A Study of Effectiveness and Safety of CNTO 136 in Patients With Active Rheumatoid Arthritis Despite Methotrexate Therapy

• ClinicalTrials.gov Identifier: NCT00718718
• Recruitment Status: Completed
• First Posted: July 21, 2008
• Results First Posted: December 4, 2017
• Last Update Posted: January 23, 2018
• Sponsor: Centocor, Inc.
• Information provided by (Responsible Party): Centocor, Inc.

Tracking Information

• First Submitted Date: July 17, 2008
• First Posted Date: July 21, 2008
• Results First Submitted Date: October 22, 2017
• Results First Posted Date: December 4, 2017
• Last Update Posted Date: January 23, 2018
• Actual Study Start Date: August 11, 2008
• Actual Primary Completion Date: March 3, 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 22, 2017)

Percentage of Participants With an American College of Rheumatology (ACR) 50 Response at Week 12 (Part B) [ Time Frame: Week 12 ]

An American College of Rheumatology (ACR) 50 response is defined as greater than or equal to (>=) 50 percent (%) improvement in both tender joint count (68 joints) and swollen joint count (66 joints) and >= 50% improvement in 3 of the following 5 assessments: participant's assessment of pain using Visual Analogue Scale (Score) VAS (0-10 scale, 0=no pain and 10=worst possible pain), participant's global assessment of disease activity by using VAS (the scale ranges from 0 to 10, [0 = very well to 10 = very poor]), 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 as 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).

• Original Primary Outcome Measures (submitted: July 17, 2008): The primary outcomes in Part A are the safety and the effectiveness of CNTO 136 as measured by the Disease Activity Score (DAS) 28 response at Week 12. The primary outcome in Part B is the American College of Rheumatology (ACR) 50 response at Week 12

Current Secondary Outcome Measures (submitted: October 22, 2017)

• Change From Baseline in Disease Activity Index Score 28 (DAS28) Based on C-reactive Protein (CRP) at Week 12 (Part A and Part B) [ Time Frame: Baseline, Week 12 ]
  The 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. A negative change from baseline in DAS28 (CRP) (that is, a decrease from baseline) indicates improvement from baseline.
• Percentage of Participants With American College of Rheumatology (ACR) 50 Response at Week 12 (Part A) [ Time Frame: Week 12 ]
  An ACR 50 response is defined as >= 50% improvement in both tender joint count (68 joints) and swollen joint count (66 joints) and >= 50% improvement in 3 of the following 5 assessments: Participant's assessment of pain using VAS (0-10 scale, 0=no pain and 10=worst possible pain), Participant's global assessment of disease activity by using VAS (the scale ranges from 0 to 10, [0 = very well to 10 = very poor]), 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 as measured by HAQ-DI (the scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area), and Serum CRP.
• Serum Sirukumab Concentrations Through Week 38 (Part A) [ Time Frame: Week 0, Day 2, Day 5, Day 8, Day 11, Week 2, Week 4, Week 8, Week 10, Week 10 Day 4, Week 10 Day 7, Week 12, Week 14, Week 18, Week 22, Week 24, and Week 38 ]
  Sirukumab Concentrations in serum were measured.
• Serum Sirukumab Concentrations Through Week 38 (Part B) [ Time Frame: Week 0, Day 5, Day 8, Day 11, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 24 Day4, Week 24 Day7, Week 26, Week 28, Week 30, Week 34 and Week 38 ]
  Sirukumab Concentrations in serum were measured.
• Percent Improvement From Baseline in Serum C-Reactive Protein (CRP) At Week 2 (Part A and Part B) [ Time Frame: Baseline, Week 2 ]
  Serum CRP is a marker of systemic inflammation. A negative change from baseline in CRP represents improvement.

