.
BACKGROUND: The incidence of cryptogenic ischemic stroke (CIS) in young adults is increasing, particularly among those without traditional vascular risk factors. Thrombophilia may contribute to CIS pathogenesis, yet guidelines differ on the relevance of screening. We investigated the sex-specific prevalence of routinely applied thrombophilia screening in young-onset CIS and its association with clinical characteristics and standard laboratory results. METHODS: We included young patients with CIS aged 18 to 49 years from the SECRETO study (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome). Routinely used thrombophilia panels obtained at admission and repeated testing within 1 year of stroke were analyzed. Ten thrombophilia markers were assessed and categorized according to the grade of deviation into lowest, low, and high thrombosis risks. Factors associated with any deviation in thrombophilia markers were investigated with multivariable logistic regression. RESULTS: Of 598 initially enrolled patients with CIS, 556 undergoing baseline thrombophilia testing were analyzed (median age, 41.0 [interquartile range, 34.1-45.8] years; male:female ratio 1.2:1). Of these, 120 (21.6%) and 36 (6.5%) were retested by 3 and 12 months, respectively. At baseline, any thrombophilia abnormality was observed in 206 patients (37.1%; men, 38.2%; women, 35.7%). High-risk thrombophilia was identified in 29 patients (5.2%) at baseline, in 13 retested patients (11.1%) at 3 months, and in 5 retested patients (13.9%) at 12 months. Overall, 45 patients (8.1%) had persistent thrombophilia abnormalities (men, 7.9%; women, 8.3%). Physical inactivity, a history of venous thromboembolism, low HDL (high-density lipoprotein)-cholesterol, and low hemoglobin were associated with any deviation in the thrombophilia markers. Anticoagulation was initiated in 50.0% of patients with abnormal baseline thrombophilia versus 35.7% without (P=0.042) and in 26.9% versus 6.2% with and without persistent abnormalities (P<0.001). CONCLUSIONS: Over a third of young adults with CIS had thrombophilia deviations at admission although high-risk thrombophilia results remained rare. Screening may be considered in young patients with CIS with a history of venous thromboembolism, physical inactivity, and low hemoglobin or HDL-cholesterol.
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. ### Competing Interest Statement In the last 3 years, JChataway has received support from the Health Technology Assessment (HTA) Programme (National Institute for Health and Care Research, NIHR), the UK MS Society, and the US National MS Society and the Rosetrees Trust. He is supported in part by the National Institute for Health and Care Research, University College London Hospitals (UCLH) Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS funded by MS Canada. A local principal investigator for commercial trials funded by: Ionis and Roche; and has taken part in advisory boards/consultancy for: Biogen, Contineum Therapeutics, FSD Pharma, InnoCare, Pheno Therapeutics and Roche. In the last 5 years ET has received honorarium for consulting work from Biogen, Janssen, Merck, Novartis, and Roche. She has received travel grants to attend or speak at educational meetings from Biogen, Merck, Neuroax, Roche, and Novartis. MP declares institutional educational grant funds or support for medicines from Novartis, Pfizer, Roche, Roche Products, Sanofi, Serum Institute of India, Shionogi, SUMVAX, Synteny Biotechnology, Takeda, Tibotec, Transgene, ViiV Healthcare, Virco Xenothera, CSL Behring, Eli-Lilly, Emergent Biosolutions, Gilead Sciences, GlaxoSmithKline, Grifols, ICON, Janssen Products, Janssen-Cilag, Janssen Pharmaceutica, Johnson & Johnson, Merck Serono, Micronoma, Modus Theraputics, MSD, Mylan, Abcodia, Advanced Accelerator Applications International, Akagera Amgen Aspirin Foundation, Astellas, AstraZeneca, AoA, Baxter, Bayer, Bristol Myers Squibb US, Bri-Bio B&C Group, Cepheid, Cipla, and Clovis JCarpenter reports grants from UK Medical Research Council, personal fees from Wiley, personal fees from Springer, personal fees from University of Bern, personal fees from Statisticians in the Pharmaceutical Industry, and personal fees from Novartis. RH received grants from NIHR DemPRU-QM, NIHR Evidence Synthesis, and NIHR Health Protection Research Unit; received consulting fees from Ministry of Justice, UK Health Security Agency, University of Nottingham, and QuidelOrtho; and leadership role on transforming health and care systems EU funding board as Chair of the Board. AJT receives a fee from being Co-Chair, University College London (UCL)-Eisai Steering Committee drug discovery collaboration; German