Developing treatments for cerebral small vessel disease: a scoping review of licensed interventions for potential repurposing

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Objectives To conduct a rapid multi-stage scoping review to identify licensed interventions that could be repurposed for testing in cSVD at phase-3. Methods First, we screened preclinical studies of potential relevance to cSVD and used a drug dictionary to identify studies of potential interventions. Separately, we screened clinical studies of relevance to cSVD and VCI. Following merging, we removed drugs that were unsuitable or impractical to assess long-term in the UK. We then performed mini-meta-analyses for shortlisted interventions assessing effects on cognition and scored these for their relevance to cSVD. Results The preclinical review created a long-list of 1,757 deduplicated interventions. Those that were available in the UK, not expensive or impractical to administer long-term were merged with 62 interventions identified from 75 relevant clinical studies to create a medium-list of 52 interventions. Focussed literature review short-listed ten interventions for review by an Independent Scientific Advisory Group; they ranked three as most suitable for immediate testing: metformin, tadalafil and isosorbide mononitrate. Conclusion This rapid review identified three interventions that are suitable for testing in a late phase-3 (platform) trial involving patients with cSVD. The approach could be improved with partial automation, text mining and generative pre-trained transformer approaches which would help manage the large data volumes. Further, our data-driven approach could be combined with genetic or other mechanistic methods to further de-risk future trials. 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F1000Research 2025, 13 :1546 ( https://doi.org/10.12688/f1000research.157890.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Systematic Review Revised Developing treatments for cerebral small vessel disease: a scoping review of licensed interventions for potential repurposing [version 2; peer review: 2 approved] Philip M Bath https://orcid.org/0000-0003-2734-5132 1,2 , Elizabeth P Phan 3 , Gwynneth Clay 1 , [...] Jesse Dawson 4 , Paresh Malhotra 5 , Rob Howard 6 , Suvankar Pal 7 , Joanna M Wardlaw https://orcid.org/0000-0002-9812-6642 8 , Terry Quinn 3 , Malcolm Macleod https://orcid.org/0000-0001-9187-9839 9 Philip M Bath https://orcid.org/0000-0003-2734-5132 1,2 , Elizabeth P Phan 3 , [...] Gwynneth Clay 1 , Jesse Dawson 4 , Paresh Malhotra 5 , Rob Howard 6 , Suvankar Pal 7 , Joanna M Wardlaw https://orcid.org/0000-0002-9812-6642 8 , Terry Quinn 3 , Malcolm Macleod https://orcid.org/0000-0001-9187-9839 9 PUBLISHED 10 Sep 2025 Author details Author details 1 Stroke Trials Unit, University of Nottingham, Nottingham, England, NG7 2UH, UK 2 Stroke, Nottingham University Hospitals NHS Trust, Nottingham, England, NG7 2UH, UK 3 School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, G4 0SF, UK 4 School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, G51 4TF, UK 5 Division of Neurology, Imperial College, London, W6 8RP, UK 6 Maple House, University College London, London, England, W1T 7NF, UK 7 Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, Midlothian, EH16 4SB, UK 8 Dementia Research Institute Centre, University of Edinburgh, Edinburgh, Midlothian, EH16 4SB, UK 9 CAMARADES Group, University of Edinburgh, Edinburgh, Midlothian, EH16 4SB, UK Philip M Bath Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation Elizabeth P Phan Roles: Data Curation, Formal Analysis, Writing – Review & Editing Gwynneth Clay Roles: Conceptualization, Supervision, Writing – Review & Editing Jesse Dawson Roles: Supervision, Writing – Review & Editing Paresh Malhotra Roles: Supervision, Writing – Review & Editing Rob Howard Roles: Supervision, Writing – Review & Editing Suvankar Pal Roles: Supervision, Writing – Review & Editing Joanna M Wardlaw Roles: Conceptualization, Validation, Writing – Review & Editing Terry Quinn Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing Malcolm Macleod Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the University College London collection. Abstract Background Cerebral small vessel disease (cSVD) is a progressive neurovascular-degenerative condition without specific treatment that causes lacunar stroke, most intracerebral haemorrhage, vascular cognitive impairment (VCI) and several neuropsychiatric conditions. Objectives To conduct a rapid multi-stage scoping review to identify licensed interventions that could be repurposed for testing in cSVD at phase-3. Methods First, we screened preclinical studies of potential relevance to cSVD and used a drug dictionary to identify studies of potential interventions. Separately, we screened clinical studies of relevance to cSVD and VCI. Following merging, we removed drugs that were unsuitable or impractical