Background
Many patients with ulcerative colitis report ongoing diarrhoea even when their disease is stable and in remission.
Design
MODULATE was a pragmatic, multicentre, seamless, adaptive, phase 2/3 open-label, parallel-group, multiarm multistage randomised controlled trial.
Setting and participants
People aged over 18 years with stable ulcerative colitis who had diarrhoea, recruited from secondary care sites in the United Kingdom.
Interventions
The control arm consisted of modified first-line dietary advice given to all patients with irritable bowel syndrome; the first interventional arm was amitriptyline, a tricyclic antidepressant, which at low doses slows colonic transit; the second intervention was loperamide, an antidiarrhoeal drug also thought to slow colonic transit; the third was ondansetron, an antiemetic thought to slow colonic transit; and the fourth was a diet low in fermentable oligo-, di-, and mono-saccharides and polyols, which is thought to reduce bloating and gas within the small intestine. All patients randomised to an interventional arm were to receive treatment for 6 months.
Main outcome measures: Primary outcome measures
Phase 2: Improvement in diarrhoea measured using the Gastrointestinal Symptom Rating Scale-irritable bowel syndrome questionnaire at 8 weeks post randomisation: improvement defined as those reporting minor discomfort from diarrhoea or less (scoring ≤ 2 on the diarrhoea subscale).
Secondary outcome measures
Phases 2 and 3: Measured at both 8 weeks and 6 months:
Improvement in diarrhoea measured using the Gastrointestinal Symptom Rating Scale-irritable bowel syndrome.
Blood for C-reactive protein, stool for faecal calprotectin at 6 months only, reviewing case notes for escalation of medical therapy for ulcerative colitis.
Anxiety and depression, via the Hospital Anxiety and Depression Scale.
Results
The MODULATE trial opened in December 2021 and closed in January 2023. Of the eight secondary care sites that completed contracting, only four opened to recruitment during this time, and one person was randomised. Trial timelines coincided with the start of the COVID-19 pandemic, causing substantial delays and, ultimately, its early closure. During this time, the trial underwent two major redesign phases, enabling a fully remote participant pathway incorporating electronic consent, remote data capture, posted blood and stool sample kits for eligibility screening, delivery of the dietary intervention via telephone or video call platform, postage of trial investigational medicinal products directly to participants’ homes and all trial follow-up appointments conducted via telephone. The second phase of redesign pushed the trial towards a fully decentralised model. However, this stage was not implemented due to the decision to close the trial early.
Limitations
The study was unable to recruit the necessary sample size, preventing the trial from progressing. The trial met with several challenges. The Trial Steering Committee’s root cause analysis concluded that the pandemic was the leading factor in trial closure, especially regarding our ability to recruit both sites and participants.
Conclusions
Although the trial closed early and with insufficient participants to proceed with full statistical analysis, lessons were learnt that could potentially inform future remote trial design and decentralised participant pathways.
Future work
MODULATE was a commissioned call in response to a priority question identified by people living with ulcerative colitis. The question remains important and unanswered; trials to address it are needed. Given the recruitment difficulties we experienced, consideration should be given to conducting these in both primary and secondary care.
CORE (COnnecting REpositories)
CORE (COnnecting REpositories)