Aerospace Center, Heath Research (ERA-NET NEURON); consultancy from Sandoz Global Advisory and Novartis. Member, National Multiple Sclerosis Society (USA) Research Programs Advisory Committee; Clinical Trials Committee, Progressive MS Alliance; Board member, European Charcot Foundation; Editor in Chief, Multiple Sclerosis Journal; Editorial Board Member, The Lancet Neurology. AJT has received fees for academic reviews for Jockey Club College at City University of Hong Kong, Health Research Board Ireland, Sant Pau Biomedical Research Institute. AJT has received support from the UCL/ UCLH NIHR Biomedical Research Centre. AJT received travel support from European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), the European Charcot Foundation, Health Research Board Emerging Clinical Scientist Award, Polish Neurological Society, and Armin Curt Farewell Symposium. He receives no fee from being Chair (Scientific Ambassadors), Stop MS Appeal Board, UK MS Society; Research and Academic Counsellor, Fundacio Privada Cemcat; Ambassador, European Brain Council. AJT additionally holds a patent for the MSIS-29 Impact Scale. FB is supported by the NIHR biomedical research centre at UCLH. He has been: on the steering committee or Data Safety Monitoring Board member for Biogen, Merck, Eisai, Prothena and Idorsia; advisory board member for Combinostics, Scottish Brain Sciences, IXICO and Alzheimer Europe; consultant for Roche, Celltrion, Merck, Bracco; research agreements with ADDI, Merck, Biogen, GE Healthcare, Icometrix, Roche; co-founder and shareholder of Queen Square Analytics LTD OC declares being NIHR Research Professor (RP-2017-08- ST2-004); over the past 2 years, member of independent data safety and monitoring board for Novartis; has received consulting fees or speaker honoraria from Lundbeck, Merck or Biogen; contributed to an advisory board for Biogen; she is Deputy Editor of Neurology, for which she receives an honorarium; has received research grant support from the UK MS Society, the NIHR UCLH Biomedical Research Centre, and the NIHR; and is vice-president of ECTRIMS (unpaid). EG is Director of Research at the UK MS Society and has no declarations. CR has received research grants from the UK Medical Research Council, Sanofi, Burden Neurological Society, University of Bristol, and Bristol Health Research Charity, and support for clinical research for the OCTOPUS trial (UK MS Society). CR has participated on a data safety monitoring board for the CCMR Two and NEuEoMS trials. Unpaid advisory roles with the UK MS Society, Burden Neurological Institute, Association of British Neurologists, and NICE HTA Assessment Group. HLF has received honoraria for advisory boards or educational activities from Merck, Novartis, and Roche. HLF has research grant support from the NIHR Health Technology Assessment Programme and Efficacy and Mechanisms Evaluation, UK MS Society, and the Horne Family Charitable Trust. She has been a local PI for multiple sclerosis clinical trials of an investigational medicinal product funded by Novartis, Roche, and Biogen Idec. LF has received honoraria for speaking or as an advisory board member from Biogen, Novartis, Merck, Sanofi Genzyme, and Roche and received support for attending educational meetings from Biogen, Novartis, Merck, Sanofi Genzyme, and Teva. MM has received travel support, speaker honoraria, or consultation fees from Merck-Sereno, Novartis, and Roche. RN receives support from UK MS Society to Imperial College and Swansea university; is a trustee of the Multiple Sclerosis Trials Collaboration charity; and attended paid advisory boards for Novartis and Roche. IG received the following funding in the last 36 months: research grants from Medical Research Council UK, National Institute for Health and Care Research, MS Society UK, Wessex Medical Research, Independent Research Fund Denmark, Rosetrees Trust, Guarantors of Brain, Kedrion, The Binding Site (Part of Thermo Fisher Scientific), and Evgen; speaker honoraria and travel funding from Novartis. D.G. and V.I. are employed by Binding Site (Part of Thermo Fisher Scientific). MBurnell has been funded by grants from the Medical Research Council (MRC), Cancer Research UK, the National Institute for Health Research (NIHR), and The Eve Appeal. RAF has participated on advisory boards, received travel grants and attended educational programmes sponsored by Roche and Novartis. SAB has been awarded funding by the Medical Research Future Fund, MS Australia and the Trish Foundation. He is a principal investigator for a clinical trials sponsored by Novartis and Sanofi, and has received speakers fees from Novartis for chairing scientific meetings. SB