Lengthening adalimumab dosing interval in quiescent Crohn's disease patients: protocol for the pragmatic randomised non-inferiority LADI study

Abstract

Introduction: Adalimumab is effective for maintenance of remission in patients with Crohn's disease (CD) at a dose of 40 mg subcutaneously every 2 weeks. However, adalimumab is associated with (long-term) adverse events and is costly. The aim of this study is to demonstrate non-inferiority and cost-effectiveness of disease activity guided adalimumab interval lengthening compared to standard dosing of every other week (EOW).

Methods and analysis: The Lengthening Adalimumab Dosing Interval (LADI) study is a pragmatic, multicentre, open label, randomised controlled non-inferiority trial. Non-inferiority is reached if the difference in cumulative incidence of persistent (>8 weeks) flares does not exceed the non-inferiority margin of 15%. 174 CD patients on adalimumab maintenance therapy in long-term (>9 months) clinical and biochemical remission will be included (C-reactive protein (CRP) <10 mg/L, faecal calprotectin (FC) <150 µg/g, Harvey-Bradshaw Index (HBI) <5). Patients will be randomised 2:1 into the intervention (adalimumab interval lengthening) or control group (adalimumab EOW). The intervention group will lengthen the adalimumab administration interval to every 3 weeks, and after 24 weeks to every 4 weeks. Clinical and biochemical disease activity will be monitored every 12 weeks by physician global assessment, HBI, CRP and FC. In case of disease flare, dosing will be increased. A flare is defined as two of three of the following criteria; FC>250 µg/g, CRP≥10 mg/l, HBI≥5. Secondary outcomes include cumulative incidence of transient flares, adverse events, predictors for successful dose reduction and cost-effectiveness.

Ethics and dissemination: The study is approved by the Medical Ethics Committee Arnhem-Nijmegen, the Netherlands (registration number NL58948.091.16). Results will be published in peer-reviewed journals and presented at international conferences.

Trial registration numbers: EudraCT registry (2016-003321-42); Clinicaltrials.gov registry (NCT03172377); Dutch trial registry (NTRID6417).

Keywords: adverse events; clinical trials; gastroenterology; health economics; inflammatory bowel disease; statistics & research methods.

Conflict of interest statement

Competing interests: DJdJ received consulting fees from Synthon Pharma, Abbvie and MSD, and travel fees from Falk Pharma, Takeda, Abbvie, MSD, Ferring, Vifor Pharma and Cablon Medical. ACDV has participated in advisory board and/or received financial compensation from the following companies: Jansen, Takeda, Abbvie and Tramedico. FH has served on advisory boards or as speaker for Abbvie, Janssen-Cilag, MSD, Takeda, Celltrion, Teva, Sandoz and Dr Falk, and received unrestricted funding from Dr Falk, Janssen-Cilag, Abbvie and Celgene. CJvdW received grant support from Falk Benelux and Pfizer; received speaker fees from AbbVie, Takeda, Ferring, Dr Falk Pharma, Hospira, Pfizer; and served as a consultant for AbbVie, MSD, Takeda, Celgene, Mundipharma and Janssen.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

Protocolised treatment recommendation in case of disease flare. T0: start of possible disease flare, which can occur at any time during follow-up, T2: 2 weeks after T0, T6−8: 6–8 weeks after T0. Lab tests include haemoglobin, leucocytes, thrombocytes, albumin, C-reactive protein, calprotectin.

Figure 2

Schematic presentation of the trial design. ADA, adalimumab; W0, week 0; W6, week 6 and so on. Lab tests include haemoglobin, leucocytes, thrombocytes, albumin, C-reactive protein, calprotectin.