Approval Probability 71%
TA Base Rate26%
Adjusted LOA41%
ML RiskLOW_RISK
| NCT ID | Title | Phase | Status | Enrollment | Velocity | Design | Start | Completion | Last Updated | Sites | Countries |
|---|---|---|---|---|---|---|---|---|---|---|---|
| NCT02019472 | A Study Comparing Sirukumab (CNTO 136) Monotherapy With Adalimumab (HUMIRA®) Monotherapy in the Treatment of Active Rheumatoid Arthritis | PHASE3 | COMPLETED | 559 | — | — | Apr 4, 2014 | Aug 17, 2016 | Oct 26, 2017 | 107 | United States, Bulgaria +14 |
| NCT01856309 | Long-term Safety and Efficacy of Sirukumab in Participants With RA Completing Studies CNTO136ARA3002 or CNTO136ARA3003 | PHASE3 | COMPLETED | 1,820 | — | — | Aug 7, 2013 | Apr 30, 2018 | May 6, 2019 | 197 | United States, Argentina +27 |
| NCT01689532 | A Study of CNTO 136 (Sirukumab) Administered Subcutaneously in Japanese Patients With Active Rheumatoid Arthritis Unresponsive to Methotrexate or Sulfasalazine | PHASE3 | COMPLETED | 122 | — | — | Nov 1, 2012 | Mar 1, 2015 | Oct 27, 2016 | 17 | Japan |
| NCT01604343 | A Study of CNTO 136 (Sirukumab), Administered Subcutaneously, in Patients With Active Rheumatoid Arthritis Despite Disease-Modifying Antirheumatic Drug (DMARD) Therapy (SIRROUND-D) | PHASE3 | COMPLETED | 1,670 | — | — | Aug 15, 2012 | Dec 6, 2016 | Jan 11, 2018 | 156 | United States, Bulgaria +16 |
| NCT01606761 | A Study of CNTO 136 (Sirukumab), a Human Anti-IL-6 Monoclonal Antibody, Administered Subcutaneously, in Patients With Active Rheumatoid Arthritis Despite Anti-TNF-Alpha Therapy (SIRROUND-T) | PHASE3 | COMPLETED | 878 | — | — | Aug 6, 2012 | Jan 12, 2016 | Mar 23, 2018 | 201 | United States, Argentina +20 |
| NCT01636557 | A Study to Evaluate the Effect of a Single Dose of CNTO 136 (Sirukumab) on CYP450 Enzyme Activities After Subcutaneous Administration in Patients With Rheumatoid Arthritis | PHASE1 | COMPLETED | 12 | — | — | Oct 11, 2012 | Oct 19, 2013 | Mar 7, 2017 | 5 | Germany, Moldova +2 |
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 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).
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
MACE was defined as a composite of Myocardial Infarction (MI), stroke, death, hospitalization for unstable angina, and hospitalization for Transient Ischemic Attack (TIA). Adjudication of these events by the Endpoint Adjudication Committee (EAC) was performed in a blinded fashion.
Percentage of participants with one or more malignancy was reported.
Percentage of participants with one or more serious infections was reported.
Percentage of participants with one or more GI perforations was reported. GI perforation is a hole that develops through the entire wall of the stomach, small intestine, large bowel, or gallbladder.
Percentage of participants with hepatobiliary abnormalities was reported.
Percentage of participants with serious or moderate/severe systemic hypersensitivity reactions, or serum sickness adverse events (AEs) was reported.
A TEAE was defined as an event that occurred in the treatment period during which it emerged (that is \[i.e.\] started or worsened in severity, relation, or other attribute), and even if the event continued to be present.
ACR 20 response is greater than or equal to (\>=) 20 percent (%) improvement in both tender joint count (68) and swollen joint count (66) and \>= 20% improvement in 3 of following 5 assessments:Participant's assessment of pain using visual analog scale (VAS) (0-10 scale, 0=no pain and 10=worst possible pain),Participant's global assessment of disease activity by using VAS (scale ranges from 0 to 10, \[0 = very well to 10 = very poor\]), Physician's global assessment of disease activity using VAS (scale ranges from 0 to 10, \[0=no arthritis activity to 10=extremely active arthritis\]), Participant's assessment of physical function as measured by Health Assessment Questionnaire-Disability Index (HAQ-DI) (scale ranges from 0= no difficulty to 3= inability to perform a task in that area), and Serum C-reactive protein (CRP). Participants were analyzed according to randomized treatment groups they were assigned, regardless of treatments they actually received. Here, TF= treatment failure.
