Arthritis, Rheumatoid
Conditions
Keywords
Active rheumatoid arthritis, Ustekinumab, STELARA, CNTO 1959
Brief summary
The purpose of this study is to evaluate the efficacy of ustekinumab and CNTO 1959 in reducing the signs and symptoms of disease in patients with active rheumatoid arthritis (RA) despite concomitant methotrexate (MTX) therapy and to evaluate the safety of ustekinumab and CNTO 1959 in this population.
Detailed description
This is a randomized (patients assigned to treatment by chance), double-blind (study personnel and patients will not know what treatment is being assigned to patients), multicenter, placebo-controlled (a placebo is a treatment identical in appearance to the study agent, but containing no active ingredient), dose-ranging study. Approximately 250 patients will be randomly assigned to 1 of 5 treatment groups. The maximum length of study participation is 54 weeks, including a 6-week screening period. The end of the study will be the last follow-up visit of the last patient. Study visits and evaluations will occur, and patient safety will be monitored throughout the study.
Interventions
DRUGPlacebo + methotrexate (MTX) (Group 1)
Placebo: form = solution for injection, route = subcutaneous use, at Weeks 0, 4, then every 8 weeks (Weeks 12, 20, and 28) + MTX (pre-study dose)
DRUGUstekinumab + MTX (Group 2)
Ustekinumab: type = exact number, unit = mg, number = 90, form = solution for injection, route = subcutaneous use, at Weeks 0, 4, then every 8 weeks (Weeks 12, 20, and 28) + MTX (pre-study dose)
DRUGUstekinumab + MTX (Group 3)
Ustekinumab: type = exact number, unit = mg, number = 90, form = solution for injection, route = subcutaneous use, at Weeks 0, 4, then every 12 weeks (Weeks 16 and 28) + MTX (pre-study dose)
DRUGCNTO 1959 + MTX (Group 4)
CNTO 1959: type = exact number, unit = mg, number = 200, form = powder for solution for injection, route = subcutaneous use, at Weeks 0, 4, then every 8 weeks (Weeks 12, 20, and 28) + MTX (pre-study dose)
DRUGCNTO 1959 + MTX (Group 5)
CNTO 1959: type = exact number, unit = mg, number = 50, form = powder for solution for injection, route = subcutaneous use, at Weeks 0, 4, then every 8 weeks (Weeks 12, 20, and 28)+ MTX (pre-study dose)
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Have had RA for at least 6 months prior to screening * Have a diagnosis of RA according to the revised 1987 criteria of the American Rheumatism Association - Be positive for either anti-cyclic citrullinated peptide antibody or rheumatoid factor in serum at screening * Have been treated with and tolerated MTX for at least 6 months prior to screening, and have a MTX dose of \>= 10 mg and \<= 25 mg per week and stable for at least 12 weeks prior to first administration of study agent * Have active RA, defined as persistent disease activity with both of the following criteria: at least 6 swollen and 6 tender joints at the time of screening and baseline; serum C-reactive protein (CRP) \>= 0.80 mg/dL at screening. The investigator may consider the patient eligible if the CRP value is at least 0.80 mg/dL in a single repeat testing during the screening period * If using oral corticosteroids, must be on a stable dose of \<= 10 mg/day of prednisone or an equipotent dose of another oral corticosteroid for at least 2 weeks prior to the first administration of study agent. If not using corticosteroids at Week 0, the patient must not have received oral corticosteroids for at least 2 weeks prior to the first administration of study agent * If using nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics regularly for RA, the patient must have been on a stable dose for at least 2 weeks prior to the first administration of study agent. If not using NSAIDs or other analgesics for RA at Week 0, the patient must have not received NSAIDs or other analgesics for RA for at least 2 weeks prior to the first administration of study agent
Exclusion criteria
