4. Discussion
Thiopurine-related adverse, UC
COLORECTAL CANCER, RECRUITMENT, ADVERSE EVENTS, DISEASE, RECRUITMENT, SECONDARY, REMISSION, CORONAVIRUS
We show here that mercaptopurine is superior to placebo in achieving [combined] clinical remission and endoscopic improvement, as well as histological remission at 1 year in UC patients following remission induction treatment with corticosteroids. In total, 55% of patients in the mercaptopurine group completed the trial. Intriguingly, 87.5% of these patients attained combined clinical remission and endoscopic improvement. The majority of patients required TDM-based dosing advice, resulting in a decreased mercaptopurine dose. We therefore conclude that mercaptopurine is a valuable treatment option for UC patients who tolerate it.Previous randomized controlled trials investigating thiopurine treatment in UC reported clinical and endoscopic remission rates varying between 40 and 76%, which is in line with 48% of patients reaching the primary endpoint in our study.Thiopurine-related adverse events hamper their use in daily practice. We observed more drug-related adverse events in the mercaptopurine group and TDM did not prevent these adverse events. The prevalence of adverse events was comparable between the two treatment groups in the second 6 months of the study. For 6-TGN and 6-MMP assays, we applied the Dervieux method with a 6-TGN target of 600–1200 pmol/8 × 10Our study has several strengths. This was the first prospective controlled study using TDM-based dosing of thiopurine treatment in UC applying random placebo dose adjustments to mimic mercaptopurine treatment in the placebo arm. Second, we used objective endpoints, including endoscopic and histological outcome measures that were assessed in a blinded fashion by experienced readers. Histological remission is today considered an additional treatment target in UC, since it seems to be associated with long-term remission and prevention of colorectal cancer.The main limitation of this study was that we did not reach the calculated sample size. Recruitment of patients was challenging because patients sometimes did not accept the risk of taking a placebo or they were unwilling to upscale treatment with a thiopurine. In addition, the coronavirus pandemic significantly interfered with patient recruitment in all clinical trials. Notwithstanding this, and despite the relatively small sample size, our results showed a significant beneficial effect of mercaptopurine using clinical, endoscopic and histological outcome measures. The relatively small sample size did, however, cause large confidence intervals of the differences in the proportion of patients who reached the primary and secondary endpoints. Second, although we conducted a double-blind study, nearly half of the mercaptopurine-treated patients were unblinded as allopurinol co-medication was started. Physicians could also see laboratory results such as MCV and leukocyte counts, which could reveal the treatment allocation. Ideally, the physician would have been blinded to laboratory results and patients in the placebo group would receive a placebo to mimic allopurinol co-medication. However, this might have jeopardized patient safety and an extra placebo would make this investigator-initiated study even more complex to perform. Third, a flare visit was done at the physician’s discretion and the criteria to subsequently withdraw a patient from the study due to inefficacy were not predefined. Nevertheless, study withdrawal was always decided in consultation with the study team and based on endoscopy. Fourth, rectal and oral 5-ASA dose escalation was allowed during the study. However, in a normal clinical setting, 5-ASA treatment should also be optimized in case of a disease flare. Moreover, it was considered unethical to discontinue 5-ASA treatment for patients in the placebo group. Lastly, the control group received placebo instead of weight-based mercaptopurine dosing. The main goal of this placebo-controlled study was to investigate efficacy of thiopurines dosed with an optimal strategy for UC. Since most clinical trials are performed with a placebo-treated control group, patients in the control arm were treated with placebo rather than with weight-based mercaptopurine. Of note, weight-based mercaptopurine treatment in the control group would have increased the required sample size.In conclusion, this study has demonstrated that proactive TDM-dosed mercaptopurine treatment is more effective than placebo in achieving clinical, endoscopic and histological outcomes in UC patients who failed 5-ASA treatment and received remission induction treatment with corticosteroids. Thiopurines remain a valid treatment option in the emerging therapeutic landscape of UC. However, more adverse events occurred in the mercaptopurine group despite applying TDM. We recommend using lower starting doses of mercaptopurine and to perform early TDM in order to reduce intolerance.