Y-ECCO Literature Review: Daniele Noviello

Methods

The target population of the LADI trial included adult patients with luminal CD in stable steroid-free clinical and biochemical remission. Specifically, such remission was defined as a 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 conventional adalimumab dose interval. Overall, 174 patients were randomly assigned (2:1) to the intervention or the control group. 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.

The primary outcome was the cumulative incidence of persistent (≥8 weeks) flare, defined together with the Dutch Crohn’s and Colitis patient organisation as clinical-biochemical disease activity (at least two of the following criteria: HBI score of ≥5, C-reactive protein ≥ 10 mg/L, faecal calprotectin ≥250 μg/g) and a treatment modification (a subsequent decrease in the adalimumab dose interval or the start of escape medication such as budesonide, prednisone or other immunomodulators).  The non-inferiority margin was set at 15% on an adjusted risk difference (aRD) scale. Key secondary outcomes at week 48 included the cumulative incidence of transient (<8 weeks) flares, the proportion of patients in clinical and biochemical remission, the proportion of patients treated with escape medication and adverse events. A cost-effectiveness analysis was also performed separately [3].

Key findings

At week 48, approximately 82% of participants in the intervention group remained on an extended dose interval, with 65% receiving adalimumab every 4 weeks and 17% every 3 weeks, whereas 11% had returned to the conventional dosing regimen. The cumulative incidence of persistent flares at week 48 in the intervention group (3%) was non-inferior to that in the control group (no flares) with an aRD of 1.86% (90% CI -0.35 to 4.07). A similar non-inferior result was found for the cumulative incidence of transient flares, with an aRD of 2.60% (95% CI -0.93 to 6.13). However, at week 48 patients in the intervention group were less likely to be in clinical and biochemical remission (aRD -16.1%; 95% CI -31.3 to -0.91) or in corticosteroid-free clinical and biochemical remission (aRD -19.16%; 95% CI -34.53 to -3.78). Furthermore, they required greater use of escape medication (aRD 8.67%; 95%CI 0.44 to 16.90) compared to the control group. Regarding the safety profile, dose reduction led to a slight reduction in infectious adverse events, mostly moderate infection necessitating antibiotics. The cost-effectiveness analysis found no discernible disparities in utility or total costs between the two groups. In detail, a medication cost per patient reduction of 33% in the intervention group was offset by an increase in non-medication health care and patient costs.

Discussion

Non-inferiority means inferior to a degree no greater than that which people are willing to accept [5]. For instance, many patients may consider a 15% increased risk of a persistent flare too high to justify an increased adalimumab dose interval but may accept the observed risk increase of 1.86%. At the same time, the use of escape medications or development of infections may be more relevant to patients compared to persistent flare. The safety findings should be contextualised within the known safety profile of adalimumab and, therefore, lengthening of the adalimumab dosing interval should probably not be recommended for the sole purpose of reducing drug-related adverse effects [5]. It should be noted that cost-utility analyses are highly dependent on drug costs at the time of the analysis (originator vs biosimilar) and based on the set levels of willingness-to-accept. The long-term extension of the LADI trial, involving an additional 2 years of follow-up, will provide information on the percentage of the intervention group remaining on an extended dose interval, efficacy persistence and whether isolated biochemical disease activity at week 48 precedes a clinical flare.

Conclusions

The LADI trial provides robust evidence that for patients in stable steroid-free clinical and biochemical remission, increased adalimumab dose intervals are non-inferior to conventional dose intervals in terms of the cumulative incidence of persistent flares at week 48. However, it is open to debate whether the cost savings achieved by increased dose intervals are sufficient to warrant acceptance of the potential risk for loss of remission, bearing in mind that adalimumab is becoming increasingly affordable. In conclusion, the findings from the LADI trial demonstrate that a strategy of dose interval lengthening could be discussed as part of a shared decision-making process. This process should consider the patient's viewpoint regarding medication use, potential adverse events and the potential risk of loss of remission.

References

1. Van Steenbergen S, Bian S, Vermeire S, et al. Dose de-escalation to adalimumab 40 mg every 3 weeks in patients with Crohn’s disease: a nested case-control study. Aliment Pharmacol Ther 2017;45:923–32.
2. Pouillon L, Lamoureux A, Pineton de Chambrun G, et al. Dose de-escalation to adalimumab 40 mg every three weeks in patients with inflammatory bowel disease – a multicenter, retrospective, observational study. Dig Liver Dis 2019;51:236–41.
3. Jansen FM, van Linschoten RCA, Kievit W, et al. Cost-effectiveness analysis of increased adalimumab dose intervals in Crohn's disease patients in stable remission: The randomized controlled LADI trial. J Crohns Colitis 2023;17:1771–80.
4. Roshanov PS, Khanna R. The clinical interpretation of noninferiority trials. Inflamm Bowel Dis 2023 Dec 30:izad314.
5. Gisbert JP, Chaparro M. De-escalation of biological treatment in inflammatory bowel disease: A comprehensive review. J Crohns Colitis 2023 Nov 1:jjad181..

Daniele Noviello - Short Biography

Daniele Noviello is a gastroenterologist at the Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico in Milan and a PhD candidate at the University of Milan. Daniele is currently studying pathogenic Th17 cells and their clinical and biological implications in Crohn’s Disease, coordinating an epidemiological study on environmental factors associated with disease course in IBD and conducting two clinical studies on real-world IBD data.