* Has other inflammatory diseases, including but not limited to psoriatic arthritis, ankylosing spondylitis (AS), systemic lupus erythematosus, or Lyme disease, that might confound the evaluation of the benefit of study agent therapy * Has current signs or symptoms of liver insufficiency or cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, psychiatric, or metabolic disturbances that are severe, progressive, or uncontrolled * Has any known malignancy or history of malignancy (with the exception of basal cell carcinoma, squamous cell carcinoma in situ of the skin, or cervical carcinoma in situ that has been treated with no evidence of recurrence, or squamous cell carcinoma of the skin that has been treated with no evidence of recurrence within 5 years prior to the first administration of study agent) * Has a history of lymphoproliferative disease, including lymphoma, or signs suggestive of possible lymphoproliferative disease such as lymphadenopathy of unusual size or location, or clinically significant splenomegaly * Has known allergies, hypersensitivity, or intolerance to ustekinumab or CNTO 1959 or its inactive ingredients * Has ever received any approved or investigational biologic agent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With American College of Rheumatology 20 (ACR 20) Response at Week 28 | Week 28 | The ACR 20 responders are participants with at least 20 percent (%) improvement from Baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: 1) patient's assessment of arthritis pain-visual analog scale, 2) patient's global assessment of disease activity-visual analog scale, 3) physician's global assessment of disease activity-visual analog scale, 4) patient's assessment of physical function as measured by health assessment questionnaire-disability index (HAQ-Di), 5) C-reactive protein (CRP). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Disease Activity Index Score 28 (DAS28; Using C-reactive Protein [CRP]) Score at Week 28 | From Baseline to Week 28 | The DAS28 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 28 joints count, CRP (mG/L) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 \<=3.2 = low disease activity, DAS28 \>3.2 to 5.1 = moderate to high disease activity. |
| Percentage of Participants With American College of Rheumatology 20 (ACR 20) Response at Week 12 | Week 12 | The ACR 20 responders are participants with at least 20 percent (%) improvement from Baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: 1) Patient's Assessment of Arthritis Pain-Visual Analog Scale, 2) Patient's Global Assessment of Disease Activity-Visual Analog Scale, 3) Physician's Global Assessment of Disease Activity-Visual Analog Scale, 4) Patient's Assessment of Physical Function as measured by Health Assessment Questionnaire-Disability Index (HAQ-DI), 5) C-reactive Protein (CRP). |
| Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Week 28 | Baseline and Week 28 | The Health Assessment Questionnaire-Disability Index (HAQ-DI): participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. 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. |
Countries
Argentina, Bulgaria, Chile, Colombia, Czechia, Hungary, Poland, Russia, Singapore, Ukraine, United States
Participant flow
Pre-assignment details
A total of 274 subjects were enrolled into the study and 273 were treated. One participant in the Ustekinumab 90 milligram (mg) every 8 weeks group did not receive the treatment due to an adverse event before dosing.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants randomized to receive matching placebo subcutaneously at Week 0, 4 and then every 8 weeks (Week 12, 20 and 28) along with methotrexate. 16 participants in placebo group early escaped to receive the study drug Ustekinmab. | 55 |
| Ustekinumab 90 mg Every 8 Weeks Participants randomized to receive ustekinumab 90 milligram (mg) subcutaneously at Week 0, 4 and then every 8 weeks (Week 12, 20 and 28) along with methotrexate. | 55 |
| Ustekinumab 90 mg Every 12 Weeks Participants randomized to receive ustekinumab 90 milligram (mg) subcutaneously at Week 0, 4 and then every 12 weeks (Week 16 and 28) along with methotrexate. | 55 |
| CNTO1959 200 mg Every 8 Weeks Participants randomized to receive CNTO1959 200 mg subcutaneously at Week 0, 4 and then every 8 weeks (Week 12, 20 and 28) along with methotrexate. | 54 |
| CNTO1959 50 mg Every 8 Weeks Participants randomized to receive CNTO1959 50 mg subcutaneously at Week 0, 4 and then every 8 weeks (Week 12, 20 and 28) along with methotrexate. | 55 |
| Total | 274 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 2 | 1 |
| Overall Study | Other | 1 | 1 | 2 | 0 | 0 |
| Overall Study | Treatment not completed/Completed f/u | 1 | 1 | 2 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 4 | 0 | 2 | 4 | 5 |
Baseline characteristics
