Elsevier

The Lancet

Volume 389, Issue 10086, 10–16 June 2017, Pages 2304-2316
The Lancet

Articles
Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial

https://doi.org/10.1016/S0140-6736(17)30068-5Get rights and content

Summary

Background

TNF inhibitors have improved treatment of Crohn's disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, and chronic plaque psoriasis, but are expensive therapies. The aim of NOR-SWITCH was to examine switching from originator infliximab to the less expensive biosimilar CT-P13 regarding efficacy, safety, and immunogenicity.

Methods

The study is a randomised, non-inferiority, double-blind, phase 4 trial with 52 weeks of follow-up. Adult patients on stable treatment with infliximab originator treated in a hospital setting for at least 6 months were eligible for participation. Patients with informed consent were randomised in a 1:1 ratio to either continued infliximab originator or to switch to CT-P13 treatment, with unchanged dosing regimen. Data were collected at infusion visits in 40 Norwegian study centres. Patients, assessors, and patient care providers were masked to treatment allocation. The primary endpoint was disease worsening during 52-week follow-up. 394 patients in the primary per-protocol set were needed to show a non-inferiority margin of 15%, assuming 30% disease worsening in each group. This trial is registered with ClinicalTrials.gov, number NCT02148640.

Findings

Between Oct 24, 2014, and July 8, 2015, 482 patients were enrolled and randomised (241 to infliximab originator, 241 to CT-P13 group; one patient was excluded from the full analysis and safety set for CT-P13) and 408 were included in the per-protocol set (202 in the infliximab originator group and 206 in the CT-P13 group). 155 (32%) patients in the full analysis set had Crohn's disease, 93 (19%) had ulcerative colitis, 91 (19%) had spondyloarthritis, 77 (16%) had rheumatoid arthritis, 30 (6%) had psoriatic arthritis, and 35 (7%) had chronic plaque psoriasis. Disease worsening occurred in 53 (26%) patients in the infliximab originator group and 61 (30%) patients in the CT-P13 group (per-protocol set; adjusted treatment difference −4·4%, 95% CI −12·7 to 3·9). The frequency of adverse events was similar between groups (for serious adverse events, 24 [10%] for infliximab originator vs 21 [9%] for CT-P13; for overall adverse events, 168 [70%] vs 164 [68%]; and for adverse events leading to discontinuation, nine [4%] vs eight [3%], respectively).

Interpretation

The NOR-SWITCH trial showed that switching from infliximab originator to CT-P13 was not inferior to continued treatment with infliximab originator according to a prespecified non-inferiority margin of 15%. The study was not powered to show non-inferiority in individual diseases.

Funding

Norwegian Ministry of Health and Care Services.

Introduction

Infliximab is a chimeric IgG1 antibody approved for treatment of Crohn's disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, and chronic plaque psoriasis. Across all these indications, infliximab and other tumour necrosis factor (TNF) inhibitors have substantially improved disease management.1 However, access to TNF inhibitors varies and is inversely related to socioeconomic conditions in each country.2 The patent for the infliximab originator (Remicade; Janssen Biologics, The Netherlands) expired in 2015 in Europe and in many other parts of the world.

The biosimilar infliximab CT-P13 was approved by the European Medicines Agency in 2013 and by the US Food and Drug Administration in 2016.

Randomised controlled trials in patients who have not previously received TNF inhibitors, comparing infliximab originator with CT-P13, have been done in ankylosing spondylitis (PLANETAS,3 a phase 1 study) and rheumatoid arthritis (PLANETRA,4 a phase 3 study). However, according to guidance for regulatory approval of biosimilars, CT-P13 has been approved for all six relevant indications.5, 6, 7 This extrapolation of indication has been debated in clinical communities, especially gastroenterology,8, 9 because the mechanisms of action for infliximab might differ between indications.10, 11 Several other TNF inhibitor biosimilars have been approved or are under regulatory review and will be available for therapeutic use in the coming years.6, 12

In Norway, an annual tender system for TNF inhibitors and related biological drugs was established in 2007. Cost calculations and impact on health-care budgets are key factors for drug selection. In 2014, CT-P13 was recommended by Norwegian Health Authorities for patients starting treatment with infliximab. The cost saving for CT-P13 was 39% in 2014 compared with originator infliximab, and increased to 69% after the 2015 tender. Thus, the introduction of biosimilar drugs could reduce financial burdens on health-care budgets. Additionally, biosimilars could improve overall and earlier access to these drugs in many countries with prescription restrictions based on their high cost.

