Arthritis, Rheumatoid
Conditions
Keywords
Rheumatoid arthritis, CNTO 136, Sirukumab, Adalimumab, HUMIRA®
Brief summary
The primary objective is to investigate the efficacy of sirukumab monotherapy compared with adalimumab monotherapy in biologic naïve subjects with active rheumatoid arthritis who are intolerant to methotrexate, who are considered inappropriate for treatment with methotrexate or who are inadequate responders to methotrexate.
Detailed description
This is a randomized, double-blind, parallel-group, global, multicenter study of subcutaneous (SC) sirukumab monotherapy compared with adalimumab monotherapy in subjects with active rheumatoid arthritis. Approximately 510 subjects will be randomly assigned in a 1:1:1 ratio to receive treatment with adalimumab 40 mg SC every 2 weeks, sirukumab 100 mg SC every 2 weeks, or 50 mg SC every 4 weeks, with approximately 170 subjects per treatment group. At Week 16, subjects in all treatment groups who have \< 20% improvement from baseline in both swollen and tender joint counts will qualify for early escape. The expected duration of the study is 68 weeks. This includes 52 weeks of treatment with study agent and 16 weeks of safety follow-up after the last study agent administration. The study will end when the last subject completes the last scheduled visit (Week 68 visit or completes the 16 week safety follow-up, whichever is later). Subject safety will be monitored through the end of the study.
Interventions
BIOLOGICALadalimumab 40 mg
SC injections
BIOLOGICALsirukumab 100 mg
SC injections
BIOLOGICALsirukumab 50 mg
SC injections
DRUGPlacebo
SC injections
Sponsors
GlaxoSmithKline
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
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 6 months before screening * Have moderately to severely active RA with at least 8 of 68 tender joints and 6 of 66 swollen joints, at screening and at baseline * Have previous or current treatment with methotrexate (MTX) and are considered intolerant to MTX, and/or are considered inappropriate for treatment with MTX, (including MTX-naïve subjects for whom it is inappropriate to administer MTX) and/or an inadequate responder to methotrexate * Must not have received MTX or any other non-biologic DMARD including but not limited to sulfasalazine, hydroxychloroquine, chloroquine, and bucillamine for at least 2 weeks prior to the first administration of the study agent * C-reactive protein \>= 10.00 mg/L or erythrocyte sedimentation rate \>=28 mm/hr at screening
Exclusion criteria
* Has Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis * Has ever received biologic therapy for RA, including but not limited to the following: TNF-alpha inhibitors, tocilizumab, rituximab, anakinra, abatacept * Has ever used tofacitinib therapy or any other JAK inhibitor * Has received intra-articular, intramuscular, 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Disease Activity Index Score 28 (DAS28) Erythrocyte Sedimentation Rate (ESR) at Week 24 | Baseline and Week 24 | The Disease Activity Index Score 28 using ESR \[DAS28 (ESR)\] is a derived score combining tender joints (28 joints), swollen joints (28 joints), ESR, and Patient's Global Assessment of Disease Activity. The 28 joints evaluated for swelling and tenderness were shoulder, elbow, wrist, MCP1, MCP2, MCP3, MCP4, MCP5, PIP1, PIP2, PIP3, PIP4, PIP5 joints of the upper right and upper left extremities as well as the knee joints of the lower right and lower left extremities. The DAS28-ESR is expressed on a score range of 0-10, with the minimum score= 0 (best) to maximum score= 10 (worst). |
| Percentage of Participants With an American College of Rheumatology (ACR) 50 Response at Week 24 | Week 24 | The ACR 50 Response is defined as greater than or equal to (\>=) 50 percent (%) improvement in swollen joint count (66 joints) and tender joint count (68 joints) and \>= 50% improvement in 3 of following 5 assessments: subject's assessment of pain using Visual Analog Scale (VAS) (0-10 millimeter \[mm\], 0 mm=no pain and 10 mm=worst possible pain), subject's global assessment of disease activity by using VAS (the scale ranges from 0 mm to 100 mm, \[0 mm=no pain to 100 mm=worst possible pain\]), physician's global assessment of disease activity using VAS (the scale ranges from 0 to 10, \[0=no arthritis activity to 10=extremely active arthritis\]), participant's assessment of physical function measured by Health Assessment Questionnaire-Disability Index (HAQ-DI) (the scale 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 |
