| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Refractory Crohn's Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Crohn's Disease that has not responded to previous treatment |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011401 |
| E.1.2 | Term | Crohn's disease |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The main objective of this trial is to assess whether autologous haematopoietic stem call transplantation (HSCT) with a low intensity treatment regimen (lite) is safe and effective in inducing regression of ileo-colonic ulceration in Crohn's Disease, where previous treatments have been unsuccessful, compared with standard care.
Definitions:
Autologous - cells or tissue obtained from the same individual
Hematopoietic - cells that give rise to blood cells |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
1. To assess the impact of HSCTlite on clinical disease activity, quality of life and adverse events compared to standard care.
2. To assess whether HSCTlite is a safe regimen for patients with refractory Crohn's Disease.
3. To assess the safety and efficacy of anti-TNF therapy in patients who demonstrate endoscopic disease recurrence at week 24 after HSCTlite. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Mechanistic substudy embedded within the main trial
HSCT is thought to induce regression of autoimmune diseases by altering the diversity of the T cell receptor repertoire and generating functional renewal of regulatory T cells. Neither the mechanism of action nor the time-course of response is known in CD.
The objectives of this mechanistic substudy are:
1. Intestinal MRI will be performed to determine the early impact on mucosal disease, at week 4 post-HSCT (intervention arm only).
2. Immune profiling of peripheral blood (samples at week 8, 14, 24, 32 and 48) and mucosal biopsies (samples at week 24 and 48) will:
a. Characterise immune re-constitution after HSCT, and assess impact of HSCT on disease activity
b. Assess immunological events that precede disease recurrence post HSCT
c. Assess the mechanism of restoration of responsiveness to anti-TNF therapies
d. Confirm appropriate responses to vaccination post HSCT |
|
| E.3 | Principal inclusion criteria |
A participant is eligible for the study if the following criteria are met:
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 been declined.
11.Endoscopic evidence of active disease in screening (SES CD ulceration sub-score of 2 or more in at least one segment).
12.Satisfactory EBMT Autoimmune Disease Working Party (ADWP) recommended screening assessment prior to HSCT.
13.Willingness to discontinue all immunosuppressant medication after randomisation if allocated to HSCT arm.
14.Participants, who, in the opinion of the TMG, are fit enough to undergo treatment. |
|
| E.4 | Principal exclusion criteria |
A participant is not eligible for the study if any of the following criteria are met:
1.Diagnosis of ulcerative colitis or indeterminate colitis.
2.No evidence of active CD on screening ileocolonoscopy.
3.Inability to assess for active disease at ileocolonoscopy due to strictures.
4.Undrained perianal fistulae (patients with previous perianal disease or perianal disease adequately drained with a seton in situ are eligible).
5.Presence of undrained perianal sepsis on screening pelvic MRI.
6.Evidence of intra-abdominal sepsis on abdominal MRI.
7.Active or latent mycobacterial infection.
8.Prior exposure to Hepatitis B, Hepatitis C or HIV.
9.Evidence of an enteric or systemic infection.
10.Participant is currently pregnant or breastfeeding, or planning pregnancy within the study duration. Current pregnancy will be confirmed with a pregnancy test at screening assessment.
11.Unwilling to use adequate contraception (if appropriate) during duration of 48 week follow up.
12.Participants with significant medical co-morbidity that precludes HSCT adjudicated by the TMG.
13.Participants with significant psychiatric co-morbidity.
14.Significant language barriers, which are likely to affect the participant’s understanding of the study, or ability to complete outcome questionnaires.
15.Concurrent participation in another interventional clinical trial.
16.Participants who are not considered medically fit for HSCT defined by any of the following. Participants who meet one or more of the below criteria, who, in the opinion of the local investigator are medically fit, may be discussed at TMG for potential inclusion, and this will be documented in the patient’s notes, and the site file:
a.Renal: creatinine clearance <40ml/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; uncontrolled ventricular arrhythmia; pericardial effusion with haemodynamic consequences as evaluated by an experienced echo cardiographer
c.Hepatic: AST > two times the upper limit of normal
d.Concurrent neoplasms or myelodysplasia
e.Bone marrow insufficiency defined as neutropenia with an absolute neutrophil count <1x109/l, or thrombocytopenia with a platelet count <50x109/l, or anaemia with a haemoglobin <80g/l
f.Uncontrolled hypertension, defined as resting systolic blood pressure >= 140ml and/or resting diastolic pressure >= 90ml mercury despite at least 2 anti-hypertensive agents (subject to discussion at TMG).
g.Uncontrolled acute or chronic infection with HIV, HTLV – 1 or 2, hepatitis viruses or any other infection the investigator or TMG consider a contraindication to participation.
h.Other chronic disease causing significant organ failure, including established cirrhosis with evidence of impaired synthetic function on biochemical testing and known respiratory disease causing resting arterial oxygen tension <8kPa or carbon dioxide tension >6.7kPa. FEV1/FVC <50%. Patients not known to have respiratory disease need not have blood gas measurements.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Treatment success at week 48 defined as mucosal healing (no endoscopic ulceration (SES CD ulcer sub score = 0, assessed by adjudication panel blind to allocation and time of assessment)) without surgery or death. Patient who do not complete the week 48 colonoscopy will be categorised as treatment failures. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 48 post stem cell transplant in the intervention arm, and week 48 (plus 49 days) post randomisation for the control arm. |
|
| E.5.2 | Secondary end point(s) |
Clinical endpoints
1.Clinical remission (CDAI <150)
2.Steroid free clinical remission (CDAI <150)
3.Clinical remission (Harvey Bradshaw Index ≤4)
4.Clinical remission (PRO2 – mean scores – abdominal pain ≤1, stool frequency ≤1.5)
5.Absolute CDAI at week 48
6.Absolute SES CD at week 48
7.Change in CDAI and SES CD between baseline and week 48
8.Proportion of patients in complete endoscopic remission (SES CD score of 0)
Safety endpoints
1.Toxicity of chemotherapy using NCI CTCAE criteria version 4.03
2.Adverse events (AEs) and Serious Adverse Events (SAEs), including mortality
Patient-reported endpoints
1.Disease specific quality of life using the IBDQ
2.Disease specific quality of life using the IBD Control
3.Quality of life using the EQ-5D-5L
4.Health care resource utilisation questionnaire
Exploratory secondary endpoints
1.Efficacy of re-introduction of anti-TNF therapy in patients with disease recurrence post-HSCT (change in CDAI at 6 weeks and change in SES CD at 22 weeks after initiation)
2.Safety of re-introduction of anti-TNF therapy in patients with disease recurrence post-HSCT
3.Presence of any of the late side effects of HSCT
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 48 post stem cell transplant in the intervention arm, and week 48 (plus 49 days) post randomisation for the control arm. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Can include steroids, immunomodulators, licensed/approved biologic therapy or enteral/IV nutrition |
|
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| LVLS. The end of the trial is defined as the date of the last recruited participant's week 48 follow up visit. Sites will be closed once data cleaning is completed and the regulatory authority and ethics committee will be informed. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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