A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study of CNTO 136 (sirukumab), a Human Anti-IL-6 Monoclonal Antibody, Administered Subcutaneously, in Subjects with Active Rheumatoid Arthritis Despite DMARD Therapy
This is a randomized, double-blind, placebo-controlled, parallel-group, global, multicenter study of sirukumab in subjects with moderately to severely active RA who are refractory to DMARDs, including MTX and sulfasalazine (SSZ).
Approximately 1500 subjects will be randomly assigned in a 1:1:1 ratio to receive treatment with placebo SC q2 weeks, sirukumab SC 100 mg q2 weeks, or 50 mg q4 weeks, with approximately 500 subjects per treatment group.
The placebo-controlled portion is 52 weeks, with opportunities for subjects in the placebo group who have and amp;lt; 20% improvement from baseline in both swollen and tender joint counts to receive sirukumab rescue therapy at Week 18 (Early Escape) or at Week 40 (Late Escape).
At Week 28, subjects in all treatment groups who have and amp;lt; 20% improvement from baseline in both swollen and tender joint counts may receive DMARD or corticosteroid dose initiation or adjustment (DCIA) from that visit onwards.
The expected duration of the study is 120 weeks. This includes 104 weeks of treatment with study agent and 16 weeks of safety follow-up after the last study agent administration. Upon completion of participation through Week 104, subjects will be eligible to enroll in a long-term safety and efficacy study (LTE study). If they elect not to participate in the LTE study, they will continue into safety follow-up for approximately 16 weeks.
Two database locks (DBL) are planned. The first DBL will occur after all subjects have either completed the Week 52 visit or terminated study. The second, planned DBL will occur after all subjects either have completed the Week 104 visit and transitioned in the LTE study, have completed their final safety visit (16 weeks after the administration of study agent) or terminated study participation. The study will end when the last subject completes the Week 104 visit and transitions into the LTE study OR completes the 16 week safety follow-up, whichever is later. The duration of treatment (interval between the first and last administrations of sirukumab or placebo) will be approximately 2
years. The placebo-controlled portion of the study is through Week 52, when placebo subjects will cross over to 1 of 2 sirukumab dose regimens. The study will remain blinded for the duration of the trial.
The primary endpoints are:
* Proportion of subjects who achieve an ACR 20 response at Week 16
* Change from baseline in vdH-S score at Week 52.
Major secondary endpoints are:
* Change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 24
* Proportion of subjects with an ACR 50 response at Week 24
* Proportion of subjects with DAS28 (CRP) remission at Week 24
* Proportion of subjects who achieve major clinical response by Week 52
Study design of Substudy for Respose to Vaccines
This is a multicenter, nonrandomized, open-label, study evaluating the responses to Tdap and pneumococcal vaccines in subjects who have received at least 6 months of treatment in the CNTO136ARA3002 study. Specifically, immune responses to tetanus toxoid and Streptococcus pneumoniae will be evaluated. Since the main study will be blinded during the course of this substudy, subjects entering the substudy will have received either placebo or sirukumab. A total of approximately 145 subjects at selected sites who are still receiving study agent at Week 28, will receive a single administration of the Tdap and pneumococcal vaccines. Subjects will be followed for safety and vaccine responses for 4 weeks.
Each vaccine will be injected intramuscularly and individually in a different arm at the same visit.
Each potential subject must satisfy all of the following criteria to be enrolled in the main study. Each
1. Be a man or a woman of 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) or older.
2. Have a diagnosis of RA (according to the revised 1987 criteria of the ARA) for at least 3 months before screening.
3. Have moderately to severely active RA with at least 6 of 68 tender joints and 6 of 66 swollen joints, at screening and at baseline.
4. Have been refractory to single-agent or combination DMARD therapy that includes MTX or SSZ due to:
* Lack of benefit after at least 12 weeks of DMARD, as assessed by the treating physician.
* Documented lack of benefit may include inadequate improvement in joint counts, physical function, or overall disease activity. It is recommended that subjects should have been exposed to the highest tolerated dose of MTX of up to 25 mg per week.
5. If using oral corticosteroids, must be on a stable dose equivalent to <=10 mg/day of prednisone for at least 2 weeks prior to the first administration of study agent. If currently not using corticosteroids, the subject must not have received oral corticosteroids for at least 2 weeks prior to the first administration of study agent.
6. If using NSAIDs or other analgesics for RA, must be on a stable dose for at least 2 weeks prior to the first administration of study agent.