|---|---|---|
| Percentage of Participants With Disease Activity Index Score 28 (DAS28) Using Erythrocyte Sedimentation Rate (ESR) Remission at Week 24 | Week 24 | The Disease Activity Index Score 28 using ESR \[DAS28 (ESR)\] is a derived score combining tender joints (28 joints), swollen joints (28 joints), ESR, and Patient's Global Assessment of Disease Activity. The 28 joints evaluated for swelling and tenderness were shoulder, elbow, wrist, MCP1, MCP2, MCP3, MCP4, MCP5, PIP1, PIP2, PIP3, PIP4, PIP5 joints of the upper right and upper left extremities as well as the knee joints of the lower right and lower left extremities. The DAS28-ESR is expressed on a score range of 0-10, with the minimum score= 0 (best) to maximum score= 10 (worst). The DAS28 (ESR) remission is defined as a DAS28 (ESR) value of less than 2.6 at a visit. |
| Percentage of Participants With an American College of Rheumatology (ACR) 20 Response at Week 24 | Week 24 | The ACR 20 Response is defined as \>= 20% improvement in swollen joint count (66 joints) and tender joint count (68 joints) and \>=20% improvement in 3 of following 5 assessments: subject's assessment of pain using VAS (0-10 mm, 0 mm=no pain and 10 mm=worst possible pain), subject's global assessment of disease activity by using VAS (the scale ranges from 0 mm to 100 mm, \[0 mm=no pain to 100 mm=worst possible pain\]), physician's global assessment of disease activity using VAS, subject'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 CRP. |
Countries
Bulgaria, Chile, Colombia, Germany, Hungary, Lithuania, Mexico, Moldova, Poland, Romania, Russia, Serbia, South Africa, Spain, Ukraine, United States
Participant flow
Pre-assignment details
A total of 559 participants were randomized and treated. All participants received at least one administration of study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Adalimumab 40 mg Participants received 40 milligram (mg) of adalimumab subcutaneously once every 2 weeks (q2w) for 52 weeks. Participants who met early escape (EE) criteria (had less than 20 percent improvement from baseline in swollen and tender joint counts) at Week 16 received adalimumab 40 mg once every week (q1w) through Week 52. | 186 |
| Sirukumab 50 mg Participants received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 52 weeks and in between placebo SC injections was received at Weeks 2, 6, 10 and 14. Participants who met EE criteria at Week 16 received 100 mg sirukumab every 2 weeks (q2w) from Week 16 through Week 52 and placebo SC injections q2w between the sirukumab injections from Week 16 through Week 50. | 186 |
| Sirukumab 100 mg Participants received 100 mg of sirukumab subcutaneous injections at Weeks 0, 2, and every 2 weeks (q2w) through Week 52. Participants who met EE criteria at Week 16 received placebo injections q2w in between the sirukumab injections through Week 52. | 187 |
| Total | 559 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 14 | 23 | 17 |
| Overall Study | Death | 0 | 1 | 1 |
| Overall Study | Lack of Efficacy | 7 | 4 | 4 |
| Overall Study | Lost to Follow-up | 0 | 2 | 1 |
| Overall Study | Other | 3 | 8 | 6 |
| Overall Study | Physician Decision | 1 | 2 | 0 |
| Overall Study | Pregnancy | 1 | 2 | 2 |
| Overall Study | Withdrawal by Subject | 11 | 10 | 11 |
Baseline characteristics
| Characteristic | Adalimumab 40 mg | Total | Sirukumab 100 mg | Sirukumab 50 mg |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 23 Participants | 73 Participants | 23 Participants | 27 Participants |
| Age, Categorical Between 18 and 65 years | 163 Participants | 486 Participants | 164 Participants | 159 Participants |
| Age, Continuous | 52.6 years STANDARD_DEVIATION 12.15 | 51.6 years STANDARD_DEVIATION 12.36 | 49.8 years STANDARD_DEVIATION 12.31 | 52.5 years STANDARD_DEVIATION 12.46 |
| Region of Enrollment Bulgaria | 1 participants | 2 participants | 0 participants | 1 participants |
| Region of Enrollment Chile | 5 participants | 10 participants | 3 participants | 2 participants |
| Region of Enrollment Colombia | 7 participants | 14 participants | 1 participants | 6 participants |
| Region of Enrollment Germany | 5 participants | 11 participants | 5 participants | 1 participants |
| Region of Enrollment Hungary | 0 participants | 3 participants | 2 participants | 1 participants |