• Original Secondary Outcome Measures (submitted: July 17, 2008): Secondary outcomes include change from baseline in Disease Activity Score (DAS) 28 response at Week 12, serum CNTO 136 concentrations, and percent change from baseline in serum C-reactive protein at Week 2.
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Effectiveness and Safety of CNTO 136 in Patients With Active Rheumatoid Arthritis Despite Methotrexate Therapy
• Official Title: A Phase 2, 2-Part, Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled, Proof-of-concept, Dose-finding Study Evaluating the Efficacy and Safety of CNTO 136 Administered Subcutaneously in Subjects With Active Rheumatoid Arthritis Despite Methotrexate Therapy
• Brief Summary: The purpose of this study is to evaluate the effectiveness and safety of subcutaneous (under the skin) administration of anti-interleukin-6 monoclonal antibody (CNTO 136) in reducing signs and symptoms of participants with active rheumatoid arthritis (RA) with methotrexate (MTX) therapy.
• Detailed Description: This is a multicenter, double-blind (neither physician nor participants knows the treatment that the participant receives), randomized (study medication is assigned by chance), placebo-controlled (an inactive substance is compared with a medication to test whether the medication has a real effect in a clinical study) study. This study will be conducted in 2 parts (Part A and Part B). Each part consists of 3 phases: screening (approximately 1 month prior to the start of study medication), treatment phase (Part A: 22 weeks and Part B: 24 weeks), and follow-up phase (approximately 4 months after the last administration of study medication). In Part A, participants will be randomly assigned to 2 groups to receive CNTO 136 100 mg and placebo for 22 weeks. All participants in Part A, will be crossed over at Week 12 from placebo to CNTO 136 (for Group 1) and from CNTO 136 to placebo (for Group 2). In Part B, participants will be randomly assigned to 5 groups to receive placebo and/or 1 of 3 doses of CNTO 136 (100mg, 50mg or 25mg) for 24 weeks. Participants in Part B, Group 1 will be crossed over at Week 12 from placebo to CNTO 136. All participants should be maintained on a stable dose of MTX for at least 6 weeks prior to the start of study medication through Week 24. Safety will be evaluated by the assessment of adverse events, vital signs, clinical findings, 12-lead electrocardiogram, and clinical laboratory tests which will be monitored throughout the study. The total duration of study participation for a participant will be approximately 42 weeks.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Arthritis, Rheumatoid

Intervention

• Drug: CNTO 136 100 mg
  CNTO 136 100 mg will be administered subcutaneously (under the skin) every 2 or 4 weeks as per the appropriate randomized arm.
  Other Name: Sirukumab
• Drug: CNTO 136 50 mg
  CNTO 136 50 mg will be administered subcutaneously every 4 weeks from Week 0 to Week 24.
  Other Name: Sirukumab
• Drug: CNTO 136 25 mg
  CNTO 136 25 mg will be administered subcutaneously every 4 weeks from Week 0 to Week 24.
  Other Name: Sirukumab
• Drug: Placebo
  Placebo will be adminstered subcutaneously as per the appropriate randomized arm.
• Drug: Methotrexate
  Stable dose of methotrexate will be maintained through Week 24.

Study Arms

• Experimental: Part A, Group 1
  Participants will receive placebo (Week 0 to Week 10) and later CNTO 136 100 mg (Week 12 to Week 22) every 2 weeks. Stable dose of methotrexate will be maintained through Week 24.
  Interventions:

  • Drug: CNTO 136 100 mg
  • Drug: Placebo
  • Drug: Methotrexate
• Experimental: Part A, Group 2
  Participants will receive CNTO 136 100 mg (Week 0 to Week 10) and later placebo (Week 12 to Week 22) every 2 weeks. Stable dose of methotrexate will be maintained through Week 24.
  Interventions:

  • Drug: CNTO 136 100 mg
  • Drug: Placebo
  • Drug: Methotrexate
• Experimental: Part B, Group 1
  Participants will receive placebo (Week 0 to Week 10) and later CNTO 136 100 mg (Week 12 to Week 24) every 2 weeks. Stable dose of methotrexate will be maintained through Week 24.
  Interventions:

  • Drug: CNTO 136 100 mg
  • Drug: Placebo
  • Drug: Methotrexate
• Experimental: Part B, Group 2
  Participants will receive CNTO 136 100 mg (Week 0 to Week 24) every 2 weeks. Stable dose of methotrexate will be maintained through Week 24.
  Interventions:

