Efficacy and Safety of Biosimilar CT-P17 Versus Reference Adalimumab in Subjects With Rheumatoid Arthritis

24-Week Results From a Randomized Study

Jonathan Kay; Janusz Jaworski; Rafal Wojciechowski; Piotr Wiland; Anna Dudek; Marek Krogulec; Slawomir Jeka; Agnieszka Zielinska; Jakub Trefler; Katarzyna Bartnicka-Maslowska; Magdalena Krajewska-Wlodarczyk; Piotr A. Klimiuk; Sang Joon Lee; Yun Ju Bae; Go Eun Yang; Jae Kyoung Yoo; Daniel E. Furst; Edward Keystone

Disclosures

Arthritis Res Ther. 2021;23(51) 

In This Article

Methods

Study Design and Procedures

This randomized, double-blind, active-controlled, multicenter, phase III study was conducted at 52 centers in six countries (Bulgaria, Hungary, Lithuania, Peru, Poland, Ukraine; see Supplementary Table 1, Additional file 1). There were three study periods: screening (days − 42 to − 1), treatment (weeks 0–48), and end-of-study (week 52). Before dosing at week 0, subjects were randomized (1:1) to receive treatment with 40 mg (100 mg/ml) of either CT-P17 or EU-adalimumab (Humira, AbbVie Deutschland GmbH Co. KG, Ludwigshafen, Germany) every 2 weeks (q2w) until week 24 (treatment period 1). Before dosing at week 26, subjects in the EU-adalimumab group were randomized (1:1) either to continue EU-adalimumab or to switch to CT-P17 (both q2w until week 48) (treatment period 2). Subjects receiving CT-P17 during treatment period 1 continued to receive CT-P17 in treatment period 2. Results up to week 24 are reported here.

CT-P17 and EU-adalimumab were administered by subcutaneous injection via prefilled syringe. After training in proper injection technique, subjects (or caregivers, as needed) could self-administer injections at home, unless injection at the study center was required for usability assessment. Subjects also received treatment with methotrexate (MTX; 12.5–25 mg/week, or 10 mg/week if intolerant to a higher dose, oral or parenteral [intramuscular or subcutaneous] dose) and folic acid (≥ 5 mg/week, oral).

Randomization was conducted using an interactive web response system (IWRS). The biostatistics team used Rave Randomization and Trial Supply Management (Medidata Solutions, New York) to generate the randomization schedule for the IWRS, which linked sequential subject randomization numbers to treatment codes. Randomization was by permuted block (block size remains blinded until final database lock) and was stratified by country and Simplified Disease Activity Index (SDAI) at screening (> 26 vs ≤ 26). As prespecified in the protocol, the study was unblinded for reporting purposes after the database lock for data up to week 24. Efficacy, PK, usability, immunogenicity, and safety endpoints were evaluated by separate, predefined unblinded teams constituted by the sponsor and by the Contract Research Organization (CRO). The investigators, subjects, and other teams in the CRO and the sponsor will remain blinded until the end of the study.

The study was performed in accordance with the Declaration of Helsinki[17] and Good Clinical Practice guidelines.[18] All national, state, and local laws or regulations were followed. Before study initiation, the study protocol was reviewed and approved by the independent ethics committee/institutional review board at each site (see Supplementary Table 1, Additional file 1). All subjects provided written informed consent. The study was registered with ClinicalTrials.gov (NCT03789292).

Subjects

Full eligibility criteria are detailed in Additional file 1. Subjects ranged between 18 and 75 years of age, were diagnosed with RA according to the 2010 American College of Rheumatology (ACR)/EULAR classification criteria,[19] and had active disease, defined by the presence of ≥ 6 swollen joints (of 66 assessed), ≥ 6 tender joints (of 68 assessed), and either erythrocyte sedimentation rate (ESR) > 28 mm/hour or serum C-reactive protein (CRP) concentration > 1.0 mg/dl (> 10 mg/l) at screening. Subjects had received oral or parenteral MTX at a dose of 12.5–25 mg/week, or 10 mg/week if intolerant to a higher dose, for ≥ 12 weeks, and had been on a stable dose and route of administration of MTX for ≥ 4 weeks before the first administration of study drug (day 1). Key exclusion criteria included prior bDMARD or targeted synthetic DMARD treatment for RA or prior TNF inhibitor treatment for any diagnosis; active or latent tuberculosis, or history of tuberculosis; or history of or current serious infection.

