Disease Activity Index Score 28 (CRP) Remission at Week 24 | 8.2 Percentage of Participants |
| Sirukumab 50 mg | Percentage of Participants With Disease Activity Index Score 28 (CRP) Remission at Week 24 | 19.2 Percentage of Participants |
| Sirukumab 100 mg | Percentage of Participants With Disease Activity Index Score 28 (CRP) Remission at Week 24 | 21.6 Percentage of Participants |
p-value: <0.00195% CI: [5.5, 16.5]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [7.8, 19.1]Cochran-Mantel-Haenszel