Mercaptopurine for the Treatment of Ulcerative Colitis: A Randomized Placebo-Controlled Trial

Abstract

Background and aims: Scepticism about the efficacy of thiopurines for ulcerative colitis [UC] is rising. This study aimed to evaluate mercaptopurine treatment for UC.

Methods: In this prospective, randomized, double-blind, placebo-controlled trial, patients with active UC, despite treatment with 5-aminosalicylates [5-ASA], were randomized for therapeutic drug monitoring [TDM]-guided mercaptopurine treatment or placebo for 52 weeks. Corticosteroids were given in the first 8 weeks and 5-ASA was continued. Proactive metabolite-based mercaptopurine and placebo dose adjustments were applied from week 6 onwards by unblinded clinicians. The primary endpoint was corticosteroid-free clinical remission and endoscopic improvement [total Mayo score ≤2 points and no item >1] at week 52 in an intention-to-treat analysis.

Results: Between December 2016 and April 2021, 70 patients were screened and 59 were randomized at six centres. In the mercaptopurine group, 16/29 [55.2%] patients completed the 52-week study, compared to 13/30 [43.3%] on placebo. The primary endpoint was achieved by 14/29 [48.3%] patients on mercaptopurine and 3/30 [10%] receiving placebo (Δ = 38.3%, 95% confidence interval [CI] 17.1-59.4, p = 0.002). Adverse events occurred more frequently with mercaptopurine [808.8 per 100 patient-years] compared to placebo [501.4 per 100 patient-years]. Five serious adverse events occurred, four on mercaptopurine and one on placebo. TDM-based dose adjustments were executed in 22/29 [75.9%] patients, leading to lower mercaptopurine doses at week 52 compared to baseline.

Conclusions: Optimized mercaptopurine treatment was superior to placebo in achieving clinical, endoscopic and histological outcomes at 1 year following corticosteroid induction treatment in UC patients. More adverse events occurred in the mercaptopurine group.

Keywords: Ulcerative colitis; immunomodulators; randomized controlled trial; therapeutic drug monitoring.

Graphical Abstract

Figure 1.

Graphical study-design. 5-ASA = 5-aminosalicylates, Calpro = faecal calprotectin test, Lab = laboratory blood tests, TDM = therapeutic drug monitoring.

Figure 2.

Flowchart. ITT = intention to treat.

Figure 3.

The proportion of patients achieving corticosteroid-free efficacy endpoints at week 52 in an intention-to-treat analysis. [A] The proportion of patients achieving the primary endpoint: corticosteroid-free combined clinical remission and endoscopic improvement [i.e. total score ≤2, and no item >1, using the 12-point Mayo score consisting of stool frequency, rectal bleeding, endoscopic Mayo score and the physician’s global assessment] and the secondary corticosteroid-free endpoints: endoscopic improvement [i.e. endoscopic Mayo score = 0 or 1], clinical remission [i.e. rectal bleeding score = 0 and stool frequency score = 0 or 1 using the 6-point Mayo score with rectal bleeding and stool frequency score] and histological remission [i.e. absence of neutrophils in the mucosa; Geboes score <2 B.1, Robarts histopathology index ≤3 and/or Nancy score ≤1], at week 52 with delta difference, 95% CI of difference and p-values. [B] The proportion of patients achieving the remaining corticosteroid-free endpoints: combined clinical and endoscopic response [i.e. 3-point and 30% reduction compared to baseline and 1-point drop in the rectal bleeding score or a rectal bleeding score ≤1], endoscopic remission [endoscopic Mayo score = 0], clinical response (≥2-point drop in the 6-point Mayo score [consisting of rectal bleeding and stool frequency items]) compared to baseline and biochemical remission [CRP <5 mg/L and faecal calprotectin <250 mg/kg] at week 52 with the delta percentage difference between groups with 95% confidence intervals.

Figure 4.

Prevalence of adverse events in the mercaptopurine and placebo group per month. The number on the x-axis corresponds to the number of the month in which adverse events occurred.

Figure 5.

Median 6-thioguaninenucleotide [6-TGN] and 6-methylmercaptopurine [6-MMP] serum concentrations in pmol/8 × 10⁸ red blood cells [RBC] per study visit for patients in the mercaptopurine group who underwent sampling. Boxplots represent interquartile ranges.