ASTIC Autologous Stem Cell Transplantation for Crohn's Disease

• * Proportion of patients in alternative sustained disease remission
• * Weeks in symptomatic remission over 1 year
• * Weeks in alternative symptomatic remission over 1 year
• * Mean change from baseline in CDAI at 1 year
• * Mean change from baseline in Harvey Bradshaw score at 1 year
• * Mean CDAI over months 3-12 after transplant date
• * Median Harvey Bradshaw score over months 3-12 after transplant date
• * Total steroid use over 1 year
• * Steroid use over months 3-12.
• * Number of days in clinical remission
• * Number of days in alternative clinical remission
• * Days in drug free remission
• * Days in alternative drug free remission
• * Time to and days in sustained disease remission
• * CRP at 1 year and average over months 3-12
• * Alpha-1 glycoprotein at 1 year and average over months 3-12
• * Platelet count at 1 year and average over months 3-12.
• * Change in CDEIS over 1 year
• * Histology

• Impact of HSCT on health related, and generic, quality of life measures [ Time Frame: 1 - 2 Years ] [ Designated as safety issue: No ]
  To evaluate the impact of HSCT on health related, and generic, quality of life measures
• To identify factors predictive of success [ Time Frame: 1-2 years ] [ Designated as safety issue: No ]
  To identify factors predictive of success

Transplant study for patients with relapsing Crohn's disease demonstrating clear intolerance or toxicity to conventional treatment.

The purpose of this study is to determine whether there is a potential clinical benefit of hematopoietic stem cell mobilisation followed by high dose immuno-ablation and autologous stem cell transplantation versus hematopoietic stem cell mobilisation only followed by best clinical practice.

Open label, phase III, randomised, multicentre study comparing early transplantation procedure with transplantation carried out to the same protocol but delayed by one year. The status of patients undergoing early HSCT will be evaluated after one year and compared to those about to undergo delayed HSCT

Patients will be randomised to:

• Hematopoietic stem cell mobilisation followed, within 4 weeks, by high dose immunoablation and autologous stem cell transplantation
• Hematopoietic stem cell mobilisation followed, after 59 weeks, by high dose immunoablation and autologous hematopoietic stem cell transplantation

All patients will be mobilised prior to randomisation. Those receiving early transplantation will be compared over the first year with those whose transplant has been delayed.

• Experimental: Transplant Arm
  Hematopoietic stem cell mobilisation followed, within 4 weeks, by high dose immunoablation and autologous stem cell transplantation
  Intervention: Procedure: Autologous haematopoietic stem cell transplant
• Experimental: Delayed Transplant
  Hematopoietic stem cell mobilisation followed, after 59 weeks, by high dose immunoablation and autologous hematopoietic stem cell transplantation
  Intervention: Procedure: Autologous haematopoietic stem cell transplant

Inclusion Criteria:

Inclusion criteria: mandatory

1. Age between 18 and 50 years (Patients aged 50-65 can participate if specially approved by the Trial Steering Committee)
2. Confirmed diagnosis of active Crohn's Disease
3. Unsatisfactory course despite 3 immunosuppressive agents (usually azathioprine, methotrexate and infliximab) in addition to corticosteroids. Patients should have relapsing disease (i.e. >1 exacerbation/year) despite thiopurines, methotrexate and/or infliximab maintenance therapy or clear demonstration of intolerance / toxicity to these drugs.

4. Impaired function and quality of life, compared to population means, on at least one of the following:

   1. IBDQ (Appendix 6)
   2. European Questionnaire of Life quality (EuroQOL-5D, Appendix 4)
   3. SF-36 Appendix 5)
   4. Impaired function on Karnofsky index (Appendix 7)
5. Current problems unsuitable for surgery and patient at risk for developing short bowel syndrome.
6. Informed consent

Inclusion criteria: discretionary

1. Wherever possible, diseased tissue should be accessible endoscopically for objective histological study but in the case of small bowel disease that is extensive but does not extend to duodenum or terminal ileum, participation without endoscopy is allowed.
2. Smokers may enter the study provided they have received intensive counselling about smoking.

Exclusion Criteria:

1. Pregnancy or unwillingness to use adequate contraception during the study
2. Concomitant severe disease
3. Diarrhoea due to short small or large bowel
4. Infection or risk thereof
5. Significant malnutrition: Body Mass Index (BMI) ≤18, serum albumin <20 g/l
6. Previous poor compliance
7. Concurrent enrolment in any other protocol using an investigational drug or hematopoietic growth factor up to four weeks before study entry.
8. Lack of funding