| Characteristic | Ustekinumab 90 mg Every 8 Weeks | Ustekinumab 90 mg Every 12 Weeks | Placebo | CNTO1959 200 mg Every 8 Weeks | CNTO1959 50 mg Every 8 Weeks | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 50.8 years STANDARD_DEVIATION 13.01 | 51.4 years STANDARD_DEVIATION 13.59 | 51.1 years STANDARD_DEVIATION 10.57 | 54.6 years STANDARD_DEVIATION 11.34 | 49.9 years STANDARD_DEVIATION 12.85 | 51.5 years STANDARD_DEVIATION 12.34 |
| Region of Enrollment Argentina | 5 participants | 6 participants | 1 participants | 5 participants | 6 participants | 23 participants |
| Region of Enrollment Bulgaria | 2 participants | 2 participants | 2 participants | 2 participants | 1 participants | 9 participants |
| Region of Enrollment Chile | 1 participants | 1 participants | 1 participants | 1 participants | 2 participants | 6 participants |
| Region of Enrollment Colombia | 9 participants | 8 participants | 10 participants | 6 participants | 10 participants | 43 participants |
| Region of Enrollment CZ Rep | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment Hungary | 5 participants | 2 participants | 6 participants | 4 participants | 3 participants | 20 participants |
| Region of Enrollment Poland | 8 participants | 6 participants | 5 participants | 7 participants | 9 participants | 35 participants |
| Region of Enrollment Russia | 15 participants | 18 participants | 20 participants | 19 participants | 14 participants | 86 participants |
| Region of Enrollment Singapore | 1 participants | 0 participants | 1 participants | 2 participants | 0 participants | 4 participants |
| Region of Enrollment Ukraine | 9 participants | 10 participants | 9 participants | 8 participants | 10 participants | 46 participants |
| Region of Enrollment USA | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Sex: Female, Male Female | 46 Participants | 47 Participants | 48 Participants | 42 Participants | 45 Participants | 228 Participants |
| Sex: Female, Male Male | 9 Participants | 8 Participants | 7 Participants | 12 Participants | 10 Participants | 46 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 55 | 6 / 16 | 15 / 54 | 15 / 55 | 18 / 54 | 14 / 55 |
| serious Total, serious adverse events | 3 / 55 | 1 / 16 | 4 / 54 | 3 / 55 | 3 / 54 | 0 / 55 |
Outcome results
Primary
Percentage of Participants With American College of Rheumatology 20 (ACR 20) Response at Week 28
The ACR 20 responders are participants with at least 20 percent (%) improvement from Baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: 1) patient's assessment of arthritis pain-visual analog scale, 2) patient's global assessment of disease activity-visual analog scale, 3) physician's global assessment of disease activity-visual analog scale, 4) patient's assessment of physical function as measured by health assessment questionnaire-disability index (HAQ-Di), 5) C-reactive protein (CRP).
Time frame: Week 28
Population: The intent-to-treat (ITT) population included all randomized participants. For early escape, data at or prior to Week 16 were carried forward through Week 28.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With American College of Rheumatology 20 (ACR 20) Response at Week 28 | 40.0 percentage of participants |
| Ustekinumab 90 mg Every 8 Weeks | Percentage of Participants With American College of Rheumatology 20 (ACR 20) Response at Week 28 | 52.7 percentage of participants |
| Ustekinumab 90 mg Every 12 Weeks | Percentage of Participants With American College of Rheumatology 20 (ACR 20) Response at Week 28 | 54.5 percentage of participants |
| CNTO1959 200 mg Every 8 Weeks | Percentage of Participants With American College of Rheumatology 20 (ACR 20) Response at Week 28 | 44.4 percentage of participants |
| CNTO1959 50 mg Every 8 Weeks | Percentage of Participants With American College of Rheumatology 20 (ACR 20) Response at Week 28 | 38.2 percentage of participants |
p-value: 0.832Cochran-Mantel-Haenszel
p-value: 0.184Cochran-Mantel-Haenszel
p-value: 0.13Cochran-Mantel-Haenszel
p-value: 0.642Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Disease Activity Index Score 28 (DAS28; Using C-reactive Protein [CRP]) Score at Week 28
The DAS28 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 28 joints count, CRP (mG/L) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 \<=3.2 = low disease activity, DAS28 \>3.2 to 5.1 = moderate to high disease activity.
