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 Anti-TNF(RegisteredTM) Therapy
This is a randomized, double-blind, placebo-controlled parallel-group multicenter study of sirukumab in
subjects with moderately to severely active Ra who are refractory or intolerant to anti-TnF[RegisteredTM] therapy.
approximately 840 subjects will be randomly assigned in a 1:1:1 ratio to receive treatment with
sirukumab placebo SC q2 weeks, sirukumab SC 100 mg q2 weeks, or 50 mg q4 weeks. Subjects in the
placebo group will cross over to receive sirukumab at Week 24. The expected duration of the study is
68 weeks. This includes 52 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 52, subjects will be
eligible to enroll in a long-term safety and efficacy (LTe) study. if they do not participate in the LTe
study they will continue into follow-up of approximately 16 weeks after the last study agent
Group 1 (n [?] 280): Placebo q2 weeks from Week 0 through Week 22, followed by a SC sirukumab
dose regimen through Week 52.
Group 2 (n [?] 280): Sirukumab 100 mg SC at Weeks 0, 2, and q2 weeks through Week 52.
Group 3 (n [?] 280): Sirukumab 50 mg SC at Weeks 0, 4, and q4 weeks through Week 52. Between
sirukumab injections, placebo SC at Weeks 2, 6, and q4 weeks through Week 52.
early escape (Week 18)
at Week 18, subjects who have [Less Than] 20% improvement from baseline in both swollen and tender joint
counts will enter early escape in a blinded fashion. Subjects in Group 1 (placebo) will be re-randomized
to Group 2 or 3 to receive a sirukumab dose regimen from Week 18 through Week 52. Subjects inGroups 2 and 3 may meet the early escape criteria defined above; however, no dose adjustments will
made for subjects in these groups at Week 18. For details see Section 5.1.
Group 1 (placebo): Subjects will start a sirukumab dose regimen from Week 18 through Week 52.
Subjects assigned to sirukumab 50 mg SC q4 weeks, will be administered a dose of sirukumab 50 mg at
Week 18, then at Week 20 and q4 weeks through Week 52. Subjects assigned to sirukumab 100 mg SC
q2 weeks, will be administered a dose of sirukumab 100 mg at Week 18, then at Week 20 and q2 weeks
through Week 52.
Group 2 (sirukumab 100 mg): Subjects will continue sirukumab 100 mg SC q2 weeks through Week 52.
Group 3 (sirukumab 50 mg): Subjects will continue sirukumab 50 mg SC q4 weeks through Week 52.
The efficacy evaluations chosen for this study are consistent with Health authority regulatory guidance
and precedent established in previous studies of therapeutic biologic agents for the treatment of Ra.
Ra response evaluations include:
* aCR 20 and aCR 50 responses
* aCR Core Set
* Disease activity index Score 28 (DaS28)
* Health assessment Questionnaire-Disability index (HaQ-Di)
* aCR/The european League against Rheumatism (euLaR) remission
aCR 20 and aCR 50 responses, the aCR core set, and DaS28 are widely accepted standard endpoints
for demonstrating therapeutic efficacy of reduction of signs and symptoms of Ra. The HaQ-Di is the
established, validated standard physical function outcome used to demonstrate prevention of disability in
Ra studies. The aCR/euLaR provisional definitions of disease remission represent a minimal disease
activity state that is an increasingly attainable treatment goal with the growth in the armamentarium of
effective Ra therapies
Patient Reported outcome (PRo) evaluations include:
* Proportion of subjects who achieve an aCR 20 response at Week 16.
Major Secondary endpoints
* Change from baseline in 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
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 ARA2) for at least
3 months before screening.
3. Have moderately to severely active RA with at least 4 of 68 tender joints and 4 of
66 swollen joints, at screening and at baseline.
4. Have had anti-TNF(RegisteredTM) therapy and were refractory by 1 of the following 2 reasons:
a. Lack of benefit to at least 1 anti-TNF(RegisteredTM) biologic therapy, as assessed by the treating
physician, after at least 12 weeks of etanercept, yisaipu, adalimumab, golimumab, or
certolizumab pegol therapy and/or at least a 14 week dosage regimen (ie, at least 4
doses) of infliximab. Documented lack of benefit may include inadequate
improvement in joint counts, physical function, or disease activity.
b. Intolerance to at least 2 anti-TNF(RegisteredTM) biologic therapy, as assessed by the treating
physician, to etanercept, yisaipu, adalimumab, golimumab, certolizumab pegol, or
infliximab or have documented intolerance to an anti-TNF(RegisteredTM) agent as described
above that precludes further administration of anti-TNF(RegisteredTM) agents.
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 DMARDs such as MTX, sulfasalazine (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 or ESR of >= 28 mm/hr 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) 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.
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 (Appendix B) or
the QuantiFERON-TB Gold test (Appendix A) 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
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. Subjects with repeatedly indeterminate QuantiFERON(RegisteredTM)-TB Gold test results from 2 samples tested in screening are ineligible.
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.