| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Highly active relapsing remitting multiple sclerosis |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028245 |
| E.1.2 | Term | Multiple sclerosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| 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 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 |
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| E.2.2 | Secondary objectives of the trial |
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
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| E.2.3 | Trial contains a sub-study | No |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Neuropsychology study (details included in main study protocol)
Objectives:
1. Assess the effect of aHSCT on cognitive recovery using the Cambridge Neuropsychological Test Automated Battery (CANTAB), an automated battery of neuropsychological assessments (https://www.cambridgecognition.com/) measured at 3, 6, 9, 12, 18 and 24 months.
2. To assess whether the two interventions differentially affect the degree of cognitive impairment after treatment using the CANTAB outcome.
Outcomes/Endpoints:
1. Cambridge Neuropsychological Test Automated Battery (CANTAB) scores at 3, 6, 9, 12, 18 and 24 months post-randomisation
Note that study sites will be provided with a tablet computer in order for participants to complete the CANTAB assessments (see section 9.6). The results of the assessments will be entered into the Prospect database by site staff. CTRU statisticians will be responsible for the analysis of the data generated by the neuropsychology study with input from Professor Venneri and her team.
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| E.3 | Principal 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. Participants who have been reviewed by the central neurology team and confirmed as eligible.
7. Participants who, in the opinion of the local haematology lead or delegate, are fit enough to undergo treatment.
8. 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.
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| E.4 | Principal 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), and for 12 months after discontinuation of Cyclophosphamide or Ocrelizumab, or 4 months after the last dose of Alemtuzumab. Male participants with female partners of child-bearing potential must use adequate contraception if they are randomised to the aHSCT arm during treatment and for at least six months following discontinuation (i.e. the last dose) 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. 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 will not be an exclusion criterion).
g. Other chronic disease causing significant organ failure, including established cirrhosis with evidence of impaired synthetic function on biochemical testing. This also includes known respiratory disease which, in the opinion of the local haematologist would represent a significant risk to the safe administration of aHSCT. Patients for whom there is concern about potential respiratory disease must undergo formal evaluation by a respiratory physician, including pulmonary function and blood gas measurement. |
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| E.5 End points |
| E.5.1 | 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. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 2 years after randomisation. |
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| E.5.2 | 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
v) Symbol digit modalities test (SDMT) 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) Global rating of change at 3, 6, 9, 12, 18 and 24 months post-randomisation
iv) MSQOL-54 scores at 3, 6, 9, 12, 18 and 24 months post-randomisation
v) NFI-MS scores at 3, 6, 9, 12, 18 and 24 months post-randomisation
vi) HADS scores at 3, 6, 9, 12, 18 and 24 months post-randomisation |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 3 months, 6 months, 9 months, 12 months, 18 months and 24 months post randomisation |
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| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 19 |
| 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 | No |
| 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
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| The end of the trial is defined as the end of the grant funding period, assuming that this is after last patient last visit (LPLV), to allow for ongoing study sample analysis. Where LPLV occurs after the end of the grant funding period the end of trial will be defined as LPLV. |
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| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | 25 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 25 |
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