has been a principal investigator in clinical trials sponsored by Biogen Idec, Novartis, Genzyme and ATARA Biotherapeutics. ORP has received honoraria and travel expenses from Biogen, Bayer, Genzyme, Merck, Novartis, Roche, Sanofi and Teva and served on advisory boards/acted as a speaker for Biogen, Celgene, Janssen, Merck, Neuraxpharm, Novartis, Roche and Sanofi. SPl is founder, chief scientific officer, and shareholder (>5%) of Cambridge Innovation Technologies Consulting and is a consultant for Aspen Therapeutics, Secretome Therapeutics, Macomics, Solute Guard Therapeutics, and Astex Pharmaceutical. SPa has been funded by grants from the National Institute for Health and Care Research (NIHR) and is a hub lead for the NIHR Leeds Clinical Research Facility. In the last 3 years DF has received research support from the UK MS Society, Higher Education Authority (Rep. of Ireland), Wellcome, Research Ireland and Sangamo Inc. She received consultancy fees for participation in an advisory board for Sangamo Inc. TA has received honoraria or consulting fees for participating in advisory boards related to trial steering committees and data and safety monitoring committees, speaker fees & research grants Janssen, Merck, Novartis, Roche and Sanofi-Genzyme. She is partially funded by the NIHR SCPRA fellowship. All other authors declare no competing interests. ### Clinical Trial ISRCTN: 14048364; EudraCT: 2021-003034-37; CTA: 20363/0445; IRAS: 1003943 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The National Research Ethics Service Committee (London, Hampstead) reviewed the trial protocol and materials to be given to participants (approved 14th October 2022, REC ref 22/LO/0622). The trial protocol and materials to be given to Australian participants has also been reviewed and approved by the Gold Coast Hospital and Health Service, Human Research Ethics Committee (approved 16th December 2024, HREC/2024/QGC/97381). This article refers to the current protocol (Version: 8.0, Date: 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 United Kingdom Multiple Sclerosis Society and full Patient and Public Involvement Engagement. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes N/A - no data is presented in the current work as it is a protocol paper Multiple Sclerosis Society, https://ror.org/043fwdk81, 135 National Institute for Health and Care Research (NIHR) Research Delivery Network (RDN) MS Australia
BACKGROUND:In young adults, the risk factors (RFs) for cryptogenic ischemic stroke (CIS) remain unclear. We aimed to investigate the association between recent mechanical venous thrombosis RFs (VTRFs) and young-onset CIS in this multicenter sex- and age-matched case-control study. METHODS:Five hundred forty-six patients aged 18 to 49 years (median age, 41 [34-46] years; 47.3% women) with a recent CIS and 546 stroke-free community-based controls were included in the study across 19 European centers between October 2013 and November 2022. Mechanical VTRFs, including surgical treatment, nonsurgical intervention, injury, and immobilization occurring within 90 days prestroke, were assessed using standardized, structured interviews. Conditional logistic regression was used to assess the association of mechanical VTRFs with CIS. Age, sex, level of education, and traditional and nontraditional stroke RFs were included as confounders. RESULTS:Mechanical VTRFs within 14 days prestroke were more prevalent in cases than controls (15.4% versus 9.6%) and independently associated with CIS after adjustment for demographics and traditional stroke RFs (odds ratio [OR], 1.67 [95% CI, 1.05-2.67]). In age-stratified analysis, this association remained significant after additional adjustment for nontraditional RFs in 18- to 39-year-olds (OR, 2.36 [95% CI, 1.02-5.46]) but was not significant in the 40- to 49-year age group (OR, 1.50 [95% CI, 0.73-3.08]). In addition, mechanical VTRFs were associated with CIS in cases with clinically relevant patent foramen ovale in a fully adjusted model (OR, 2.06 [95% CI, 1.21-3.51]) but not in those without (OR, 1.29 [95% CI, 0.76-2.18]). No significant associations were observed for mechanical VTRFs occurring >14 days before stroke. Baseline blood thrombophilia markers did not differ between cases with and without mechanical VTRFs 0 to 14 or 15 to 90 days before stroke. CONCLUSIONS:Recent mechanical VTRFs occurring within 14 days preceding stroke contribute to the risk of young-onset CIS, particularly in younger individuals and those with a clinically relevant patent foramen ovale. This risk does not appear to be conveyed by thrombophilic factors assessed. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01934725.