The van der Heijde-modified Sharpe (vdH-S) score is defined as a measurement of progression in structural damage. It is the sum of joint erosion (32 joints of the hands and 12 joints of the feet) score and joint space narrowing (JSN) (30 joints of the hands and 12 joints of the feet) score. The joint erosion assessment is scored according to the surface area involved, from 0 to 5, with 0 indicating no erosion and 5 indicating complete collapse of bone whereas the JSN assessment including subluxation, is scored from 0 (normal) to 4 (bony ankylosis or complete luxation). The total score ranges from 0 (best) to 448 (worst) with higher scores indicating more joint damage. Participants were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received. Here, EE= early escape.
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).
Pharmacokinetic parameters will include the maximum observed plasma concentration (Cmax), time to reach the maximum observed plasma concentration (Tmax), area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration (AUClast), area under the plasma concentration-time curve from time 0 to 96 hours (AUC0-96h) (S-warfarin only), area under the plasma concentration versus time curve from time 0 to infinity with extrapolation of the terminal phase (AUCinf).
| Arm | Type | Description |
|---|---|---|
| Group 1 (adalimumab 40 mg) | EXPERIMENTAL | Adalimumab 40 mg SC at Weeks 0, 2, and every 2 weeks through Week 52. At Week 16, subjects who have \< 20% improvement from baseline in both swollen and tender joint counts will early escape in a blinded fashion and receive adalimumab 40 mg every week through Week 52. |
| Group 2 (sirukumab 100 mg) | EXPERIMENTAL | Sirukumab 100 mg SC at Weeks 0, 2, and every 2 weeks through Week 52. Subjects may meet the early escape criteria at Week 16 (\< 20% improvement from baseline in both swollen and tender joint counts) but no sirukumab dose adjustments will made for these subjects. However, these subjects will receive placebo injections every 2 weeks between the sirukumab injections (ie, subjects that early escape will receive a weekly injection of alternating sirukumab and placebo, to preserve the blind). |
| Group 3 (sirukumab 50 mg) | EXPERIMENTAL | Sirukumab 50 mg SC at Weeks 0, 4, and every 4 weeks through Week 52. Between sirukumab injections, placebo SC injections will be administered at Weeks 2, 6, and every 4 weeks through Week 50. At Week 16, subjects who have \< 20% improvement from baseline in both swollen and tender joint counts will early escape in a blinded fashion and receive sirukumab 100 mg every 2 weeks through Week 52 and placebo injections every 2 weeks between the sirukumab injections (ie, subjects that early escape will receive a weekly injection of alternating sirukumab and placebo, to preserve the blind). |
| Sirukumab 100 mg | EXPERIMENTAL | - |
| Sirukumab 50 mg / placebo | EXPERIMENTAL | - |
| Sirukumab 50 mg and Placebo | EXPERIMENTAL | - |
| Placebo then Sirukumab 50 mg or Sirukumab 100 mg | EXPERIMENTAL | - |
| Sirukumab 50 mg + Placebo | EXPERIMENTAL | - |
| Group 1 | EXPERIMENTAL | Patients will receive placebo every 2 weeks from Week 0 through Week 22, followed by a subcutaneous (SC) sirukumab dose regimen every 2 weeks through Week 52. |
| Group 2 | EXPERIMENTAL | Patients will receive sirukumab 100 mg SC at Weeks 0, 2, and every 2 weeks through Week 52. |
| Group 3 | EXPERIMENTAL | Patients will receive sirukumab 50 mg SC at Weeks 0, 4, and every 4 weeks through Week 52. Between sirukumab injections, placebo SC administrations will be made at Weeks 2, 6, and every 4 weeks through Week 52. |
| Sirukumab and 5-probe cocktail | EXPERIMENTAL | The 5-probe cocktail will consist of oral doses of midazolam, warfarin/vitamin K, omeprazole, and caffeine. |
| Name | Type | Description |
|---|---|---|
| adalimumab 40 mg | BIOLOGICAL | SC injections |
| sirukumab 100 mg | BIOLOGICAL | SC injections |
| sirukumab 50 mg | BIOLOGICAL | SC injections |
| Placebo | DRUG | SC injections |
| Sirukumab | DRUG | 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 52 through Week 104. |
| Midazolam | DRUG | Type=exact number, unit=mg/kg, number 0.03, form=commercially available form, route=oral use, on Days 1, 15, 29, and 50 |
| Warfarin | DRUG | Type=exact number, unit=mg, number= 10, form=commercially available form, route=oral use, on Days 1, 15, 29, and 50 |
| Vitamin K | DRUG | Type=exact number, unit=mg, number =10, form=commercially available form, route=oral use, on Days 1, 15, 29, and 50 |
| Omeprazole | DRUG | Type=exact number, unit=mg, number=20, form=commercially available form, route=oral use, on Days 1, 15, 29, and 50 |
| Caffeine | DRUG | Type=exact number, unit=mg, number=100, form=commercially available form, route=oral use, on Days 1, 15, 29, and 50 |
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...