A randomised controlled trial to assess the safety and effectiveness of stem cell transplantation using a reduced intensity regimen in patients with treatment resistant Crohn’s disease

INTERVENTION: Following consent, and confirmation of eligibility, participants are randomised, using a web‐based system to receive either the HSCTlite intervention, or standard care, in the ratio 2:1. HSCTlite Intervention: Participants receive HSCT therapy, some stem cells are removed (harvested) from the patient and stored for later use. The patient will then undergo a process to eliminate their immune cells. Then the stem cells that were harvested earlier are transplanted (re‐infused) back into the patient's blood. The re‐infused stem cells give rise to a new generation of immune cells, replacing cells of the original ‘sick’ immune system. The following are the steps: Mobilisation: Autologous stem cells are mobilised with cyclophosphamide 1g/m2 and G‐CSF 5mcg/kg starting 5 days after the infusion of cyclophosphamide. Daily CD34+ counts commence on day 8 following cyclophoshamide. Existing treatment other than corticosteroids (eg prednisolone) are stopped prior to HSCT as specified in the protocol. Mesna is given in line with local practice to prevent haemorrhagic cystitis. Leukapheresis: Once there are sufficient stem cells in the bloodstream (10x106/L), they are harvested via leukapheresis (minimum harvest is 2x106 CD34+ve cells). The collected cells are cryopreserved until later use at transplantation. Immunoablation: The conditioning regimen comprises cyclophosphamide (60mg/kg/day) given on each of 2 days, with Fludarabine, 3 days prior to this at 25mg/m2/day for 5 days. Antithymocyte globulin (‘ATG’) is also given for 3 days starting the same day as cyclophosphamide at 2.5mg/kg/day. Methylprednisolone (1mg/kg/day) are used to reduce side effects. Mesna and all supportive care are given in line with local practice Stem cell transplant (day 0): Stem cells are reinfused into the patient on trial day 0. G‐CSF (5mcg/kg/day) starts after 5 days. Follow up tests and visits that are routine following HSCT are carried out according to local policies, and may be in addition to CONDITION: Refractory Crohn's disease ; Digestive System ; Crohn's disease PRIMARY OUTCOME: Regression of mucosal ulceration is assessed using the SES‐CD ulcer sub score on colonoscopy at week 48. SECONDARY OUTCOME: Current secondary outcome measures as of 15/03/2018:; Clinical secondary outcome measures:; 1. Clinical remission is measured using the Crohn’s Disease Activity Index (CDAI) at baseline, week 8, week 14, week 24, week 32, week 40 and week 48; 2. Steroid free clinical remission is measured using the CDAI at baseline, week 8, week 14, week 24, week 32, week 40 and week 48; 3. Clinical remission is measured using the Harvey Bradshaw Index (HBI) at baseline, week 8, week 14, week 24, week 32, week 40 and week 48; 4. Clinical remission is measured using the PRO2 at baseline, week 8, week 14, week 24, week 32, week 40 and week 48; 5. Absolute Crohn’s Disease activity is measured using the CDAI at baseline and week 48; 6. Endoscopic ulceration is measured using the SES‐CD at baseline and week 48; 7. Change in CDAI score is measured between baseline and week 48; 8. Change in SES‐CD score is measured between baseline and week 48; 9. Complete endoscopic remission is measured using the SES‐CD at baseline and week 48; ; Safety secondary outcome measures:; 1. Toxicity of chemotherapy is measured using NCI CTCAE grading of adverse events at week 4, week 8, week 14, week 24, week 32, week 40 and week 48; 2. Adverse events are measured through documentation of adverse events at week 4, week 8, week 14, week 24, week 32, week 40 and week 48; ; Patient‐reported secondary outcome measures:; 1. Crohn’s disease specific quality of life is measured using the IBDQ at baseline, week 8, week 14, week 24, week 32, week 40 and week 48; 2. Crohn’s disease specific quality of life is measured using the IBD Control questionnaire at baseline, week 8, week 14, week 24, week 32, week 40 and week 48; 3. Quality of life is measured using the EQ‐5D‐5L at baseline, week 8, week 14, week 24, week 32, week 40 and week 48; 4. Healthcare resource use is measured using the healthcare resource utilisation questionnaire at baseline, week 8, week 14, week 24, week 32, week 40 and week 48; ; Exploratory secondary outcome measures:; 1. Efficacy of re‐introduction of anti‐TNF therapy in patients with disease recurrence post‐HSCT is measured using the change in CDAI between baseline and 6 weeks after initiation of anti‐TNF therapy; 2. Efficacy of re‐introduction of anti‐TNF therapy in patients with disease recurrence post‐HSCT is measured using the change in SES‐CD between 0 and 22 weeks after initiation of anti‐TNF therapy; 3. Safety of re‐introduction of anti‐TNF therapy in patients with disease recurrence post‐HSCT is measured through documentation of adverse events at week 32, week 40 and week 48; ; Mechanistic secondary outcome measures:; 1. Timeline of response to HSCTlite is measured through MRI at week 4 and week 48; 2. Nature of immune re‐constitution after HSCT is measured through blood sample analysis at week 8, week 14, week 24, week 32 and week 48; 3. Immunological events that precede the onset of disease recurrence post HSCT is measured through blood sample analysis at week 8, week 14, week 24, week 32 and week 48; 4. Mechanism of restoration of responsiveness to anti‐TNF therapies if appropriate is measured through blood sample analysis at week 8, week 14, week 24, week 32 and week 48; ; ; Previous version:; Clinical secondary outcome measures:; 1. Clinical remission is measured using the Crohn’s Disease Activity Index (CDAI) at baseline, week 8, week 14, week 24, week 32, week 40 and week 48; 2. Steroid free clinical remission is measured using the CDAI at baseline, week 8, week 14, week 24, week 32, week 40 and week 48; 3. Clinical remission is measured using the Harvey Bradshaw Index (HBI) at baseline, week 8, week 14, week 24, week 32, week 40 and week 48; 4. Clinical remission is measured using the PRO2 at baseline, week 8, week 14, week 24, week 32, week 40 and week 48; 5. Absolute Crohn’s Disease activity is measured using the CDAI at baseline and week 48; 6. Endoscopic ulceration is measured using the SES‐CD at baseline and week 48; 7. Change in CDAI score is measured between baseline and week 48; 8. Change in SES‐CD score is measured between baseline and week 48; 9. Complete endoscopic remission is measured using the SES‐CD at baseline and week 48; ; Safety secondary outcome measures:; 1. Toxicity of chemotherapy is measured using NCI CTCAE grading of adverse events at week 4, week 8, week 14, week 24, week 32, week 40 and week 48; 2. Adverse events are measured through documentation of adverse events at week 4, week 8, week 14, week 24, week 32, week 40 and week 48; ; Patient‐reported secondary outcome measures:; 1. Crohn’s disease specific quality of life is measured using the IBDQ at baseline, week 8, week 14, week 24, week 32, week 40 and week 48; 2. Crohn’s disease specific quality of life is measured using the IBD Control questionnaire at baseline, week 8, week 14, week 24, week 32, week 40 and week 48; 3. Quality of life is measured using the EQ‐5D‐5L at baseline, week 8, week 14, week 24, week 32, week 40 and week 48; 4. Healthcare resource use is measured using the healthcare resource utilisation questionnaire at baseline, week 8, week 14, week 24, week 32, week 40 and week 48; ; Exploratory secondary outcome measures:; 1. Efficacy of re‐introduction of anti‐TNF therapy in patients with disease recurrence post‐HSCT is measured using the change in CDAI between baseline and 6 weeks after initiation of anti‐TNF therapy; 2. Efficacy of re‐introduction of anti‐TNF therapy in patients with disease recurrence post‐HSCT is measured using the change in SES‐CD between 0 and 22 weeks after initiation of anti‐TNF therapy; 3. Safety of re‐introduction of anti‐TNF therapy in patients with disease recurrence post‐HSCT is measured through documentation of adverse events at week 32, week 40 and week 48; ; Mechanistic secondary outcome measures:; 1. Timeline of response to HSCTlite is measured through MRI at week 4 and week 48; 2. Nature of immune re‐constitution after HSCT is measured through blood sample analysis at week 8, week 14, week 24, week 32 and week 48; 3. Immunological events that precede the onset of disease recurrence post HSCT is measured through blood sample analysis at week 8, week 14, week 24, week 32 and week 48; 4. Mechanism of restoration of responsiveness to anti‐TNF therapies if appropriate is measured through blood sample analysis at week 8, week 14, week 24, week 32 and week 48; 5. Responses to vaccination post HSCT is measured through blood sample analysis at week 8, week 14, week 24, week 32 and week 48 INCLUSION CRITERIA: 1. Participant of any gender, aged between 18 – 60 2. Participants must be willing and able to provide full informed consent 3. Participants should be well nourished and of healthy weight in the opinion of the PI (typically BMI >18.5) 4. Diagnosis of CD using colonoscopy, histology and/or radiology 5. Disease duration of at least six months 6. Disease distribution accessible to endoscopic assessment (ileal, ileo‐caecal, or colonic) 7. Active clinical CD activity with impaired quality of life at any time within 3 months prior to randomisation into the trial, as assessed by a gastroenterology clinician 8. Participants will be refractory or intolerant to azathioprine, mercaptopurine or methotrexate 9. Participants will be refractory or intolerant to at least two classes of biologic therapy (currently anti‐TNF therapy, Vedolizumab or Ustekinumab) despite dose optimisation 10. Participants where surgery is considered not appropriate or has bee