Efficacy and Safety of CMAB008 Compared with Innovator Infliximab in Patients with Moderate-to-Severe Rheumatoid Arthritis Receiving Concomitant Methotrexate: A Randomized, Double-blind, Multi-center, Phase III Non-inferiority Study

Patients

The study recruited patients aged ≥ 18 with RA according to the 1987 American College of Rheumatology (ACR) classification criteria. Eligible patients had moderate-to-severe active disease with Disease Activity Score (DAS28) score ≥ 3.2 at screening and experienced at least one type of disease-modifying antirheumatic drugs (DMARDs) failure; subjects had to have received MTX for ≥ 3 months and with a fixed dose 7.5–15 mg/week for ≥ 4 weeks without any other DMARDs. Oral glucocorticoids treatment with a stable dose below the equivalent dose of 10 mg/day prednisone for ≥ 4 weeks and a stable dose of NSAIDs for ≥ 2 weeks prior to randomization were permitted, but the use of any traditional Chinese medicine for  ≥ 4 weeks before screening, intramuscular injection, intravenous injection and intra-articular injection of glucocorticoids, and intramuscular adrenocorticotropic hormone were not allowed. Tuberculosis (TB) and latent TB were excluded. For more details of inclusion and exclusion criteria, see Supplementary Materials.

Study Design

The study was a randomized, double-blinded, parallel, positive-control design, multicenter study. It consisted of a stratified block randomization method by study centers. The subjects were enrolled with a ratio of 1:1 to receive intravenous CMAB008 or infliximab combined with background MTX therapy. Blindness was maintained from a generation of random numbers, numbering of the study drugs, enrollment and medication of subjects, recording and evaluation of study results, and monitoring of the study process, and data management. CMAB008 and infliximab were completely the same in respect to dosage form, appearance, description, and odor, etc. The vial label of both CMAB008 and infliximab adopted the name of “Recombinant Anti-Tumor Necrosis Factor-α Human-Mouse Chimeric Monoclonal Antibody for Injection”. Both investigators and patients were blinded to treatment assignment. Patients in two groups were treated with the same dose of 3 mg/kg except those weighing 67–75 kg, who were administered 200 mg/dose, at weeks 0, 2, 6, 14, 22, and 30. All subjects received combined treatment of oral MTX at a fixed does of 7.5–15 mg/week.

The efficacy was evaluated at weeks 2, 6, 14, 22, and 30, and safety evaluation was up to week 38. Any adverse event (AE) must be recorded throughout the study and the outcome should be followed up unless a withdrawal of the informed consent. The pharmacokinetic (PK) population was selected from certain specified sites for assessing PK profiles, whose blood samples were collected.

The study was conducted according to the Declaration of Helsinki and the criteria for the Quality Control of Clinical Trial of drugs, registered with ClinicalTrials.gov (NCT03478111). The study was carried out at 31 centers in China with reviews and approvals of regulatory authorities and the ethics committees of each center. Written informed consent was obtained from all patients.

Study EndpointsEfficacy

The primary efficacy endpoint was the ratio of subjects achieving American College of Rheumatology criteria (28 joints) for 20% improvement (ACR20) at week 30. The secondary efficacy endpoints included proportions of patients achieving ACR50 and ACR70 criteria, as well as improvement of DAS28, morning stiffness duration, counts of swelling joints, counts of tenderness joints, subject’s visual analogue scale score (VAS) on pain, subject’s VAS score on disease activity, investigator’s VAS score on disease activity, health assessment questionnaire (HAQ) score, efficacy-related levels of erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) from baseline.

Safety

Safety was assessed through AEs throughout the study, characterized by their type, incidence, severity, duration, seriousness, and relatedness to study drug. The safety endpoints were incidence rates of AEs and causality between AEs and study drug. The incidence and prognosis of TB were specially monitored in view of increased risk of TB associated with TNF-α inhibitors [9].

Exploratory Endpoint

An equivalence analysis was conducted ulteriorly in regard to primary efficacy endpoint, which was determined in the statistical analysis plan prior to locking database at the request of the authorities.

Immunogenicity

The immunogenicity endpoint was antidrug antibody (ADA)-positive rate at week 30 and incidence of neutralizing antibody (NAb), which was only detected in the ADA-positive population.

PK

The primary PK parameters were Cmax and AUC0-τ, as well as coefficient of variation (CV). The PK equivalence would be primarily inferred if 90% CI of AUC0-τ geometric mean ratio of CMAB008 to infliximab was within the range of 0.80–1.25.

Statistical Analyses

Referring to the results in the package insert of infliximab globally published, comparing infliximab with placebo, the response rates of ACR20 are 50% and 20%, respectively. As a consequence, the calculated margin was 15%, which was consistent with the margin of a biosimilar [10] study of infliximab approved by the European Union. The one-sided significant level (α) was 0.025, while the power was 0.80, with the ratio of 1:1 and a dropout rate of no more than 10%, a sample size of approximately 392 patients was planned for enrollment, 196 patients in each group.

Efficacy analysis was performed separately in full analysis set (FAS) and per protocol set (PPS). A Last Observation Carried Forward strategy was applied in FAS analysis to impute missing values. For primary efficacy endpoint, Breslow–Day test was used for assessing central effects. Then, Farrington–Manning test was performed to calculate the difference of ACR20 response rate between two groups with a one-sided 97.5% CI. CMAB008 would be non-inferior to infliximab if the lower limit of 97.5% CI was greater than − 15%. To further explore, an equivalence test was conducted with respect to the primary efficacy endpoint in FAS and PPS, two-sided 95% CI for the difference also calculated by Farrington–Manning test and α was 0.05. Equivalence of CMAB008 to infliximab would be concluded, if 95% CI within the range of − 15% to 15%. Fisher’s exact test and χ2 test were conducted to compare the differences of ACR20 response rates in subgroup analysis.

As to secondary efficacy endpoints, analysis of variance, χ2 test, or nonparametric test by means of rank transformation (two-sided test, 95% CI, α = 0.05) was applied to measure differences between two groups, while Cochran–Mantel–Haenszel test was performed to estimate central effects. About safety-related values, descriptive statistical analysis was used, and χ2 test or Fisher’s exact test (two-sided test, 95% CI, α = 0.05) was performed for comparison of differences.

Patient and Public Involvement

There was no involvement of patients/the public in the clinical trial design, conduct, reporting, or dissemination plans.

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