Stem cell transplantation versus disease modifying therapy (alemtuzumab or ocrelizumab) for patients with highly active relapsing remitting MS

Phase 1

• Conditions: Highly active relapsing remitting multiple sclerosis; MedDRA version: 20.1Level: PTClassification code 10028245Term: Multiple sclerosisSystem Organ Class: 10029205 - Nervous system disorders; Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

• Registration Number: EUCTR2019-001549-42-GB
• Lead Sponsor: Sheffield Teaching Hospitals

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-02-03
• Last Update Posted: 29 June 2020

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 198

Inclusion Criteria

1. Diagnosis of MS using the 2017 McDonald criteria.
2. Age 16-55 inclusive.
3. EDSS 0-6.0 inclusive*. If the EDSS score is 6.0 this must be due to confirmed relapse rather than progressive disease.
4. Severe inflammatory disease defined as RRMS course with 2 or more protocol defined relapses, or 1 such relapse and evidence of MRI disease activity >3 months before or after its onset, in last 12 months despite being on a DMT*.
5. Clinical stability for >30 days following last relapse at the time of screening.
6. Satisfactory EBMT Autoimmune Disease Working Party (ADWP) recommended screening assessment prior to aHSCT.
7. Participants who have been reviewed by the central neurology team and confirmed as eligible.
8. Participants who, in the opinion of the local haematology lead or delegate, are fit enough to undergo treatment.
9. Able to undergo MRI examination.

* Patients with EDSS scores of 0-1.5 or those who failed only first line treatments must also fulfil following criteria: short illness duration (<5 years), active disease clinically and radiologically (i.e. at least 2 relapses in the last 12 months and evidence of multiple Gad enhancing MRI lesion), high brain lesion load and brain or spinal cord atrophy.

Are the trial subjects under 18? yes
Number of subjects for this age range: 20
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 178
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

Exclusion Criteria

1. Diagnosis of primary or secondary progressive MS.
2. Disease duration of >10 years from symptom onset (note: symptoms must be clearly attributable to MS).
3. Previous use of alemtuzumab, ocrelizumab or cladribine.
4. Previous HSCT for any reason, or any previous experimental or commercial stem cell therapy.
5. JCV antibody Index of >1.5 in patients previously treated with natalizumab (unless they are CSF JCV PCR negative).
6. Prior diagnosis of Hepatitis B, Hepatitis C or HIV infection or current TB infection.
7. Pregnant or breast-feeding females.
8. Unwilling to use adequate contraception during the trial. Female participants of child-bearing potential must be willing to use adequate contraception for the duration of the trial (24 months). Male participants with female partners of child-bearing potential must be willing to use adequate contraception if they are randomised to the aHSCT arm until at least 6 months after discontinuation of cyclophosphamide.
9. Unable to comply with treatment protocol.
10. Contraindication to the use of cyclophosphamide, G-CSF (filgrastim or lenograstim) or rabbit ATG.
11. Participants with significant medical co-morbidity that precludes aHSCT as assessed by the local haematology team.
12. Significant language barriers, which are likely to affect the participant’s understanding of the study, or ability to complete outcome questionnaires.
13. Concurrent participation in another interventional clinical trial.
14. AST and ALT >2.5 x upper limit of normal (ULN), bilirubin > 1.5 x ULN or direct bilirubin >ULN for participants with total bilirubin levels >1.5 x ULN
15. Current diagnosis of a clinically defined bleeding disorder (patients with platelet counts of 100x109/l or above up to normal range are not excluded, as per section 18d. Persistently abnormal coagulation tests should be addressed to determine whether they constitute a defined bleeding disorder).
16. Current diagnosis of a clinically defined autoimmune disorder other than multiple sclerosis. (i.e. meeting full current international clinical and laboratory criteria for a specific autoimmune disorder).
17. Patients with history of myocardial infarction, angina pectoris, stroke or arterial dissection
18. Participants who are not considered medically fit for aHSCT defined by any of the following. Note that these criteria are not automatic exclusion criteria but if any of these criteria are met, and in the opinion of the PI the participant is medically fit enough to undergo aHSCT, the case may be put forward to the central team for discussion about eligibility:
a.Renal: creatinine clearance <40ml/min (measured or estimated)
b.Cardiac: clinical evidence of refractory congestive heart failure, left ventricular ejection fraction <45% by cardiac echo; uncontrolled ventricular arrhythmia; pericardial effusion with haemodynamic consequences as evaluated by an experienced echo cardiographer
c.Concurrent neoplasms or myelodysplasia
d.Bone marrow insufficiency defined as neutropenia with an absolute neutrophil count <1x109/l, or thrombocytopenia with a platelet count <100x109/l, or anaemia with a haemoglobin <100g/l
e. Diagnosis of hypertension, which is uncontrolled despite at least 2 anti-hypertensive agents.
f.Uncontrolled acute or chronic infection with any infection the investigator or central team consider a contraindication to participation. (N.B. Baseline JC virus serology will be recorded, but positivity w

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified