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Note: This record shows only 22 elements of the WHO Trial Registration Data Set. To view changes that have been made to the source record, or for additional information about this trial, click on the URL below to go to the source record in the primary register.
Register: EUCTR
Last refreshed on: 29 June 2020
Main ID:  EUCTR2019-001549-42-GB
Date of registration: 03/02/2020
Prospective Registration: Yes
Primary sponsor: Sheffield Teaching Hospitals
Public title: Stem cell transplantation versus disease modifying therapy (alemtuzumab or ocrelizumab) for patients with highly active relapsing remitting MS
Scientific title: A multicentre, randomised controlled trial to evaluate the efficacy of autologous haematopoietic stem cell transplantation versus alemtuzumab or ocrelizumab in relapsing remitting multiple sclerosis. - StarMS
Date of first enrolment: 27/03/2020
Target sample size: 198
Recruitment status: Authorised-recruitment may be ongoing or finished
URL:  https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-001549-42
Study type:  Interventional clinical trial of medicinal product
Study design:  Controlled: yes
Randomised: yes
Open: yes
Single blind: no
Double blind: no
Parallel group: yes
Cross over: no
Other: no
If controlled, specify comparator, Other Medicinial Product: yes
Placebo: no
Other: no
Number of treatment arms in the trial: 2
 
Phase:  Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no
Countries of recruitment
United Kingdom
Contacts
Name: Jennifer Petrie   
Address:  Room 2027 Regent Court, 30 Regent Street S1 4DA Sheffield United Kingdom
Telephone: 01142220676
Email: j.petrie@sheffield.ac.uk
Affiliation:  Sheffield Clinical Trials Research Unit, The University of Sheffield
Name: Jennifer Petrie   
Address:  Room 2027 Regent Court, 30 Regent Street S1 4DA Sheffield United Kingdom
Telephone: 01142220676
Email: j.petrie@sheffield.ac.uk
Affiliation:  Sheffield Clinical Trials Research Unit, The University of Sheffield
Key inclusion & exclusion criteria
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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes
Health Condition(s) or Problem(s) studied
Highly active relapsing remitting multiple sclerosis
MedDRA version: 20.1 Level: PT Classification code 10028245 Term: Multiple sclerosis System Organ Class: 10029205 - Nervous system disorders
Therapeutic area: Diseases [C] - Nervous System Diseases [C10]
Intervention(s)

Product Name: Cyclophosphamide
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: Cyclophosphamide monohydrate
CAS Number: 50-18-0
Concentration unit: gm/m2 gram(s)/square meter
Concentration type: equal
Concentration number: 2 -
INN or Proposed INN: Cyclophosphamide monohydrate
CAS Number: 50-18-0
Concentration unit: mg/kg milligram(s)/kilogram
Concentration type: equal
Concentration number: 50-

Product Name: Filgrastim
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Filgrastim
CAS Number: 121181-53-1
Concentration unit: µg/kg microgram(s)/kilogram
Concentration type: range
Concentration number: 5-10

Trade Name: Thymoglobuline
Product Name: Thymoglobuline
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: Rabbit anti-human thymocyte immunoglobulin
Concentration unit: mg/kg milligram(s)/kilogram
Concentration type: equal
Concentration number: 0.5-
INN or Proposed INN: Rabbit anti-human thymocyte immunoglobulin
Concentration unit: mg/kg milligram(s)/kilogram
Concentration type: equal
Concentration number: 1-
INN or Proposed INN: Rabbit anti-human thymocyte immunoglobulin
Concentration unit: mg/kg milligram(s)/kilogram
Concentration type: equal
Concentration number: 1.5-

Trade Name: Alemtuzumab
Product Name: Alemtuzumab
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Alemtuzumab
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 12-

Product Name: Lenograstim
Pharmaceutical Form: Powder and solvent for solution for injection/infusion
INN or Proposed INN: Lenograstim
CAS Number: 135968-09-1
Concentration unit: µg/kg microgram(s)/kilogram
Concentration type: equal
Concentration number: 5-10

Trade Name: Ocrelizumab
Product Name: Ocrelizumab
P
Primary Outcome(s)
Main Objective: The main objective of this trial is to assess whether autologous haematopoietic stem cell transplantation (aHSCT) is more effective at maintaining clinical stability in patients with highly active relapsing remitting multiple sclerosis (RRMS) than treatment with a disease modifying therapy (alemtuzumab or ocrelizumab).

Definitions:
Autologous = cells or tissue obtained from the same individual
Haematopoietic = cells that give rise to blood cells
Primary end point(s): Proportion of patients who have maintained NEDA status (defined as the absence of all three of the following: protocol defined clinical relapses; 6 months confirmed EDSS progression of at least 1 point with an absence of relapse at the time of assessment; any evidence of MRI disease activity as defined by T1 Gd-enhanced lesion or new and/or enlarging T2 lesion after month 6) in the 2-year post-randomisation follow up period.
Secondary Objective: The secondary objectives are:
- to assess the safety and toxicity of aHSCT compared to DMTs (alemtuzumab or ocrelizumab)
- to assess the impact of aHSCT compared to DMTs (alemtuzumab or ocrelizumab) on disability and quality of life
- to assess the impact of aHSCT compared to DMTs (alemtuzumab or ocrelizumab) on other clinical outcomes

Timepoint(s) of evaluation of this end point: 2 years after randomisation.
Secondary Outcome(s)
Secondary end point(s): Safety

i) Serious adverse event (SAE) rate within the 2-year follow up period for each treatment arm
ii) Mortality rate (grade 5 SAEs) within the 2-year follow up period for each treatment arm
iii) Combined grade 4 and 5 SAE rates within the 2-year follow up period for each treatment arm
iv) Total number of adverse events (AEs) experienced by each patient in the 100 days post-randomisation
v) Total number of AEs within the 2-year follow up period for each treatment arm
vi) Long term safety events, including rates of significant infections, endocrine and reproductive dysfunction, secondary autoimmune diseases, incidence of late cardiovascular events, neoplasia and any other significant organ dysfunction within the 2-year follow up period (Ongoing data will be recorded for aHSCT participants via routine BSBMT/EBMT registry however follow up and analysis will be subject to additional funding and support). Please refer to section 8 for the suggested long term screening assessments for late effects of HSCT.

Clinical outcomes

i) Time to evidence of disease activity. Disease activity is defined as the presence of one of the following: protocol defined clinical relapses; confirmed EDSS progression of at least 1 point sustained for 6 months with an absence of relapse at the time of assessment; evidence of MRI disease activity defined as T1 Gd-enhanced lesion or new and/or enlarging T2 lesion after the re-baseline MRI at 6 months post-randomisation.
ii) EDSS scores at 3, 6, 9, 12, 18 and 24 months post-randomisation
iii) MSFC scores at 3, 6, 9, 12, 18 and 24 months post-randomisation
iv) Low contrast visual acuity scores at 3, 6, 9, 12, 18 and 24 months post-randomisation

Quality of Life/Health Economic Measures

i) EQ-5D-5L utility scores at 3, 6, 9, 12, 18 and 24 months post-randomisation
ii) Eight RAND SF-36 dimension (Physical functioning, Role limitations due to physical health, Role limitations due to emotional problems, Energy/fatigue, Emotional well-being, Social functioning, Pain, General Health) scores at 3, 6, 9, 12, 18 and 24 months post-randomisation
iii) WHO QOL-Bref scores at 3, 6, 9, 12, 18 and 24 months post-randomisation
iv) Global rating of change at 3, 6, 9, 12, 18 and 24 months post-randomisation
Timepoint(s) of evaluation of this end point: 3 months, 6 months, 9 months, 12 months, 18 months and 24 months post randomisation
Secondary ID(s)
STH19379
Source(s) of Monetary Support
Secondary Sponsor(s)
Ethics review
Status: Approved
Approval date: 20/03/2020
Contact:
Results
Results available:
Date Posted:
Date Completed:
URL:
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