Protocol and Other Essential Documents

Title

Autologous Stem Cell Transplantation - International Crohn's Disease Trial (ASTIC).

Indication 

Crohn's Disease.

Principle

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

Primary 

Objective

To evaluate the 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 in patients with Crohn's disease.

Secondary

Objectives

To evaluate the safety of Hematopietic Stem Cell Transplantation (HSCT) in Crohn's disease patients who have not responded to immunosuppressant medication.

To evaluate the impact of HSCT on health related, and generic, quality of life measures.

To identify factors predictive of success.

Primary Endpoint

The primary endpoint will be the proportion of patients in sustained disease remission at one year. Sustained disease remission, based upon ECCO consensus is defined as: A minimum of a 3 month period of Crohn's disease activity index (CDAI, 16) < 150 without steriods or immunosuppressive drugs and no mucosal erosion or ulceration at ileocolonoscopy and no definate evidence of small bowel Crohn's Disease on barium studies.

Secondary Endpoints

The Secondary endpoints are listed in full in Section 4.

Study Design

Open label, 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.

Medication

All medication used in the study is currently marketed and will be prescribed through the hospital pharmacies according to normal practice.

Study Sites

This is a multi-centre study involving hospitals in a number of European hospitals approved by the Trial Steering Committee as having appropriate clinical experience. 

Sample Size & Power

Minimum 48 patients, 24 per treatment arm. The Study will have 90% power to detect a rise in the rate of sustained remission from 30% to 75% (80% power for 70%).

L: leukapheresis

Cyclo: cyclophosphamide 

G-CSF: filgrastim

R: randomisation

ATG: antithymocyte globulin

M: mobilisation phase time point

PM: post mobilisation time point  

M and PM time points are flexible but every attempt should be made to make sure that M34 is simulaneous with visit T0 (which must be no more than  3 days before the first conditioning dose of cylcophosphamide).

1) Age between 18 and 50 years

a)Patients aged 50-65 can participate if specially approved by the Trial Steering Committee.

2) Confirmed diagnosis of active Crohn's Disease.

a) Diagnosis of Crohn's disease based on radiological appearances and / or typical histology.

b) Active disease at the time of registration to the trial, defined as:

i)Crohn's disease activity index (CDAI) ≥ 250 at any time within 3 months prior to trial entry and ≥ 2 of the following:

ii) raised CRP,

iii) endoscopic evidence of active disease confirmed on histology

iv) clear evidence of active small bowel Crohn's disease on small bowel barium study.

3) Unsatisfactory course  despite  3 immunosuppressive agents (usually azathioprine, methotrexate and infliximab) in addition to corticosteriods. Patients should have relapsing disease (i.e. ≥ 1 exacerbation/year) despite thiopurines, methotrexate and/or infliximab maintenance therapy or clear demonstrations of intolerance / toxicity to these drugs.

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

a) IBDQ (Appendix 5)

b) European Questionnaire of Lifequality (EuroQol-5D, Appendix 4)

c) Impaired function on Karnofsky index (Appendix 6)

5) Current problems unsuitable for surgery and patient is at risk for developing short bowel syndrome.

6) Informed consent

Sample Information Sheet and Consent Form given in Appendices 1 and 2 respectively)

a) Prepared to enter the controlled study

b) Prepared to undergo additional study proceedures as per trial schedule

c) Patient has undergone intensive counselling about the risks

d) Consent to future genotyping assessments is optional, but is not required for the patient to enter the trial 

1.2 Inclusion critieria: discretionary

1. Wherever possible, diseased tissue should be accessible endoscopically for objective histological study

a) Small bowel disease is that is extensive but does not extend to duodenum or terminal ileum is an exception, which will allow participation without endoscopy of diseased areas. All patients will however undergo flexible sigmoidoscopy

2. Smokers may enter the study provided they have received intensive counselling about smoking.

3. Patients with an ileostomy or colostomy may enter the study. Clinical activity should be assessed using modified CDAI and Harvey Bradshaw scoring method (See Appendix 3 and 8).

Exclusion criteria 

1) Pregnancy or unwillingness to use adequate contraception during the study, if a woman of childbearing age

2) Concomitant severe disease

a) renal: creatinine clearance ≤ 40 ml/min (measured or estimated).

b) cardiac: clinical evidence of refractory congestive heart failure; left ventricular ejection fraction ≤ 45% by multigated radionuclide angiography (MUGA) or cardiac echo; chronic atrial fibrillation necessitating oral anticoagulation; uncontrolled ventricular arrhythmia; pericardial effusion with hemodynamic consquences as evaluated by an experienced echocardiographer.

c) psychiatric disorders including active drug or alcohol abuse.

d) concurrent neoplasms or myelodyplasia

e) bone marrow insufficiency defined as leucocytopenia ≤ 3.0 x 10⁹ /1 thrombocytopenia ≤ 50 x 10⁹/1 anemia ≤ 8g/dl, CD4+ T Lymphopenia ≤ 200 x 10⁶/1

f) uncontrolled hypertension, defined as resting systolic blood pressure ≥ 140ml and / or resting diastolic pressure ≥ 90ml mercury despite at least 2 anti-hypertensive agents .

g) uncontrolled acute or chronic infection with HIV, HTLV - 1 or 2, hepatitis viruses or any other infection the investigator or Steering Committee consider a contraindication to participation.

h) Other chronic disease causing significant organ failure, including established cirrhosis with evidence or impaired synthetic function on biochemical testing and known respiratory disease causing resting arterial oxygen tension ≤ 8 kpa or carbon dioxide tension ≥ 6.7 kpa. Patients not known to have respiratory disease need not have blood gas measurements.

i) Crohn's disease symptoms predominantly due to fibrotic stricturing and unlikely to respond to immune manipulation, in the opinion of any of the investigators or the Steering Committee.

3) Infection or risk thereof.

a) Current abscess or significant active infection.

b) Perianal sepsis is not an exclusion provided there is natural free drainage or a Seton suture(s) have been placed.

c) History of tuberculosis or at current increased risk or tuberculosis.

d) Mantoux test result or other investigations that the investigator or Steering Committee regard as evidence of active tuberculosis.

e) Abnormal chest x ray (CXR) consistent with active infection or neoplasm.

4) Significant malnutrition:   Body Mass Index (BMI) ≤ 18, serum albumin < 20 g/l.

5) Previous poor compliance.

6) Concurrent enrolment in any other protocol using an investigational drug or hematopoietic growth factor up to four weeks before study entry.

7) Lack of funding.