Phase 3 study for people with Multiple Sclerosis

Reproduced exactly, unedited. Written for researchers rather than for patients.

Inclusion criteria: Current key inclusion criteria as of 05/06/2026: 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 (as defined in protocol section 6.5.6), 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 assessor 1. Aged 25 - 70 years old inclusive on the day of randomisation 2. Adequate renal function at screening, defined as eGFR ≥60ml/min/1.73m2 (as per local method) 3. Normal liver function at screening consisting of all the following: a. Serum bilirubin <1.5 x ULN (except for participants with Gilbert’s disease, for whom the upper limit of serum bilirubin is 51.3 µmol/l or 3mg/dl) b. Either aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <3 x ULN; (it must be stated whether one or both tests were performed. Where both results are available, both must confirm eligibility) c. Alkaline phosphatase <3 x ULN 4. Must be able and willing to comply with the treatment and assessment schedule and requirements including being able to start trial treatment ≤ 2 weeks after randomisation. 5. Written informed consent provided 6. [Please note no longer core inclusion criteria in Analysis Stage 2 - Must have a QC approved (as defined in MRI guide) MRI ≤ 4 weeks before randomisation] 7. [Please note no longer core inclusion criteria in Analysis Stage 2 - Willing and able to have MRI scans in accordance with the assessment schedule and no contraindication to MRI (please refer to MRI Procedures and Protocol for further detail)] _____ Previous inclusion criteria as of 06/05/2025: 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 x ULN (except for participants with Gilbert’s disease, for whom the upper limit of serum bilirubin is 51.3 μmol/l or 3mg/dl) 7.2. Either aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <3 x ULN; (it must be stated whether one or both tests were performed. Where both results are available, both must confirm eligibility) 7.3. Alkaline phosphastase <3 x ULN 8. Must be able and willing to comply with the treatment and assessment schedule and requirements including being able to start trial treatment ≤ 2 weeks after randomisation. 9. Written informed consent provided 10. [Please note no longer core inclusion criteria in Analysis Stage 2 - Must have a QC approved (as defined in MRI guide) MRI ≤ 4 weeks before randomisation] 11. [Please note no longer core inclusion criteria in Analysis Stage 2 - Willing and able to have MRI scans in accordance with the assessment schedule and no contraindication to MRI (please refer to MRI Procedures and Protocol for further detail)] Redacted drug B Inclusion Criteria: Participants will be considered eligible for randomisation in this trial if they fulfil all the core inclusion criteria and none of the exclusion criteria as defined in sections 3.1 and 3.2 in the main protocol in addition to the arm specific criteria below. If a participant is ineligible for this arm, they can be assessed for eligibility and randomised to other open arms. Redacted drug A Inclusion Criteria: Participants will be considered eligible for randomisation in this trial if they fulfil all the core inclusion criteria and none of the exclusion criteria as defined in sections 3.1 and 3.2 in the main protocol in addition to the arm specific criteria below. If a participant is ineligible for this arm, they can be assessed for eligibility and randomised to other open arms. _____ Previous inclusion criteria as of 16/10/2024: 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 x ULN (except for participants with Gilbert’s disease, for whom the upper limit of serum bilirubin is 51.3 μmol/l or 3mg/dl) 7.2. Either aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <3 x ULN; (it must be stated whether one or both tests were performed. Where both results are available, both must confirm eligibility) 7.3. Alkaline phosphastase <3 x ULN 8. Must be able and willing to comply with the treatment and assessment schedule and requirements including being able to start trial treatment ≤ 2 weeks after randomisation. 9. Written informed consent provided 10. Must have a QC-approved (as defined in MRI guide) MRI ≤ 4 weeks before randomisation (Stage 1 of study ONLY) 11. Willing and able to have MRI scans in accordance with the assessment schedule and no contraindication to MRI (Stage 1 of study ONLY) please refer to MRI Procedures and Protocol for further detail. Redacted drug B Inclusion Criteria: Participants will be considered eligible for randomisation in this trial if they fulfil all the core inclusion criteria and none of the exclusion criteria as defined in sections 3.1 and 3.2 in the main protocol in addition to the arm specific criteria below. If a participant is ineligible for this arm, they can be assessed for eligibility and randomised to other open arms. Redacted drug A Inclusion Criteria: Participants will be considered eligible for randomisation in this trial if they fulfil all the core inclusion criteria and none of the exclusion criteria as defined in sections 3.1 and 3.2 in the main protocol in addition to the arm specific criteria below. If a participant is ineligible for this arm, they can be assessed for eligibility and randomised to other open arms. _____ Previous 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 x ULN (except for participants with Gilbert’s disease, for whom the upper limit of serum bilirubin is 51.3 μmol/l or 3mg/dl) 7.2. Either aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <3 x ULN; (it must be stated whether one or both tests were performed. Where both results are available, both must confirm eligibility) 7.3. Alkaline phosphastase <3 x ULN 8. Must be able and willing to comply with the treatment and assessment schedule and requirements including being able to start trial treatment ≤ 2 weeks after randomisation. 9. Written informed consent provided 10. Must have a QC-approved (as defined in MRI guide) MRI ≤ 4 weeks before randomisation 11. Willing and able to have MRI scans in accordance with the assessment schedule and no contraindication to MRI (please refer to MRI Procedures and Protocol for further detail) Redacted drug B Inclusion Criteria: Participants will be considered eligible for randomisation in this trial if they fulfil all the core inclusion criteria and none of the exclusion criteria as defined in sections 3.1 and 3.2 in the main protocol in addition to the arm specific criteria below. If a participant is ineligible for this arm, they can be assessed for eligibility and randomised to other open arms. Redacted drug A Inclusion Criteria: Participants will be considered eligible for randomisation in this trial if they fulfil all the core inclusion criteria and none of the exclusion criteria as defined in sections 3.1 and 3.2 in the main protocol in addition to the arm specific criteria below. If a participant is ineligible for this arm, they can be assessed for eligibility and randomised to other open arms.