7. If using non-biologic DMARD such as MTX, SSZ, hydroxychloroquine (HCQ), chloroquine (CQ), or bucillamine, must be on a stable dose for at least 4 weeks prior to the first administration of study agent and should have no serious toxic side effects attributable to the DMARD. If using MTX, the recommended doses are within the range of 7.5 up to 25 mg PO or SC weekly, and treatment should have started at least 6 months prior to the first administration of study agent. If using SSZ, HCQ, CQ or bucillamine, should have started treatment at least 3 months prior to the first
administration of study agent. If currently not using MTX, SSZ, HCQ, CQ, or bucillamine, must not have received these DMARDs for at least 4 weeks prior to the first administration of the study agent.
8. CRP >= 8.00 mg/L at screening.
9. Subjects must meet 1 of the following 3 criteria prior to the first administration of study agent:
(a) anti-CCP antibody-positive at screening,
(b) RF-positive at screening, or
(c) documented history of radiographic evidence of erosive RA in hands or feet prior to the first administration of study agent.
10. Women, sexually active or otherwise capable of pregnancy, must practice a method of birth control, including abstinence, intrauterine device, double barrier method (eg, condoms, diaphragm, or cervical cap with spermicidal foam, cream or gel) or male partner sterilization, consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. If using hormonal contraceptives, including oral, injections and patches, a secondary method of contraception must be used. Contraception must be used for the duration of their participation in the study, and for 4 months after the last study agent administration.The exception to this restriction is if the subject or her male partner is sterilized; this situation does not require birth control.
11. Men, if sexually active with women capable of pregnancy are to use an effective method of birth control and to not donate sperm during the study and for 4 months after the last study agent administration. The exception to this restriction is if the subject or his female partner is sterilized; this situation does not require birth control.
12. Be willing and able to adhere to (a) the prohibitions and restrictions specified in this protocol (b) the study visit schedule.
13. Be able to read, understand, and complete study questionnaires.
14. Sign an informed consent document indicating that they understand the purpose of and
procedures required for the study and are willing to participate in the study.
15. Subjects will be included according to the following TB screening criteria:
a. Have no history of latent or active TB prior to screening unless currently receiving treatment for latent TB and there is no evidence of active TB. An exception is made for subjects who have a history of latent TB (defined for the purposes of this study as having had a positive result from either the tuberculin skin test or the QuantiFERON-TB Gold test prior to screening) and documentation of having completed an adequate treatment regimen for latent TB within 3 years prior to the first administration of study agent under this protocol. These subjects do not need to be retested with the QuantiFERON-TB Gold test (or PPD) during screening. Adequate treatment for latent TB is defined according to local country guidelines for immunocompromised patients. If no local guidelines for
immunocompromised patients exist, US guidelines must be followed. It is the responsibility of the investigator to verify the adequacy of previous anti-TB treatment and provide appropriate documentation.
b. Have no signs or symptoms suggestive of active TB upon medical history and/or physical examination.
c. Have had no recent close contact with a person with active TB or, if there has been such contact, will be referred to a physician specializing in TB to undergo additional evaluation and, if warranted, receive appropriate treatment for latent TB prior to or simultaneously with the first administration of study agent.
d. Within 6 weeks of the first administration of study agent, have a negative QuantiFERON-TB Gold test result or have a newly identified positive QuantiFERON-TB Gold test result in which active TB has been ruled out and for which appropriate treatment for latent TB has been initiated either prior to or simultaneously with the first administration of study agent. A negative tuberculin skin test or a newly identified positive tuberculin skin test result in which active TB has been ruled out and for which appropriate treatment for latent TB has been initiated either prior to or simultaneously with the first administration of study agent is additionally required if the QuantiFERON-TB Gold test is not approved/registered in that country. An exception is
made for subjects who have a history of latent TB (a
positive result from either the tuberculin skin test or
the QuantiFERON-TB Gold test prior to screening) and documentation of having completed an adequate treatment regimen for latent TB within 3 years prior to the first administration of study agent. These subjects do not need to be retested with the QuantiFERON-TB
Gold test (or PPD) during screening.
e. Have a chest radiograph (both posterior-anterior (PA) and lateral view[s] unless local guidelines recommend only a single view), taken within 3 months of the first administration of study agent and read by a qualified pulmonologist or radiologist, with no evidence of current, active TB or old, inactive TB.
16. Sign the informed consent form (ICF) for pharmacogenetics research indicating willingness to participate in the pharmacogenetics component of the study (in order to participate in the optional pharmacogenetics component of this study) where local regulations permit. Refusal to give consent for this component does not exclude a subject from participation in the clinical study.
Substudy for Response to Vaccines:
1. Be currently enrolled in the CNTO136ARA3002 study.