Title: Autologous Stem cell Transplantation In refractory Crohn’s disease - Low Intensity Therapy Evaluation (ASTIClite)
Funder: Department of Health and Social Care

Abstract: INTRODUCTION: Treatment refractory Crohn’s disease (CD) drives chronic symptoms, poor QOL and high costs. Enthusiasm for autologous hematopoietic stem cell transplantation (HSCT) based upon case reports was tempered by the ASTIC trial, which failed its ambitious primary endpoint and reported high toxicity. Subsequent analysis shows that HSCT led to mucosal healing in > 50%, and that the toxicity may relate to high dose cyclophosphamide. HYPOTHESIS: HSCT with reduced dose cyclophosphamide mobilization and low intensity conditioning (HSCTlite) will induce regression of ileo-colonic ulceration in patients with refractory CD compared to standard of care. HSCTlite will have an acceptable side effect profile. Immunological profiling of blood and mucosa before and after HSCTlite will identify its mechanism of action. DESIGN: UK multicentre randomized controlled clinical trial with 2:1 randomization comparing HSCTlite with standard of care. Eligible outpatients with treatment refractory CD will be randomized to HSCT with 1g/m2 cyclophosphamide / G-CSF mobilization and fludarabine / low dose cyclophosphamide / ATG conditioning versus standard of care and followed up for 48 weeks. Pre-specified interim analyses will be undertaken to confirm that the mobilization regimen is effective for stem cell harvest with no negative impact on disease activity. Colonoscopy at week 24 will assess the requirement for re-initiation of maintenance anti TNF therapy. OUTCOME: The primary outcome will be resolution of mucosal inflammation on endoscopy at week 48 in the ITT population assessed by a blinded adjudication panel. Secondary outcomes at week 48 will include clinical remission, and QOL, absolute CDAI, absolute SES CD and change in CDAI and SES CD. Long term clinical / safety follow up will be provided by the EBMT registry for at least 4 years post HSCTlite. ASSESSMENTS: Disease activity will be assessed by clinical score (CDAI), QOL (IBDQ), and mucosal disease activity (Ileo-colonoscopy and MRI). HSCT patients will have early MRI at week 4 which combined with blood and mucosal immune phenotype profiling will generate insight into the mechanism of action of HSCT and Crohn’s disease relapse. POWER: 62 patients in HSCT group and 31 in control group are required to detect a difference of 35%, based on 50% response in the HSCT group and 15% in controls, with 90% power. Allowing for 6% dropout, we will recruit 99 patients (66 to intervention & 33 to control) STATISTICAL ANALYSES will be based on ITT population. Parametric regression models will be fitted to the primary and secondary outcome measures to estimate treatment effects, controlling for study centre, and the corresponding baseline assessment for the outcome under investigation where appropriate. Secondary analyses will test treatment-effect mechanisms and possible predictive markers to select appropriate patients. RECRUITMENT: Based on experience with ASTIC, we anticipate recruitment will take 36 months. TIMELINE Trial set up commences: Month 1 First patient first visit: Month 9 Last patient consent: Month 44 Last patient visit: Month 56 Analysis / data cleaning: Month 64 Manuscript submission: Month 64 Long term follow up complete: Month 104

Lay abstract: Crohn’s disease occurs when the gut immune system becomes allergic to its bacterial content and causes bowel inflammation. Patients who have disease that does not respond to therapy suffer debilitating symptoms, poor quality of life and may require multiple operations which can result in a stoma. Initial reports suggested that the disease could be ‘cured’ with stem cell transplantation (HSCT), where a patient’s own stem cells are given back to them after their current immune system is destroyed by chemotherapy. Our original ASTIC trial showed that cure is rarely seen and that high dose chemotherapy led to significant side effects and one death. However, half the patients experienced complete healing of their intestinal inflammation, many responded to treatments which they had previously failed and the side effects were thought to be related to the high dose chemotherapy used. This trial (ASTIClite) will test our belief that HSCT with much lower doses of chemotherapy will still be effective but also safer. We also aim to assess the mechanism by which HSCT works. When we asked them, patients with refractory disease were keen to try this type of treatment. We propose to recruit 99 patients with active disease who are failing best current treatment. We will randomize 2 patients to low intensity HSCT for every patient that continues on standard care. At 24 weeks we will check whether HSCT patients have recurrent disease and treat them if required. At 48 weeks we will see if HSCT is more likely to lead to healing of gut inflammation than normal care. We will follow all patients to assess disease activity and adverse effects for a further 4 years. Scientific studies will be performed to assess the way that transplant helps Crohn’s disease. The trial has been designed by gastroenterologists, haematologists, scientists and patients. We anticipate it will give a clear answer as to whether HSCT is an effective and safe option in Crohn’s disease.

Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: ORAL AND GASTROINTESTINAL