CMAB008 With MTX Therapy in Adult Patients With Moderately to Severely Active Rheumatoid Arthritis

A Randomized, Double-blind, Methotrexate (MTX) Based, Parallel-group, Multicenter Phase III Study to Evaluate Efficacy and Safety of CMAB008 in Adult Patients With Moderately to Severely Active Rheumatoid Arthritis, Compared to Remicade

CMAB008 is an infliximab biosimilar candidate. The host cell of Remicade is mouse myeloma SP2/0 cell, however, the host cell of CMAB008 is CHO (Chinese hamster ovary cell). It seems that CMAB008 has lower immunogenicity and higher safety, because Remicade comprises more complex-type and hybrid-type glycans than CMAB008. However, it is not yet known whether CMAB008 is not inferior to Remicade. This randomized, double-blind trial investigates the efficacy and safety of CMAB008 for moderately to severely active rheumatoid arthritis, compared to Remicade.

This is a non-inferiority trial. The primary outcome is the percentage of subjects achieving ACR20. According to the global instruction of Remicade, the effective rate of Remicade is 50%, and the placebo is 20%. Calculate the critical value δ=（50%-20%）×50%=15%, one-side α=0.025, β=0.20, experimental group : control group = 1:1, the results are: CMAB008 group 175 participants, control group 175 participants, 350 participants in total. Take 10% drop-out into consideration, the finial sample sizes are: CMAB008 group 196 participants, control group 196 participants, 392 participants in total.

During the entire duration of the study, all adverse events (AE) and all serious adverse events (SAEs) are collected, fully investigated and documented in source documents and case report forms (CRF). Study duration encompassed the time from when the participant sign the informed consent until the last protocol-specific procedure has been completed, including a safety follow up period.

This study will be conducted in compliance with the protocol, the current version of the Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) as well as all national legal and regulatory requirements.

Inclusion Criteria:

1. Age≥18 years, males or females;
2. Diagnosis of rheumatoid arthritis according to American College of Rheumatology (ACR) 1987 Revised Criteria for the Classification of Rheumatoid Arthritis, and in moderately to severely active stage during screening;
3. Have had one or more DMARDs failure (defined as "failure of traditional/conventional DMARD(s) due to lack of efficacy/desired response or side effects" according to 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis);
4. Non-use of DMARDs (including: Chloroquine, Hydroxychloroquine, Gold Compound, Penicillamine, Salicylazosulfapyridine, Azathioprine, Cyclophosphamide, Cyclosporine A, Leflunomide, Thalidomide etc.) except for MTX in the last 4 weeks before screening;
5. Have completed at least 3 months of treatment with MTX, and steadily at the dosage of 7.5mg~15mg/w at least 4 weeks prior to screening;
6. Non-use of Non-steroidal Anti-inflammatory Drugs (NSAIDs) in the last 2 weeks before enrollment, or if using NSAIDs, should stabilize dose at least 2 weeks;
7. Non-use of glucocorticoid (including intramuscular corticotropin) systematically (e.g., oral administration, intramuscular or intravenous injection) or intra-articular injection; or if concurrent taking glucocorticoid orally, dose (equivalent to the dose of Prednisone) should stabilize≤10mg/d at least 4 weeks;
8. Non-use of Chinese medicine (e.g., Tripterygium, Total Glucosides of Paeony Capsules) for rheumatoid arthritis in the last 4 weeks before screening;
9. Pregnancy test should be negative for procreative female, or not lactating. Both male and female subjects should consent to take effective contraception throughout the study and at least 6 months after the study;
10. Signed the informed consent form;
11. Can participate in visits on schedule;
12. Can understand and complete assessment forms correctly.

Exclusion Criteria:

1. Weight>75Kg;

2. Inoculated live (attenuated) viral/bacterial vaccine in the last 4 weeks before screening;

3. Use of biologicals (including but nor limited to Infliximab, Etanercept, Adalimumab, Tocilizumab, Rituximab etc.) for rheumatoid arthritis in the last 3 months before screening;

4. Severe infection (e.g., acute hepatitis, pneumonia, acute pyelonephritis) in the last 2 months before enrollment, or previous hospitalization due to infection, or previous use of antibiotics, antifungal or antiviral drugs due to infection. However, low-grade infection (e.g., acute upper respiratory infections, simplex urinary tract infection) is not considered as exclusion criteria, whether the subject can be chosen depends on investigator;

5. Suffering from acute infection or recurrent infections disease during screening, e.g., respiratory system infection (influenza, upper respiratory infection, bronchiectasia etc.), acute episode of chronic pyelonephritis, infectious skin wound etc,;

6. Previous opportunistic infection (e.g., herpes zoster, active cytomegalovirus, mycoplasma, pneumocystis pneumonia, histoplasma, aspergillus, mycobacteria except for mycobacterium tuberculosis) in the last 6 months before screening;

7. History of prosthetic joint infections, or suspicious prosthetic joint infections with antibiotic therapy and unremoved prosthetic joint;

8. History of severe hepatic diseases; or HbsAg positive; or only HbcAb positive in Second Liver 5 Indexes, and HBV-DNA positive; or HCV-infected patient;

9. AIDS-infected patient or HIVpositive;

10. One of the following situations relating to tuberculosis:

    1. Concurrent or previous active tuberculosis. Chest X-ray examination (suggest chest anteroposterior and lateral position films) should be performed in the last 3 months before screening, to provide evidence for concurrent or previous tuberculosis;
    2. Intimate contact with active tuberculosis patient recently; or high-risk and/or immunocompromised group (e.g., long-term use of glucocorticoids, immunosuppressor), and with any signs of latent tuberculosis infection;
    3. PPD test (inject 5IU TB-PPD intradermally, measure the diameter of skin induration 72 hours later) performed in the last 3 weeks before screening: diameter of induration≤15mm, and with vesicle or necrosis; or diameter of induration>15mm;
    4. If cannot perform PPD test, perform T-SPOT test: T-SPOT test positive, chest file and clinical evidence indicate that the patient is unsuitable for participation;

11. History of organ allograft operation (except for keratoplasty more than 3 months before the first use of investigational drug);

12. Concurrent or previous malignant tumor (except for total excision and no recurrence of cutaneous squamous cell carcinoma, basal-cell carcinoma or carcinoma in situ of cervix) in the last 5 years before screening;

13. History of lymphoid malignancies (lymphoma) or lymphoproliferative disease; or symptoms and signs indicate that may be lymphoproliferative disease (e.g., lymph node enlargement at neck, clavicle or axilla) during screening; or splenomegaly (≥subcostal 2cm);

14. Concurrent or previous demyelinating diseases of the central nervous system (e.g., multiple sclerosis);

15. Concurrent or previous congestive heart failure;

16. Concurrent or previous other autoimmune disease, and may be expected to affect the assessment of investigational drug;

17. Severe, progressive, uncontrolled cardiovascular, hepatic, renal, pulmonic, gastrointestinal, hematopoietic, endocrine, neural diseases, or other situations that the patient is considered as unsuitable for participation by investigator;

18. History of severe drug or alcohol abuse with clinical symptoms; history of poor drug compliance; or other situations that may interfere protocol compliance (e.g., mental disease, frequent travel, lack of willingness);

19. Laboratory tests results meet one of the following indexes: HGB<8.5g/dL, WBC<3.5*10^9/L, PLT<80*10^9/L, ALT/AST>2*upper limit of normal value, CREA>upper limit of normal value;

20. Allergic reaction against human immunoglobulin, infliximab or other ingredient;

21. Participation in another drug clinical trial in the last 30 days before screening or within 5 half-lives of drug (longer time shall prevail).