Increased versus conventional adalimumab dose interval for patients with Crohn's disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trial.

Background: Despite its effectiveness in treating Crohn's disease, adalimumab is associated with an increased risk of infections and high health-care costs. We aimed to assess clinical outcomes of increased adalimumab dose intervals versus conventional dosing in patients with Crohn's disease in stable remission.
Methods: The LADI study was a pragmatic, open-label, multicentre, non-inferiority, parallel, randomised controlled trial, done in six academic hospitals and 14 general hospitals in the Netherlands. Adults (aged ≥18 years) diagnosed with luminal Crohn's disease (with or without concomitant perianal disease) were eligible when in steroid-free clinical and biochemical remission (defined as Harvey-Bradshaw Index [HBI] score <5, faecal calprotectin <150 μg/g, and C-reactive protein <10 mg/L) for at least 9 months on a stable dose of 40 mg subcutaneous adalimumab every 2 weeks. Patients were randomly assigned (2:1) to the intervention group or control group by the coordinating investigator using a secure web-based system with variable block randomisation (block sizes of 6, 9, and 12). Randomisation was stratified on concomitant use of thiopurines and methotrexate. Patients and health-care providers were not masked to group assignment. Patients allocated to the intervention group increased adalimumab dose intervals to 40 mg every 3 weeks at baseline and further to every 4 weeks if they remained in clinical and biochemical remission at week 24. Patients in the control group continued their 2-weekly dose interval. The primary outcome was the cumulative incidence of persistent flares at week 48 defined as the presence of at least two of the following criteria: HBI score of 5 or more, C-reactive protein 10 mg/L or more, and faecal calprotectin more than 250 μg/g for more than 8 weeks and a concurrent decrease in the adalimumab dose interval or start of escape medication. The non-inferiority margin was 15% on a risk difference scale. All analyses were done in the intention-to-treat and per-protocol populations. This trial was registered at ClinicalTrials.gov, NCT03172377, and is not recruiting.
Findings: Between May 3, 2017, and July 6, 2020, 174 patients were randomly assigned to the intervention group (n=113) or the control group (n=61). Four patients from the intervention group and one patient from the control group were excluded from the analysis for not meeting inclusion criteria. 85 (50%) of 169 participants were female and 84 (50%) were male. At week 48, the cumulative incidence of persistent flares in the intervention group (three [3%] of 109) was non-inferior compared with the control group (zero; pooled adjusted risk difference 1·86% [90% CI -0·35 to 4·07). Seven serious adverse events occurred, all in the intervention group, of which two (both patients with intestinal obstruction) were possibly related to the intervention. Per 100 person-years, 168·35 total adverse events, 59·99 infection-related adverse events, and 42·57 gastrointestinal adverse events occurred in the intervention group versus 134·67, 75·03, and 5·77 in the control group, respectively.
Interpretation: The individual benefit of increasing adalimumab dose intervals versus the risk of disease recurrence is a trade-off that should take patient preferences regarding medication and the risk of a flare into account.
Funding: Netherlands Organisation for Health Research and Development.
Competing Interests: Declaration of interests FMJ has received a research grant from ZonMW. DJdJ has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Galapagos and held leadership roles in the Dutch Initiative on Crohn and Colitis and the IBD workgroup of the Dutch Gastroenterology Society. ACdV has received research grants from Takeda, Janssen, and Pfizer. RLW has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Ferring, Pfizer, Galapagos, AbbVie, and Janssen. TEHR has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie and has participated in the advisory board for Galapagos. MWMDL has received a grant for podcasts from Pfizer; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen-Cilag and Galapagos; participated in advisory boards of BMS and Galapagos; and held leadership roles in the Elisabeth Twee Steden Ziekenhuis. AAvB has received research grants from AbbVie, Celgene/BMS, Janssen, Pfizer, Teva, and ZonMW; consulting fees from Ferring, Galapagos, AbbVie, and BMS; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Ferring, Galapagos, and Janssen; support for attending meetings from Janssen; and held leadership roles in committees of the Dutch Gastroenterology Society and National Federation of Medical Specialists. BO has received research grants from Galapagos, Takeda, Ferring, and Celltrion; received consulting fees from AbbVie, Galapagos, Pfizer, Ferring, Takeda, and Janssen; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, Galapagos, AbbVie, and Ferring; and was chairman of the IBD Committee of the Dutch Association of Gastroenterology. MJP has received consulting fees from Takeda, Janssen, Galapagos, and AbbVie; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen. NKdB has received research grants from Teva, Takeda, and the Dutch Gastroenterology and Hepatology Patient Association (MLDS); and has received consulting fees from Teva. RCM-H has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen-Cilag and is a member of the national IBD Committee of the Dutch Association for Gastroenterology and Hepatology. AEvdM-dJ has received research grants from Galapagos, Nestle, Cablon, and Norgine; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Galapagos, Tramedico, and Janssen-Cilag; and has participated in an advisory board for Ferring. FH has received research grants from Janssen, AbbVie, Pfizer, and Takeda; and has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Janssen, Takeda, and Pfizer. CJvdW has received research grants from ZonMW, Falk, and Pfizer; has received consulting fees from Janssen, Galapagos, and Pfizer; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Ferring and AbbVie; and had leadership roles in the European Crohn's and Colitis Organisation, United European Gastroenterology Council, and the Dutch Association for Gastroenterology. All other authors declare no competing interests.
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