Time frame: From Baseline to Week 28
Population: The modified-ITT population included participants who received at least 1 (partial or complete) dose of study agent. For early escape, data at or prior to Week 16 were carried forward through Week 28.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Disease Activity Index Score 28 (DAS28; Using C-reactive Protein [CRP]) Score at Week 28 | -0.94 units on scale | Standard Error 0.174 |
| Ustekinumab 90 mg Every 8 Weeks | Change From Baseline in Disease Activity Index Score 28 (DAS28; Using C-reactive Protein [CRP]) Score at Week 28 | -1.52 units on scale | Standard Error 0.185 |
| Ustekinumab 90 mg Every 12 Weeks | Change From Baseline in Disease Activity Index Score 28 (DAS28; Using C-reactive Protein [CRP]) Score at Week 28 | -1.49 units on scale | Standard Error 0.183 |
| CNTO1959 200 mg Every 8 Weeks | Change From Baseline in Disease Activity Index Score 28 (DAS28; Using C-reactive Protein [CRP]) Score at Week 28 | -1.21 units on scale | Standard Error 0.17 |
| CNTO1959 50 mg Every 8 Weeks | Change From Baseline in Disease Activity Index Score 28 (DAS28; Using C-reactive Protein [CRP]) Score at Week 28 | 6.07 units on scale | Standard Error 0.821 |
p-value: 0.019ANCOVA
p-value: 0.025ANCOVA
p-value: 0.248ANCOVA
p-value: 0.045ANCOVA
Secondary
Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Week 28
The Health Assessment Questionnaire-Disability Index (HAQ-DI): participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. 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 28
Population: The m-ITT included participants who received at least 1 (partial or complete) dose of study agent. For early escape, data at or prior to Week 16 were carried forward through Week 28.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Week 28 | -0.30 units on scale | Standard Error 0.074 |
| Ustekinumab 90 mg Every 8 Weeks | Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Week 28 | -0.48 units on scale | Standard Error 0.072 |
| Ustekinumab 90 mg Every 12 Weeks | Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Week 28 | -0.44 units on scale | Standard Error 0.071 |
| CNTO1959 200 mg Every 8 Weeks | Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Week 28 | -0.41 units on scale | Standard Error 0.075 |
| CNTO1959 50 mg Every 8 Weeks | Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Week 28 | -0.39 units on scale | Standard Error 0.076 |
p-value: 0.06ANCOVA
p-value: 0.134ANCOVA
p-value: 0.28ANCOVA
p-value: 0.345ANCOVA
Secondary
Percentage of Participants With American College of Rheumatology 20 (ACR 20) Response at Week 12
The ACR 20 responders are participants with at least 20 percent (%) improvement from Baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: 1) Patient's Assessment of Arthritis Pain-Visual Analog Scale, 2) Patient's Global Assessment of Disease Activity-Visual Analog Scale, 3) Physician's Global Assessment of Disease Activity-Visual Analog Scale, 4) Patient's Assessment of Physical Function as measured by Health Assessment Questionnaire-Disability Index (HAQ-DI), 5) C-reactive Protein (CRP).
Time frame: Week 12
Population: The m-ITT population included participants who received at least 1 (partial or complete) dose of study agent.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With American College of Rheumatology 20 (ACR 20) Response at Week 12 | 29.1 percentage of participants |
| Ustekinumab 90 mg Every 8 Weeks | Percentage of Participants With American College of Rheumatology 20 (ACR 20) Response at Week 12 | 37.0 percentage of participants |
| Ustekinumab 90 mg Every 12 Weeks | Percentage of Participants With American College of Rheumatology 20 (ACR 20) Response at Week 12 | 34.5 percentage of participants |
| CNTO1959 200 mg Every 8 Weeks | Percentage of Participants With American College of Rheumatology 20 (ACR 20) Response at Week 12 | 33.3 percentage of participants |
| CNTO1959 50 mg Every 8 Weeks | Percentage of Participants With American College of Rheumatology 20 (ACR 20) Response at Week 12 | 20.0 percentage of participants |
p-value: 0.381Cochran-Mantel-Haenszel
p-value: 0.543Cochran-Mantel-Haenszel
p-value: 0.629Cochran-Mantel-Haenszel
p-value: 0.273Cochran-Mantel-Haenszel