Study Endpoints

The primary efficacy endpoint was the proportion of subjects achieving clinical response according to 20% improvement by ACR response criteria (ACR20) at week 24. Secondary efficacy endpoints up to week 24 were ACR20, ACR50, and ACR70 response, hybrid ACR response, Disease Activity Score in 28 joints (DAS28)-CRP response, EULAR (CRP) response, SDAI and Clinical Disease Activity Index (CDAI) remission rate, and 36-item Short Form Health Survey (SF-36) physical and mental component scores. DAS28-CRP and Boolean remission rates were analyzed post hoc. Trough serum adalimumab concentration (C trough) was evaluated as a secondary PK endpoint. Usability evaluations (Bulgaria and Poland only) included subject-reported outcomes from the Self-Injection Assessment Questionnaire (SIAQ) administered before (PRE-SIAQ) and after (POST-SIAQ) self-injection, and successful self-injection as determined by Self-Injection Assessment Checklist completed by study center staff. Safety was evaluated throughout; immunogenicity and local site pain were also assessed.

Study Assessments

Study assessments and time points for evaluation are specified in Supplementary Table 2 (Additional file 1). For efficacy assessments, procedures were performed at the study center before study drug administration. A blinded independent joint assessor was assigned at each study center. Blood samples for PK analysis were obtained predose (immediately before study drug injection) for all PK sampling time points. Usability assessments were conducted at weeks 4, 6, 8, and 24. Safety assessments performed throughout included treatment-emergent adverse events (TEAEs), TEAEs of special interest (TEAESI), immunogenicity, clinical monitoring for tuberculosis, and review of prior and concomitant medications. TEAEs were recorded according to the Common Terminology Criteria for Adverse Events v5.0 and were coded to System Organ Class (SOC) and Preferred Term according to the Medical Dictionary for Regulatory Affairs v22.0. Prior and concomitant medications were coded using the World Health Organization Drug Dictionary (March 2019 version). Protocol-specified TEAESIs were injection-site reactions (ISRs), hypersensitivity/allergic reactions, infections, and malignancies. Local site pain was assessed by using a 100-mm visual analog scale (VAS) at all study visits (except weeks 12 and 20).

Immunogenicity was evaluated at all study visits. Anti-drug antibodies (ADAs) were detected using a validated electrochemiluminescent bridging assay with acid dissociation. ADA-positive samples underwent further analysis to confirm the specificity of binding and to quantify ADA titer. If a sample was confirmed positive for specific ADAs, the presence of neutralizing antibodies (NAbs) was investigated. A validated electrochemiluminescent assay with affinity capture elution was used to measure neutralizing activity against adalimumab in human serum.

Statistical Analyses

A sample size of 450 subjects (225 per treatment group) was determined to provide ≥ 80% statistical power to demonstrate equivalence of ACR20 response at week 24, using nQuery Adviser (v7.0; nQuery, Boston, MA). This calculation was based on two sets of statistical assumptions to meet the different requirements of regulatory authorities in the European Union and the USA: an equivalence margin of − 15 to 15% using a 2 1-sided 2.5% significance level of an equivalence test (predefined in the protocol; EMA assumption), and an asymmetric equivalence margin of − 12 to 15% using a 2 1-sided 5% significance level of an equivalence test (FDA assumption). To allow for a possible dropout rate of 20%, the target sample size was 564 subjects (282 per treatment group).

Analysis populations are described in Additional file 1. The intention-to-treat (ITT) population included all subjects enrolled and randomized to receive a dose of either study drug, regardless of whether study drug dosing was completed. The ITT population was the primary analysis population for the primary endpoint, which was also assessed in the per-protocol (PP) population as a supportive analysis. The analysis was conducted by the exact binomial approach using a Farrington-Manning score method (inverting 2 1-sided test).[20] A sensitivity analysis for the primary efficacy endpoint was performed in both the ITT and the PP populations using logistic regression with treatment group as a fixed effect and country and disease activity by SDAI at screening as covariates. Selected analyses were also conducted by ADA status. Post hoc analyses were conducted to compare parameters between treatment groups (Table 1, Table 2 and Table 3), with p values generated by the Wald test (for proportional values) or t test (for mean values). All statistical analyses were performed using SAS software v9.4 (SAS Institute, Cary, NC).

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