  • Drug: CNTO 136 100 mg
  • Drug: Methotrexate
• Experimental: Part B, Group 3
  Participants will receive CNTO 136 100 mg (Week 0 to Week 24) every 4 weeks and placebo at interim visits (Weeks 2, 6, 10, 14, 18, and 22). Stable dose of methotrexate will be maintained through Week 24.
  Interventions:

  • Drug: CNTO 136 100 mg
  • Drug: Placebo
  • Drug: Methotrexate
• Experimental: Part B, Group 4
  Participants will receive CNTO 136 50 mg (Week 0 to Week 24) every 4 weeks and placebo at interim visits (Weeks 2, 6,10, 14, 18, and 22). Stable dose of methotrexate will be maintained through Week 24.
  Interventions:

  • Drug: CNTO 136 50 mg
  • Drug: Placebo
  • Drug: Methotrexate
• Experimental: Part B, Group 5
  Participants will receive CNTO 136 25 mg (Week 0 to Week 24) every 4 weeks and placebo at interim visits (Weeks 2, 6,10, 14, 18, and 22). Stable dose of methotrexate will be maintained through Week 24.
  Interventions:

  • Drug: CNTO 136 25 mg
  • Drug: Placebo
  • Drug: Methotrexate

• Publications *: Smolen JS, Weinblatt ME, Sheng S, Zhuang Y, Hsu B. Sirukumab, a human anti-interleukin-6 monoclonal antibody: a randomised, 2-part (proof-of-concept and dose-finding), phase II study in patients with active rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis. 2014 Sep;73(9):1616-25. doi: 10.1136/annrheumdis-2013-205137. Epub 2014 Apr 3.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 17, 2011): 187
• Original Estimated Enrollment (submitted: July 17, 2008): 160
• Actual Study Completion Date: March 3, 2011
• Actual Primary Completion Date: March 3, 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Diagnosed with rheumatoid arthritis (RA) for at least 4 months prior to screening
• Have been treated and having an inadequate response with the tolerated dose of methotrexate (MTX) (at least 15mg/week) for at least 4 months prior to screening. MTX doses of 10 or 12.5 mg/week are allowed if participant had intolerance of 15 mg/week
• MTX route of administration and dose (not to exceed 25 mg/week) should be stable for at least 6 weeks prior to the start of the study medication
• Have active RA as defined by persistent disease activity with at least 6 swollen and 6 tender joints, at the time of screening and baseline, and either anti-cyclic citrullinated peptide antibody-positive or rheumatoid factor positive at screening
• C-reactive protein greater than or equal to 1.0 mg/dL (10 mg/L)
• Agree to use one of the contraception methods defined in the protocol

Exclusion Criteria:

• Have inflammatory diseases other than RA that might confound the evaluation of the benefit of CNTO 136 therapy in arthritis
• Family history of/ have long QT syndrome; or a history of second or third-degree heart block
• Received systemic immunosuppressives or disease modifying antirheumatic drug other than MTX, sulfasalazine, hydroxychloroquine or chloroquine within 4 weeks prior to the start of study medication
• Received intra articular (into joints), intramuscular, or intravenous corticosteroids within 4 weeks prior to the start of study medication
• Positive human immunodeficiency virus test, hepatitis B or hepatitis C
• History of / have chronic or recurrent infectious disease, history of / active tuberculosis
• Have serious infection within 2 months prior to start of study medication

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Hungary, Japan, Korea, Republic of, Mexico, Poland, Russian Federation, United States
• Removed Location Countries: Argentina, Taiwan, Ukraine

Administrative Information

• NCT Number: NCT00718718
• Other Study ID Numbers: CR015214; C1377T04 ( Other Identifier: Centocor ); 2007-006603-20 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Centocor, Inc.
• Original Responsible Party: Not Provided
• Current Study Sponsor: Centocor, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Centocor Clinical Trial; Centocor, Inc.

• PRS Account: Centocor, Inc.
• Verification Date: December 2017