Testing and comparing multiple drugs at once against the standard treatment for progressive multiple sclerosis treatment

INTERVENTION: Participants will be randomised at each site via the OCTOPUS eDC System, a centrally managed system hosted by MRC CTU, accessible to authorised members of the research teams at recruiting site using a web‐based interface. Eligibility and consent will be verified before each participant is randomised and is then confirmed within the system at the time of randomisation. If participants are ineligible for an arm, they can be assessed for eligibility and randomised to other open arms. Participants will be allocated using an eDC system into one of the three arms in a 1:1:1 ratio utilising minimisation based on key prognostic factors and a random element. OCTOPUS is a blinded trial therefore all participants have the same dosing and assessment schedule. Following randomisation, participants will initially be asked to take the “low dose” of 2 capsules a day in the evening shortly after a meal (called the low dose) for 4 weeks. If the participant is tolerating this dose and they are happy to do so, they will then have their dosage increased to the high dose of 2 capsules twice a day shortly after meals (a total of 4 capsules). Participants will be asked to visit your study doctor at one month; have a telephone call at three months, and then another visit at si Xmonths. After this you will be asked to visit the hospital every 6 months for up to 5 years. Between the 6 monthly visits you will be asked to do a urine test and have a telephone call with the research nurse to report the result. At each visit to the hospital, participants will have the physical assessments to test the neurological system, and fill in questionnaires on pain, fatigue, mobility, and quality of life. Further tests will be done to check their progress and if they have any CONDITION: Primary progressive multiple sclerosis and secondary progressive multiple sclerosis ; Nervous System Diseases PRIMARY OUTCOME: ; Primary Outcome for Analysis stage 1: Whole brain atrophy rate, as measured by the SIENA technique at baseline, 26, 78, and 104 weeks (i.e. baseline, 6, 18 and 24 months).; ; Primary Outcome for Analysis stage 2: Time to initial disability progression, which must be confirmed 6 months later i.e. Confirmed Disability Progression (CPE). It is measured by multicomponent measure of sustained disability progression comprising the Expanded Disability Status Scale (EDSS), timed 25‐foot walk (T25FW) and 9‐hole peg test (9HPT). These are carried out 6‐monthly from baseline until last available score recorded at last attended clinic appointment.; ; Progression of disability is defined by progression on at least one of the three parameters:; 1. EDSS – an increase of at least 1 point if EDSS score at baseline (randomisation) visit is <5.5, or an increase of 0.5 point if EDSS score at baseline (randomisation) is =5.5.; 2. Increase of 20% or more from baseline on the T25FW.; 3. Increase of 20% or more from baseline (on either hand) on the 9HPT.; SECONDARY OUTCOME: ; Secondary outcome measures for analysis stage 1:; A. MRI outcome measures; 1. Regional atrophy; 2. Cervical cord atrophy; 3. T2 lesion quantification, measured at baseline, 26, 78, and 104 weeks (i.e. baseline, 6, 18 and 24 months); B. Clinician reported outcome measures. All measured at baseline and si Xmonthly until 5 years or primary analysis, whichever comes first; 1. Time to initial disability progression; 2. Expanded Disability Status Scale (EDSS); 3. Timed 25‐Foot Walk (T25FW); 4. 9 Hole Peg Test (9HPT); 5. Symbol Digit Modalities Test (SDMT); 6. MS Functional Composite Z score (comprising of T25FW, 9HPT, SDMT); 7. Sloan Low contrast visual acuity (SLCVA); 8. Relapse rate; C. Patient‐reported outcome measures. All measured at baseline and si Xmonthly until 5 years or primary analysis, whichever comes first; 1. Multiple Sclerosis Impact Scale v2 (MSIS29v2); 2. Multiple Sclerosis Walking Scale v2 (MSWSv2); 3. Fatigue (MFIS‐21 and CFQ); 4. Pain assessment (Neuropathic Pain Scale and Numerical Pain Rating Score); ; Secondary outcome measures for analysis stage 2:; All measured at baseline and every 26 weeks (6 monthly) until 5 years; A. Clinician reported outcome measures; 1. Time to initial disability progression; 2. Expanded Disability Status Scale (EDSS); 3. Timed 25‐Foot Walk (T25FW); 4. 9 Hole Peg Test (9HPT); 5. Symbol Digit Modalities Test (SDMT); 6. MS Functional Composite Z score (comprising of T25FW, 9HPT, SDMT); 7. Sloan Low contrast visual acuity (SLCVA); 8. Relapse rate; B. Patient‐reported outcome measures; 1. Multiple Sclerosis Impact Scale v2 (MSIS29v2); 2. Multiple Sclerosis Walking Scale v2 (MSWSv2); 3. Fatigue (MFIS‐21 and CFQ); 4. Pain assessment (Neuropathic Pain Scale and Numerical Pain Rating Score); C. Health‐related quality of life and resource use; 1. EQ 5D 5L Health Questionnaire; 2. Client Services Receipt Inventory (CSRI); INCLUSION CRITERIA: Core INCLUSION CRITERIA: 1. Participants with a confirmed diagnosis of MS 2. A diagnosis of Secondary Progressive MS (SPMS) or Primary Progressive MS (PPMS) 3. Steady progression as assessed by the treating clinician, rather than relapse, must be the major cause of increasing disability in the preceding 2 years. Progression can be evident from either an increase of at least 1 point if on the Expanded Disability Status Scale (EDSS) score <5.5, or an increase of at least 0.5 point if EDSS score =5.5, and/or clinical documentation of increasing disability 4. EDSS 4.0 – 8.0 (inclusive) as assessed at the time of randomisation by the assessing clinician 5. Aged 25 ‐ 70 years old inclusive on the day of randomisation 6. Adequate renal function at screening, defined as eGFR =60ml/min/1.73m² (as per local method) 7. Normal liver function at screening consisting of all the following: 7.1. Serum bilirubin <1.5 XU