OCTOPUS (PLATYPUS in Australia)

Treatment tested

• Redacted drug A
• redacted drug B

Other measures (1)

Inclusion: 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

Background and study aims Multiple sclerosis (MS) affects more than 130,000 people in the UK and over 2.5 million people worldwide. MS often begins with a relapsing-remitting phase (RRMS). However, over time, many people with RRMS start to find that they no longer recover after a flare-up (also known as a relapse) and get steadily worse, resulting in increased disability. This is known as secondary progressive MS (SPMS). A smaller number of people experience a gradual decline from the beginning, known as primary progressive MS (PPMS). SPMS and PPMS together are known as progressive MS. Recently, the first treatments have become available through the NHS for people with progressive MS. However, these treatments are only available to those who have had a relapse or have shown activity on an MRI scan. There are few clinical trials testing for effective treatments in progressive MS even though it is a major unmet need. The main aim of OCTOPUS is to find treatments that can slow down, and ultimately stop, the progression of disability in people with progressive MS. This will be done by testing “repurposed” treatments (i.e. treatments already in use for other conditions), over several years, using the multi-arm multi-stage (MAMS) trial design. This method has many advantages over traditional trials. Firstly, it allows several treatments to be tested at the same time against a common control (i.e. “multi-arm”). Secondly, it allows data to be analysed while the trial is ongoing, rather than only at the end. This means that decisions can be made on early results about stopping treatments that do not show promise. Thirdly, when new information about different treatments becomes available, these treatments can be added into the trial. Finally, treatments which appear to be effective from the early data can continue onto the next trial phase without the team having to stop and set up a new trial (i.e. “multi-stage”). Using repurposed treatments means there is already an understanding of their safety and possible side effects and it will take less time to test them for progressive MS. By using this approach and adding new treatment arms when promising treatments are found, we can find effective new treatments for progressive MS quicker. Who can participate? Adults with progressive MS who are between 25 and 70 years of age and meet the trial's eligibility criteria. What does the study involve? The trial compares “repurposed” treatment groups against a control (often referred to as a placebo) group. People eligible to join OCTOPUS treatments will be randomly assigned (by a computer programme) to one of the groups, also known as ‘arms’. To ensure a fair and unbiased trial neither the research team nor the participant will know which treatment they are taking. All groups will receive the current standard of care for people with progressive MS (i.e. the same care they would receive if they were not part of OCTOPUS) plus the treatment they have been randomly allocated to (i.e. control (placebo) or a “repurposed” treatment group). Disability will be measured in different ways, including testing strength, coordination and sensation, walking assessments and tests of upper limb function. Results will be measured at the trial visits. Optional blood samples may be taken, with participants’ permission. The visits will at first be monthly and then six monthly. An early sign of the potential effectiveness of a treatment is a change in brain size. To measure changes in brain size, participants will undergo brain MRIs in Stage 1 of the study (four scans). Based on these scans, a decision will be made by an independent Trial Steering Committee on whether a treatment should be stopped or continued. Participants who are in an arm that is stopped will be offered the opportunity to be re-randomised into a different arm, after a wash-out period. Other assessments, done every six months will include tests of memory, vision; and questionnaires about symptoms of MS including fatigue, mobility, and quality of life. Blood tests will also be performed to check the safety of the treatments. New clinical trial processes may allow some of these assessments to be done at home, e.g. the questionnaires. What are the possible benefits and risks of participating? It is hoped that the treatments will help people with progressive MS by slowing down, and ultimately stopping, the progression of disability; however, this is not known for sure, which is why it is being tested in this trial. It is possible that the results may not help people with progressive MS who join the trial individually but the information from this trial will help improve treatment for people with Progressive MS in the future. Risks of participating include those of extra visits to hospital, MRI scans, and blood tests. Participants may also experience different or extra side effects. The most common unwanted side effects will be described in all information provided to potential participants. The risks in pregnancy are unclear, therefore, participants will be asked to use contraceptives whilst on the trial. Where is the study run from? The study is run by Neurology trial centres around the UK and Australia, is sponsored by UCL and is managed by the MRC Clinical Trials Unit at UCL. Griffith University is the National Sponsor in Australia. Note that in Australia the trial is known as “PLATYPUS, the Australian extension of OCTOPUS”. When is the study starting and how long is it expected to run for? August 2022 to December 2028 Who is funding the study? MS Society (UK) with supportive funding from MS Australia and MS Western Australia to cover Australian operations. Who is the main contact? mrcctu.octopus@ucl.ac.uk