Research in context

Evidence before this study

Patients starting biological treatment can receive biosimilar CT-P13 in many countries. However, switching of stable patients who are doing well on originator infliximab is controversial. Follow-up data from the PLANETAS and PLANETRA studies, as well as observational data, suggest that switching from originator infliximab to CT-P13 is safe and does not reduce effectiveness of treatment, but independent and randomised studies have been lacking. We searched PubMed and the abstracts of major conferences using the terms “biosimilar”, “infliximab”, “switch”, and either “IBD” or one of the individual diseases (“Crohns disease”, psoriasis” etc) on Oct 23, 2016, with no constraints on the timeframe for the search and no language restrictions. We identified no published, randomised, switch studies on infliximab.

Added value of this study

NOR-SWITCH addresses the important issue of switching from originator to biosimilar infliximab in stable patients, and is the first government-funded randomised study to do so. The study examined patients in all six relevant disease groups, using disease worsening as the common primary outcome.

Implications of all the available evidence

The NOR-SWITCH trial showed that switching from originator infliximab to CT-P13 was not inferior to continued treatment with the originator drug according to a prespecified non-inferiority margin of 15%. Thus, the findings suggest that patients can be switched from originator infliximab to biosimilar infliximab CT-P13. The study findings could substantially affect the use of CT-P13 and health budgets in many countries. However, caution is recommended in generalising these findings to other biological agents.

Cost savings are even more relevant if patients on stable treatment with an originator drug could safely be switched to the biosimilar. Concerns have been raised with regard to efficacy, safety, and formation of anti-drug antibodies (ADAbs) when switching to a biosimilar in patients who are doing well on a stable treatment with an originator drug.13, 14 To date, switch data from infliximab originator to infliximab biosimilar have been available only from open cohort studies15, 16, 17, 18 and from the second year extensions of the PLANETAS and PLANETRA studies.19, 20

The Norwegian Government granted 20 million NOK (€2·2 million) in the 2014 governmental budget for a study to examine whether switching from the originator to the biosimilar is safe. The NOR-SWITCH study was designed as a randomised controlled trial encompassing all six relevant diagnoses for which infliximab is currently approved to assess if CT-P13 was non-inferior to infliximab originator regarding efficacy, safety, and immunogenicity in patients who had been on stable infliximab originator treatment for at least 6 months.

Section snippets

Study design and participants

The NOR-SWITCH study was designed as a 52-week randomised, double-blind, parallel-group, multicentre, non-inferiority comparative phase 4 study, in a hospital setting. Each hospital department was considered a study centre, and 19 gastroenterology departments, 16 rheumatology departments, and five dermatology departments from 25 Norwegian hospitals recruited patients to the study. The study was conducted and analysed according to the protocol and the statistical analysis plan (appendix p 20).

Results

Between Oct 24, 2014, and July 8, 2015, 498 patients were recruited and 482 were randomised into the trial at 40 centres. 241 patients were assigned to receive continued treatment with infliximab originator and 241 to switch from infliximab originator to CT-P13. The patients were followed up for 52 weeks in each treatment group. The full analysis set included 481 patients (241 in the infliximab originator group and 240 in the CT-P13 group; one randomly assigned patient withdrew consent before

Discussion

NOR-SWITCH is, to our knowledge, the first randomised study to show that switching from an originator to a biosimilar TNF inhibitor is not inferior to continued treatment with the originator drug, according to a prespecified non-inferiority margin of 15%.

Data from observational studies and from the extensions of the PLANETRA and PLANETAS studies have not raised any major concerns about the efficacy or safety of the infliximab biosimilar CT-P13.15, 16, 19, 20 However, treatment-emergent adverse

References (31)

  • DH Yoo et al.

    A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study

    Ann Rheum Dis

    (2013)
  • CK Schneider

    Biosimilars in rheumatology: the wind of change

    Ann Rheum Dis

    (2013)
  • T Dorner et al.

    The changing landscape of biosimilars in rheumatology

    Ann Rheum Dis

    (2016)
  • A Blauvelt et al.

    Biosimilars for psoriasis: clinical studies to determine similarity

    Br J Dermatol

    (2016)
  • KB Gecse et al.

    Biosimilar monoclonal antibodies for inflammatory bowel disease: current comfort and future prospects

    Drugs

    (2016)
  • Cited by (633)

    View all citing articles on Scopus
    *

    Contributed equally as first authors

    Contributed equally as senior authors

    View full text