| Region of Enrollment Lithuania | 12 participants | 36 participants | 9 participants | 15 participants |
| Region of Enrollment Mexico | 3 participants | 11 participants | 3 participants | 5 participants |
| Region of Enrollment Moldova | 2 participants | 12 participants | 4 participants | 6 participants |
| Region of Enrollment Poland | 21 participants | 58 participants | 20 participants | 17 participants |
| Region of Enrollment Romania | 4 participants | 13 participants | 4 participants | 5 participants |
| Region of Enrollment Russian Federation | 30 participants | 92 participants | 33 participants | 29 participants |
| Region of Enrollment Serbia | 20 participants | 65 participants | 26 participants | 19 participants |
| Region of Enrollment South Africa | 8 participants | 24 participants | 7 participants | 9 participants |
| Region of Enrollment Spain | 1 participants | 2 participants | 0 participants | 1 participants |
| Region of Enrollment Ukraine | 42 participants | 118 participants | 39 participants | 37 participants |
| Region of Enrollment United States | 25 participants | 88 participants | 31 participants | 32 participants |
| Sex: Female, Male Female | 156 Participants | 467 Participants | 154 Participants | 157 Participants |
| Sex: Female, Male Male | 30 Participants | 92 Participants | 33 Participants | 29 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 |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 71 / 173 | 3 / 13 | 74 / 186 | 79 / 160 | 13 / 26 | 92 / 186 | 86 / 187 |
| serious Total, serious adverse events | 15 / 173 | 1 / 13 | 16 / 186 | 23 / 160 | 6 / 26 | 29 / 186 | 22 / 187 |
Outcome results
Primary
Change From Baseline in Disease Activity Index Score 28 (DAS28) Erythrocyte Sedimentation Rate (ESR) at Week 24
The Disease Activity Index Score 28 using ESR \[DAS28 (ESR)\] is a derived score combining tender joints (28 joints), swollen joints (28 joints), ESR, and Patient's Global Assessment of Disease Activity. The 28 joints evaluated for swelling and tenderness were shoulder, elbow, wrist, MCP1, MCP2, MCP3, MCP4, MCP5, PIP1, PIP2, PIP3, PIP4, PIP5 joints of the upper right and upper left extremities as well as the knee joints of the lower right and lower left extremities. The DAS28-ESR is expressed on a score range of 0-10, with the minimum score= 0 (best) to maximum score= 10 (worst).
Time frame: Baseline and Week 24
Population: Full analysis set was defined as all randomized participants who received at least 1 (partial or complete) dose of study agent. Participants with missing DAS28 (ESR) at baseline were excluded from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Adalimumab 40 mg | Change From Baseline in Disease Activity Index Score 28 (DAS28) Erythrocyte Sedimentation Rate (ESR) at Week 24 | Baseline | 6.89 units on a scale | Standard Deviation 0.851 |
| Adalimumab 40 mg | Change From Baseline in Disease Activity Index Score 28 (DAS28) Erythrocyte Sedimentation Rate (ESR) at Week 24 | Change from Baseline at Week 24 | -2.19 units on a scale | Standard Deviation 1.437 |
| Sirukumab 50 mg | Change From Baseline in Disease Activity Index Score 28 (DAS28) Erythrocyte Sedimentation Rate (ESR) at Week 24 | Baseline | 6.90 units on a scale | Standard Deviation 0.881 |
| Sirukumab 50 mg | Change From Baseline in Disease Activity Index Score 28 (DAS28) Erythrocyte Sedimentation Rate (ESR) at Week 24 | Change from Baseline at Week 24 | -2.58 units on a scale | Standard Deviation 1.524 |
| Sirukumab 100 mg | Change From Baseline in Disease Activity Index Score 28 (DAS28) Erythrocyte Sedimentation Rate (ESR) at Week 24 | Baseline | 6.91 units on a scale | Standard Deviation 0.863 |
| Sirukumab 100 mg | Change From Baseline in Disease Activity Index Score 28 (DAS28) Erythrocyte Sedimentation Rate (ESR) at Week 24 | Change from Baseline at Week 24 | -2.96 units on a scale | Standard Deviation 1.58 |
p-value: <0.00195% CI: [-1.07, -0.46]ANCOVA
p-value: =0.01395% CI: [-0.69, -0.08]ANCOVA
Primary
Percentage of Participants With an American College of Rheumatology (ACR) 50 Response at Week 24
