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.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Arthritis, Rheumatoid	Drug: CNTO 136 100 mg; Drug: CNTO 136 50 mg; Drug: CNTO 136 25 mg; Drug: Placebo; Drug: Methotrexate	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 187 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: August 11, 2008
• Actual Primary Completion Date: March 3, 2011
• Actual Study Completion Date: March 3, 2011

Arms and Interventions

Arm	Intervention/treatment
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.	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: Placebo; Placebo will be adminstered subcutaneously as per the appropriate randomized arm.; Drug: Methotrexate; Stable dose of methotrexate will be maintained through Week 24.
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.	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: Placebo; Placebo will be adminstered subcutaneously as per the appropriate randomized arm.; Drug: Methotrexate; Stable dose of methotrexate will be maintained through Week 24.
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.	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: Placebo; Placebo will be adminstered subcutaneously as per the appropriate randomized arm.; Drug: Methotrexate; Stable dose of methotrexate will be maintained through Week 24.
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.	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: Methotrexate; Stable dose of methotrexate will be maintained through Week 24.
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.	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: Placebo; Placebo will be adminstered subcutaneously as per the appropriate randomized arm.; Drug: Methotrexate; Stable dose of methotrexate will be maintained through Week 24.
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.	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: Placebo; Placebo will be adminstered subcutaneously as per the appropriate randomized arm.; Drug: Methotrexate; Stable dose of methotrexate will be maintained through Week 24.
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.	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.

Outcome Measures

Primary Outcome Measures :

1. 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).

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Florida

Aventura, Florida, United States

United States, Kentucky

Lexington, Kentucky, United States

United States, Maryland

Frederick, Maryland, United States

United States, Michigan

Kalamazoo, Michigan, United States

United States, North Carolina

Charlotte, North Carolina, United States

Winston-Salem, North Carolina, United States

United States, Pennsylvania

Duncansville, Pennsylvania, United States

United States, South Carolina

Anderson, South Carolina, United States

Hungary

Budapest, Hungary

Győr, Hungary

Kecskemét, Hungary

Japan

Goshogawara, Japan

Hitachi, Japan

Kawagoe, Japan

Kitakyushu, Japan

Miyazaki, Japan

Sasebo, Japan

Shinjuku-Ku, Japan

Tomigusuku, Japan

Korea, Republic of

Busan, Korea, Republic of

Dae-Gu, Korea, Republic of

Daejeon, Korea, Republic of

Seoul, Korea, Republic of

Mexico

Ciudad De Mexico, Mexico

Guadalajara, Mexico

Mexico, Mexico

Poland

Bialystok, Poland

Bydgoszcz N/A, Poland

Elblag, Poland

Gdynia, Poland

Krakow, Poland

Lublin, Poland

Poznan, Poland

Warszawa, Poland

Russian Federation

Kemerovo, Russian Federation

Moscow, Russian Federation

Novosibirsk, Russian Federation

St Petersburg, Russian Federation

Sponsors and Collaborators

Centocor, Inc.

Investigators

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Centocor, Inc.
• ClinicalTrials.gov Identifier: NCT00718718
• Other Study ID Numbers: CR015214; C1377T04 ( Other Identifier: Centocor ); 2007-006603-20 ( EudraCT Number )
• First Posted: July 21, 2008
• Results First Posted: December 4, 2017
• Last Update Posted: January 23, 2018
• Last Verified: December 2017

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

Keywords provided by Centocor, Inc.:

Arthritis, Rheumatoid; Rheumatoid Arthritis; Active Rheumatoid Arthritis; CNTO 136; Interleukin-6; Anti-interleukin-6 monoclonal antibody; Methotrexate; Placebo

Additional relevant MeSH terms:

Arthritis; Arthritis, Rheumatoid; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Methotrexate; Antibodies, Monoclonal; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Physiological Effects of Drugs; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Dermatologic Agents; Enzyme Inhibitors; Folic Acid Antagonists; Immunosuppressive Agents; Immunologic Factors; Antirheumatic Agents; Nucleic Acid Synthesis Inhibitors