Background and AimsWe aimed to assess cost-effectiveness of increasing adalimumab dose intervals compared to the conventional dosing interval in patients with Crohn’s disease [CD] in stable... Show moreBackground and AimsWe aimed to assess cost-effectiveness of increasing adalimumab dose intervals compared to the conventional dosing interval in patients with Crohn’s disease [CD] in stable clinical and biochemical remission.DesignWe conducted a pragmatic, open-label, randomized controlled non-inferiority trial, comparing increased adalimumab intervals with the 2-weekly interval in adult CD patients in clinical remission. Quality of life was measured with the EQ-5D-5L. Costs were measured from a societal perspective. Results are shown as differences and incremental net monetary benefit [iNMB] at relevant willingness to accept [WTA] levels.ResultsWe randomized 174 patients to the intervention [n = 113] and control [n = 61] groups. No difference was found in utility (difference: −0.017, 95% confidence interval [−0.044; 0.004]) and total costs (−€943, [−€2226; €1367]) over the 48-week study period between the two groups. Medication costs per patient were lower (−€2545, [−€2780; −€2192]) in the intervention group, but non-medication healthcare (+€474, [+€149; +€952]) and patient costs (+€365 [+€92; €1058]) were higher. Cost–utility analysis showed that the iNMB was €594 [−€2099; €2050], €69 [−€2908; €1965] and −€455 [−€4,096; €1984] at WTA levels of €20 000, €50 000 and €80 000, respectively. Increasing adalimumab dose intervals was more likely to be cost-effective at WTA levels below €53 960 per quality-adjusted life year. Above €53 960 continuing the conventional dose interval was more likely to be cost-effective.ConclusionWhen the loss of a quality-adjusted life year is valued at less than €53 960, increasing the adalimumab dose interval is a cost-effective strategy in CD patients in stable clinical and biochemical remission. Show less
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... Show moreBackground: 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 mu g/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 mu g/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 center dot 86% [90% CI -0 center dot 35 to 4 center dot 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 center dot 35 total adverse events, 59 center dot 99 infection-related adverse events, and 42 center dot 57 gastrointestinal adverse events occurred in the intervention group versus 134 center dot 67, 75 center dot 03, and 5 center dot 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. Show less
Snijders, R.J.A.L.M.; Stoelinga, A.E.C.; Gevers, T.J.G.; Pape, S.; Biewenga, M.; Verdonk, R.C.; ... ; Dutch Autoimmune Hepatitis Working 2022
Background: Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which... Show moreBackground: Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH. Method:s: CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks. Discussion: The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases. Show less
