Optimal Clinical Trials Platform for Progressive Multiple Sclerosis (OCTOPUS): protocol for an international, multi-arm, multi-stage, platform, randomized controlled, double-blind, phase 3 clinical trial.
Introduction Current treatments for multiple sclerosis (MS) do not address the pathological processes of neurodegeneration and chronic demyelination. This, coupled with the significant challenges of translating promising phase 2 results to phase 3 trial success, highlights the need for more efficient trial designs, such as platform multi-arm multi-stage (MAMS) trial approaches. MAMS trials have demonstrated success in areas such as oncology and infectious diseases. They are typified by a statistically robust core trial design that allows the addition of further treatment arms and utilisation of interim outcome analyses at pre-defined timepoints, to determine whether to terminate a treatment arm early or proceed to the final outcome analysis. To address the challenges in progressive multiple sclerosis (PMS) treatment discovery, the Optimal Clinical Trials Platform for PMS (OCTOPUS) trial was developed. It currently utilises MRI whole-brain atrophy as its interim outcome measure and the clinically relevant composite Expanded Disability Status Scale Plus (EDSS-Plus) as its final outcome measure. A rigorous and systematic drug selection process that assessed preclinical in vitro and animal model evidence, along with additional human data, led to the prioritisation of R/S-alpha lipoic acid (R/S-ALA) and metformin for testing against placebo, targeting pathobiological mechanisms relevant to PMS. All participants will be eligible to receive the current standard of care, including disease-modifying treatments (DMTs). Method and analysis OCTOPUS will be a multi-centre, randomised, placebo-controlled, double-blind, phase 3, MAMS trial of participants aged 25 to 70 years (inclusive) with PMS and an EDSS score of 4.0 to 8.0 (inclusive). Steady progression must be the major cause of increasing disability rather than relapse in the preceding 2 years. In the trial s first candidate drug cycle, participants will be allocated to R/S-ALA, metformin, or placebo in a 1:1:1 ratio. Cycle 1 active treatments will start as R/S-ALA 600 mg once daily, increased after 4 weeks to 600 mg twice daily, or metformin 1 g once daily, increased after 4 weeks to 1 g twice daily. The trial will be multinational, with participation from 28 hospitals across the UK and 10 hospitals in Australia. Clinician-reported measures will include: the EDSS-Plus and the individual components: EDSS, Timed 25 Foot Walk (T25FW); 9 Hole Peg Test (9HPT); Symbol Digit Modalities Test (SDMT); Sloan Low Contrast Visual Acuity (SLCVA); and Relapse assessment. Patient-reported outcomes include MS specific walking, fatigue, pain, and impact scales. We will include a health economic analysis. Analysis stage 1 will require randomisation of 125 participants per arm and utilise MRI percentage brain volume change (PBVC) with the Structural Image Evaluation using Normalisation of Atrophy (SIENA) technique from baseline to 78 weeks. A positive outcome in analysis stage 1 will detect a 0.15% per year whole brain atrophy difference with a one-sided alpha of 0.35 and power of 95%, ensuring a low probability of erroneously rejecting a treatment arm at this stage. Any arms that show a positive effect will proceed to final analysis stage 2. Analysis stage 2 will require 600 participants per arm. Participants included in stage 1 will also be included in the stage 2. Analysis stage 2 will evaluate time to 6-month confirmed disability progression in the EDSS-Plus, in order to detect a 25% hazard ratio reduction with 90% power and an alpha of 0.05. Assuming one treatment arm proceeds to analysis stage 2, the trial will recruit approximately 1,200 participants and last about 6 years. This is approximately two-thirds the size and half the duration of separately conducted two-arm phase 2 and 3 trials. Ethics and dissemination The protocol was approved by the London Hampstead REC (22/LO/0622). This manuscript is based on protocol version 8.0, 28th August 2025. The findings of this trial will be disseminated through peer-reviewed publications and conference presentations. There will be a close communication strategy developed with the UK MS Society (MSS) and full patient and public involvement and engagement (PPIE). Trial registration ISRCTN: 14048364 EudraCT number: 2021-003034-37 CTA 20363/0445 IRAS number: 1003943 Secondary identifying numbers: ND001, CPMS 54274 Strengths and limitations - The OCTOPUS trial will be the first platform multi-arm multi-stage phase 3 trial in PMS, offering the potential to significantly expedite clinical trial processes with advantages in cost- and time-efficiency, focusing specifically on the poorly treated pathobiological processes of chronic neurodegeneration and demyelination - It will begin by assessing two promising drug candidates, immediate-release metformin and R/S-ALA, and will expand over the duration of the trial to include more drug arms under the same trial master protocol - The flexible and statistically robust trial design means that several components of the design (such as the early analysis stage 1 interim outcome) can be updated in line with evolving scientific knowledge - It will ultimately be the largest ever investigator-initiated phase 3 trial in PMS - It will include a range of national and international trial sites, including neuroscience centres and district general hospitals - It will have a high inclusion limit for age (up to 70 years) and disability (up to EDSS 8.0) - Several components (the telephone EDSS and virtual patient-reported outcome measures) will be amenable to remote collection increasing inclusivity and thus addressing public and participant suggestions, while minimising the risk of missing data - The main challenges in this trial design are the statistical and methodological complexity involved in design and implementation, and interpretation of interim trial results. Conclusion The trial launched cycle 1 in January 2023. Analysis stage 1 recruitment of 375 participants was achieved in November 2024, enabling planned interim analysis stage 1 to be conducted by late 2026 (Figure 1). On the 1st of June 2026, in the UK, 24 sites are active with a further 4 in set-up as part of stage 2, and in the Australian extension, Platform Adaptive Trial for Remyelination and Neuroprotection in Multiple Sclerosis (PLATYPUS), 1 site is active, with 9 additional sites in set-up.