2.2 Study design
Infections, UC
ADVERSE EVENTS, ADVERSE EVENT, DISEASE, INFECTIONS, ADVERSE EVENT
This was a prospective, multicentre, double-blind, randomized, placebo-controlled study on mercaptopurine treatment for UC with a follow-up period of 52 weeks [Graphical study-design. 5-ASA = 5-aminosalicylates, Calpro = faecal calprotectin test, Lab = laboratory blood tests, TDM = therapeutic drug monitoring.Participants were randomized in a 1:1 ratio using variable block randomization with a maximum block size of eight. Randomization was stratified for prednisone or budesonide treatment. Patients and physicians were blinded to treatment allocation. After inclusion, the site investigator requested randomization via the online electronic case report forms [eCRF] website [Castor EDC] using certified randomization software. Subsequently, an unblinded research coordinator [EC] performed the randomization centrally. After randomization, the unblinded research coordinator sent the results to the trial pharmacy of the Amsterdam UMC, location Academic Medical Center [AMC], which provided the study medication.Participants underwent complete colonoscopy or sigmoidoscopy with mucosal biopsies of the most severely affected mucosa at screening and at week 52. Biopsies were taken from the rectum when no endoscopic disease activity was observed. All procedures were videotaped and assessed using the endoscopic Mayo score by a central reader [ML], who was blinded to treatment assignments and clinical information. A blinded pathologist [AM] assessed histological disease activity using the Geboes score, Robarts histopathology index and Nancy score. Faecal calprotectin levels were measured at screening, week 12 and week 52. Laboratory measurements were performed at baseline and weeks 2, 6, 12, 18, 24, 36 and 52. TDM was applied simultaneously, starting from week 6 onwards. Laboratory measurements included haemoglobin, haematocrit, mean corpuscular volume [MCV], red and white blood cell count, white blood cell differentiation, platelet count, creatinine, C-reactive protein [CRP], albumin, aspartate aminotransferase [AST], alanine transaminase [ALT], alkaline phosphatase, gamma-glutamyl transferase and lipase. Adverse events were documented throughout the study and were graded as mild, moderate or severe at the physician’s discretion. Infections were classified as mild [no oral antibiotics or antiviral medication required], moderate [requiring oral antibiotics or antiviral medication] or severe [requiring intravenous treatment or hospitalization]. In case of early discontinuation of the study drug, adverse events were documented until 30 days after the last dose. A possible relationship of the adverse event with mercaptopurine or placebo was based on the physician’s discretion. In case of a worsening of UC, 5-ASA treatment could be optimized, and an additional mercaptopurine TDM could be performed. A ‘flare visit’ was performed if suspicion of active UC persisted. At this visit, infectious stool and faecal calprotectin tests were taken, blood analysis was performed and, if appropriate, an additional endoscopy was performed. Patients could continue the study drug if endoscopic and clinical disease activity were absent or had sufficiently improved, according to the physician’s discretion. Patients were considered a treatment failure when clinical and endoscopic active disease was confirmed, and these were treated at the physician’s discretion thereafter.The medical ethics committee of the Amsterdam UMC, location AMC, Amsterdam, the Netherlands, approved this study. Data were collected in an online eCRF [Castor EDC]. A trial monitor performed data source verification at each study site.