Exclusion criteria: Current key exclusion criteria as of 05/06/2026: CORE EXCLUSION CRITERIA 1. Relapse (as defined in protocol section 6.5.6) ≤ 12 weeks before randomisation 2. Significant comorbidity (as confirmed by treating clinician) that includes but not limited to the following: a. Cardiac failure (clinical diagnosis) b. Significant Respiratory comorbidity c. Renal failure d. Malignancy (except if in complete remission) – e.g. solid organ or haematological or melanoma e. Uncontrolled thyroid disease f. Significant non-MS neurological comorbidity g. Hepatic impairment 3. [Please note this number is no longer core exclusion criteria: moved to Metformin exclusion criteria only - Rare hereditary problems of galactose intolerance or glucose-galactose] 4. Active partial or total malabsorptive disease (e.g. coeliac disease) 5. Alcohol use disorder or illicit drug use within the last 5 years (excluding cannabis for symptomatic relief) 6. Female participants that are pregnant or breast-feeding. 7. Women of child-bearing potential (WOCBP) who are unwilling or unable to use an acceptable method of contraception (see protocol Appendix 1) whilst on trial treatment and up to 12 weeks after the last dose of study drug. 8. Use of an investigational medicinal product or investigational medical device ≤ 26 weeks before randomisation. 9. Men with a partner of child-bearing potential unwilling to use an acceptable method of contraception during the trial and for 12 weeks after the last dose of trial treatment. 10. Male participants unwilling to desist from sperm donation during the trial and for 12 weeks after the last dose of trial treatment. 11. Been treated with steroids (intravenous and/or oral) for MS relapse or progression ≤ 12 weeks before randomisation* Note: Participants on steroids for another medical condition may be included in the trial provided the steroid prescription is not for any aspects of their MS. 12. Current or previous treatment with OCTOPUS IMPs ≤ 26 weeks before randomisation. With the exception of participants taking health supplements, including multi-vitamins, that contain a dose of ≤100mg of Alpha Lipoic Acid. These participants can be randomised but must wait 7 days from the last dose before randomisation. 13. Commencement of DMT and/or fampridine (or 3,4-aminopyridine) ≤ 26 weeks before randomisation* 14. Contraindicated medications that are not permitted with OCTOPUS IMPs (refer to protocol section 5.14). Please note a careful approach should be applied to those listed with caution. Please contact the OCTOPUS team if further advice is required. 15. Participants who are not eligible for any of the trial IMPs, according to the eligibility criteria listed in the individual drug appendices. Please note that participants can enter the trial if they are eligible for at least one of the trial treatment arms, but do not need to be eligible for all. 16. Previous treatment with alemtuzumab or autologous haematopoietic stem cell therapy (AHSCT) ≤ 52 weeks prior to randomisation* 17. Albumin Creatinine Ratio (ACR) result of ≥34 mg/mmol (>300 mg/g) at screening, regardless of urine dipstick results. 18. Participants with a diagnosis of diabetes mellitus. These participants may undergo a further screening visit once the specified window has expired and may be included if no further treatment has been administered in the intervening period. _____ Previous key exclusion criteria: 1. Relapse ≤ 12 weeks before randomisation 2. Significant comorbidity (as confirmed by treating clinician) 2.1. Cardiac failure (clinical diagnosis) 2.2. Significant Respiratory comorbidity 2.3. Renal failure 2.4. Malignancy (except if in complete remission) – e.g. solid organ or haematological or melanoma 2.5. Uncontrolled thyroid disease 3. Rare hereditary problems of galactose intolerance or glucose-galactose malabsorption 4. Active partial or total malabsorptive disease (e.g. coeliac disease) 5. Has a history of alcohol use disorder and/or drug abuse (excluding cannabis for symptomatic relief) 6. Female participants that are pregnant or breast-feeding. 7. Women of child-bearing potential (WOCBP) who are unwilling or unable to use an acceptable method of contraception whilst on trial treatment and up to 12 weeks after the last dose of study drug. 8. Participation in another clinical trial of an investigational medicinal product or medical device ≤ 26 weeks before randomisation 9. Men with a partner of child-bearing potential unwilling to use an acceptable method of contraception during the trial and for 12 weeks after the last dose of trial treatment. 10. Male participants unwilling to desist from sperm donation during the trial and for 12 weeks after the last dose of trial treatment. 11. Been treated with steroids (intravenous and/or oral) for MS relapse or progression ≤ 12 weeks before randomisation Note: Participants on steroids for another medical condition may be included in the trial provided the steroid prescription is not for any aspects of their MS. 12. Current or previous treatment with Analysis Stage 1 IMPs ≤ 26 weeks before randomisation. With the exception of participants taking [redacted drug name and dosage]. These participants can be randomised but must wait 7 days from the last dose before randomisation. 13. Commencement of DMT and/or fampridine ≤ 26 weeks before randomisation* 14. Contraindicated medications that are not permitted with OCTOPUS IMPs. Please note a careful approach should be applied to those listed with caution. Please contact the OCTOPUS team if further advice is required. 15. Participants who are not eligible for any of the trial IMPs, according to the eligibility criteria listed in the individual drug appendices. Please note that participants can enter the trial if they are eligible for at least one of the trial treatment arms, but do not need to be eligible for all. *These participants may undergo a further screening visit once the specified window has expired and may be included if no further treatment has been administered in the intervening period. Redacted drug B Exclusion Criteria: Arm-specific exclusion criteria to be added when drug names released Redacted drug A Exclusion Criteria: Arm-specific exclusion criteria to be added when drug names released