The ACR 50 Response is defined as greater than or equal to (\>=) 50 percent (%) improvement in swollen joint count (66 joints) and tender joint count (68 joints) and \>= 50% improvement in 3 of following 5 assessments: subject's assessment of pain using Visual Analog Scale (VAS) (0-10 millimeter \[mm\], 0 mm=no pain and 10 mm=worst possible pain), subject's global assessment of disease activity by using VAS (the scale ranges from 0 mm to 100 mm, \[0 mm=no pain to 100 mm=worst possible pain\]), physician's global assessment of disease activity using VAS (the scale ranges from 0 to 10, \[0=no arthritis activity to 10=extremely active arthritis\]), participant's assessment of physical function measured by Health Assessment Questionnaire-Disability Index (HAQ-DI) (the scale 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: Full analysis set was defined as all randomized participants who received at least 1 (partial or complete) dose of study agent.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adalimumab 40 mg | Percentage of Participants With an American College of Rheumatology (ACR) 50 Response at Week 24 | 31.7 Percentage of participants |
| Sirukumab 50 mg | Percentage of Participants With an American College of Rheumatology (ACR) 50 Response at Week 24 | 26.9 Percentage of participants |
| Sirukumab 100 mg | Percentage of Participants With an American College of Rheumatology (ACR) 50 Response at Week 24 | 35.3 Percentage of participants |
p-value: 0.30695% CI: [-14.1, 4.4]Cochran-Mantel-Haenszel
p-value: 0.46495% CI: [-6, 13.1]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With an American College of Rheumatology (ACR) 20 Response at Week 24
The ACR 20 Response is defined as \>= 20% improvement in swollen joint count (66 joints) and tender joint count (68 joints) and \>=20% improvement in 3 of following 5 assessments: subject's assessment of pain using VAS (0-10 mm, 0 mm=no pain and 10 mm=worst possible pain), subject's global assessment of disease activity by using VAS (the scale ranges from 0 mm to 100 mm, \[0 mm=no pain to 100 mm=worst possible pain\]), physician's global assessment of disease activity using VAS, subject'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 CRP.
Time frame: Week 24
Population: Full analysis set was defined as all randomized participants who received at least 1 (partial or complete) dose of study agent.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adalimumab 40 mg | Percentage of Participants With an American College of Rheumatology (ACR) 20 Response at Week 24 | 56.5 Percentage of participants |
| Sirukumab 50 mg | Percentage of Participants With an American College of Rheumatology (ACR) 20 Response at Week 24 | 53.8 Percentage of participants |
| Sirukumab 100 mg | Percentage of Participants With an American College of Rheumatology (ACR) 20 Response at Week 24 | 58.8 Percentage of participants |
p-value: 0.60395% CI: [-12.8, 7.4]Cochran-Mantel-Haenszel
p-value: 0.64495% CI: [-7.6, 12.3]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Disease Activity Index Score 28 (DAS28) Using Erythrocyte Sedimentation Rate (ESR) Remission at Week 24
The Disease Activity Index Score 28 using ESR \[DAS28 (ESR)\] is a derived score combining tender joints (28 joints), swollen joints (28 joints), ESR, and Patient's Global Assessment of Disease Activity. The 28 joints evaluated for swelling and tenderness were shoulder, elbow, wrist, MCP1, MCP2, MCP3, MCP4, MCP5, PIP1, PIP2, PIP3, PIP4, PIP5 joints of the upper right and upper left extremities as well as the knee joints of the lower right and lower left extremities. The DAS28-ESR is expressed on a score range of 0-10, with the minimum score= 0 (best) to maximum score= 10 (worst). The DAS28 (ESR) remission is defined as a DAS28 (ESR) value of less than 2.6 at a visit.
Time frame: Week 24
Population: Full analysis set was defined as all randomized participants who received at least 1 (partial or complete) dose of study agent.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adalimumab 40 mg | Percentage of Participants With Disease Activity Index Score 28 (DAS28) Using Erythrocyte Sedimentation Rate (ESR) Remission at Week 24 | 7.5 Percentage of participants |
| Sirukumab 50 mg | Percentage of Participants With Disease Activity Index Score 28 (DAS28) Using Erythrocyte Sedimentation Rate (ESR) Remission at Week 24 | 12.9 Percentage of participants |
| Sirukumab 100 mg | Percentage of Participants With Disease Activity Index Score 28 (DAS28) Using Erythrocyte Sedimentation Rate (ESR) Remission at Week 24 | 20.3 Percentage of participants |
p-value: 0.08695% CI: [-0.7, 11.4]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [5.9, 19.7]Cochran-Mantel-Haenszel