De novo combination allopurinol-thiopurine vs standard thiopurine in inflammatory bowel disease (IBD) patients escalating to immunomodulators: a randomized controlled trial

INTERVENTION: De novo combination therapy with allopurinol 100mg orally and gradual pre‐specified dose increments of azathioprine (or mercaptopurine) starting at 50mg (or 25mg) orally daily as determined by measuring thiopurine metabolite levels at week 14 and the absence of serious side effects. The decision to commence azathioprine or mercaptopurine will be at the discretion of the treating clinician as per their standard practice. Medications will be supplied in sealed non‐distinguishable treatment bottles which will be supplied every eight weeks and drug/ packaging will be returned to assess adherence at the relevant study visit(s). The overall duration of study treatment will be six months. CONDITION: Inflammatory Bowel Disease PRIMARY OUTCOME: The proportion of patients in each group achieving remission as determined by normalization of faecal calprotectin (to <150 µg/g)and improvement in disease activity score to SCCAI<4 (for UC) or HBI<5 (for CD) at 26 weeks. This is a composite outcome. SECONDARY OUTCOME: Changes in white cell counts (measured by serum full blood counts) Incidence of adverse reactions (by type) ‐ compared by proportion of patients in each group reporting or have laboratory testing consistent with one or more episodes of a significant adverse reaction attributable to either thiopurine or allopurinol at one or more study visits with investigator(s). Examples of adverse reactions include nausea, rash, myalgia/ arthralgia, malaise, abdominal pain, serious infection, leukopenia, deranged liver function. Incidence of adverse reactions to the treatments based on study specific report forms from medical records Incidence of treatment failure as defined by requirement for rescue therapy, surgery and hospitalisations for CD or UC based on study specific report forms from medical records Mean change in alanine transaminase (ALT) on serum analysis Mean change in faecal calprotectin concentration at weeks 14 and 26 Mean change in HBI or SCCAI scores. This is a composite outcome. Mean change in serum CRP Mean change in thiopurine metabolites 6‐TGN and 6‐MMP on blood assay Mean change in total white cell count on blood assay Remission rate and incidence of adverse reactions on thioguanine based on study specific report forms from medical records The proportion of patients in each group remaining on either thiopurine monotherapy or thiopurine allopurinol co‐therapy at week 26 based on study specific report forms from medical records INCLUSION CRITERIA: • Age 18 ‐ 80 years • Confirmed UC or CD diagnosis • Evidence for active disease as determined by baseline faecal calprotectin > or = 150µg/g and/or SCCAI > or = 4 (for UC) or HBI > or = 5 (for CD) at baseline screening visit • Require commencement of thiopurine therapy according to the patient’s treating physician • Stable doses of other IBD medications (standardized prednisolone weaning schedule only, maintenance biologics only, aminosalicylates at same dose only) for three months prior to enrolment