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    Summary
    EudraCT Number:2019-001549-42
    Sponsor's Protocol Code Number:STH19379
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-02-03
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2019-001549-42
    A.3Full title of the trial
    A multicentre, randomised controlled trial to evaluate the efficacy of autologous haematopoietic stem cell transplantation versus alemtuzumab or ocrelizumab in relapsing remitting multiple sclerosis.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Stem cell transplantation versus disease modifying therapy (alemtuzumab or ocrelizumab) for patients with highly active relapsing remitting MS
    A.3.2Name or abbreviated title of the trial where available
    StarMS
    A.4.1Sponsor's protocol code numberSTH19379
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN88667898
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorSheffield Teaching Hospitals
    B.1.3.4Country
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSheffield Clinical Trials Research Unit, The University of Sheffield
    B.5.2Functional name of contact pointJennifer Petrie
    B.5.3 Address:
    B.5.3.1Street AddressRoom 2027 Regent Court, 30 Regent Street
    B.5.3.2Town/ citySheffield
    B.5.3.3Post codeS1 4DA
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01142220676
    B.5.6E-mailj.petrie@sheffield.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCyclophosphamide
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCyclophosphamide monohydrate
    D.3.9.1CAS number 50-18-0
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit gm/m2 gram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCyclophosphamide monohydrate
    D.3.9.1CAS number 50-18-0
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameFilgrastim
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFilgrastim
    D.3.9.1CAS number 121181-53-1
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit µg/kg microgram(s)/kilogram
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number5 to 10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Thymoglobuline
    D.2.1.1.2Name of the Marketing Authorisation holderGenzyme Europe B.V
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameThymoglobuline
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRabbit anti-human thymocyte immunoglobulin
    D.3.9.4EV Substance CodeAS4
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRabbit anti-human thymocyte immunoglobulin
    D.3.9.4EV Substance CodeAS8
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRabbit anti-human thymocyte immunoglobulin
    D.3.9.4EV Substance CodeAS9
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Alemtuzumab
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi Belgium
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAlemtuzumab
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAlemtuzumab
    D.3.9.4EV Substance CodeAS5
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLenograstim
    D.3.4Pharmaceutical form Powder and solvent for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLenograstim
    D.3.9.1CAS number 135968-09-1
    D.3.9.4EV Substance CodeAS6
    D.3.10 Strength
    D.3.10.1Concentration unit µg/kg microgram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5 to 10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 6
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Ocrelizumab
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameOcrelizumab
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOcrelizumab
    D.3.9.1CAS number 637334-45-3
    D.3.9.4EV Substance CodeAS7
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number600
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Highly active relapsing remitting multiple sclerosis
    E.1.1.1Medical condition in easily understood language
    Multiple sclerosis
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10028245
    E.1.2Term Multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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
    E.2.2Secondary 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

    E.2.3Trial contains a sub-study No
    E.2.3.1Full 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.

    E.3Principal 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.
    E.4Principal 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.
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    2 years after randomisation.
    E.5.2Secondary 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
    E.5.2.1Timepoint(s) of evaluation of this end point
    3 months, 6 months, 9 months, 12 months, 18 months and 24 months post randomisation
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned19
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    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.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days25
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days25
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 20
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 20
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 178
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state198
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 198
    F.4.2.2In the whole clinical trial 198
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The intervention is not a continuous therapy. Patients will continue to be monitored as per normal clinical practice after the trial is complete, and may have other treatment started if needed.
    During the study or when the research is complete, participants may be offered the opportunity to switch to the treatment given in the alternate arm to that which they were randomly allocated, if their illness remains active. All participants will receive ongoing care from their local NHS organisation.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation CRN Yorkshire and Humber
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-03-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-03-20
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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