to assess long-term in the UK. We then performed mini-meta-analyses for shortlisted interventions assessing effects on cognition and scored these for their relevance to cSVD. Results The preclinical review created a long-list of 1,757 deduplicated interventions. Those that were available in the UK, not expensive or impractical to administer long-term were merged with 62 interventions identified from 75 relevant clinical studies to create a medium-list of 52 interventions. Focussed literature review short-listed ten interventions for review by an Independent Scientific Advisory Group; they ranked three as most suitable for immediate testing: metformin, tadalafil and isosorbide mononitrate. Conclusion This rapid review identified three interventions that are suitable for testing in a late phase-3 (platform) trial involving patients with cSVD. The approach could be improved with partial automation, text mining and generative pre-trained transformer approaches which would help manage the large data volumes. Further, our data-driven approach could be combined with genetic or other mechanistic methods to further de-risk future trials. READ ALL READ LESS Keywords cerebral small vessel disease; isosorbide mononitrate, metformin, tadalafil, treatment, repurposing Corresponding Author(s) Philip M Bath ( [email protected] ) Close Corresponding author: Philip M Bath Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Bath PM et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Bath PM, Phan EP, Clay G et al. Developing treatments for cerebral small vessel disease: a scoping review of licensed interventions for potential repurposing [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1546 ( https://doi.org/10.12688/f1000research.157890.2 ) First published: 20 Dec 2024, 13 :1546 ( https://doi.org/10.12688/f1000research.157890.1 ) Latest published: 10 Sep 2025, 13 :1546 ( https://doi.org/10.12688/f1000research.157890.2 ) Revised Amendments from Version 1 The text has been revised to address comments by the two reviewers. The abstract is corrected to say that drugs had to be available in the UK (as opposed to be not available). The criteria assessed by the Independent Scientific Advisory Group (ISAG) have been expanded in the methods section; further, references to Independent Scientific Advisory Committee have been corrected to ISAG. Three additional limitations have been added to the Discussion; first, of assessing English language-only trials (and do excluding other trials); second, of the potential for imprecision or bias in converting standardised mean difference to odds ratio; and third, the potential for excluded drugs and classes to be relevant to cSVD, e.g. in low resource countries. Some minor typographical errors have also been corrected. The text has been revised to address comments by the two reviewers. The abstract is corrected to say that drugs had to be available in the UK (as opposed to be not available). The criteria assessed by the Independent Scientific Advisory Group (ISAG) have been expanded in the methods section; further, references to Independent Scientific Advisory Committee have been corrected to ISAG. Three additional limitations have been added to the Discussion; first, of assessing English language-only trials (and do excluding other trials); second, of the potential for imprecision or bias in converting standardised mean difference to odds ratio; and third, the potential for excluded drugs and classes to be relevant to cSVD, e.g. in low resource countries. Some minor typographical errors have also been corrected. See the authors' detailed response to the review by Jade L. Taylor READ REVIEWER RESPONSES Introduction Rationale Dementia is the commonest known brain disorder with rates increasing as populations age: 1 world prevalence will treble by 2050 2 and reach 1.7 million people in England & Wales by 2040. 3 Common types comprise Alzheimer’s disease (AD), vascular dementia (VaD) and mixed dementia, mostly combined AD and VaD. 1 Most vascular cognitive impairment (VCI) and VaD, with or without AD, is caused by cerebral small vessel disease (cSVD), 4 a progressive neurovascular-degenerative condition that is typically diagnosed on neuroimaging. 5 , 6 cSVD increases the future risk of stroke, dementia and functional decline 2-to-3 fold. 7 cSVD, including that which is covert, is extremely common and estimated to affect 10% of the world’s population, i.e. approximately 750M worldwide, more so in low-middle income countries. 8 cSVD contributes to 45% of dementias. 9 Further, cSVD causes lacunar ischaemic stroke (25% of the 17M strokes/year worldwide), 10 most intracerebral haemorrhages (ICH, 10% of strokes) and underlies many mobility, gait, falls, neurobehavioral, mood/depression and urinary incontinence disorders in older people. 1 , 4 , 9 Importantly, the biggest concern expressed by patients with cSVD is the development of VCI/VaD. 11 Unfortunately, cSVD has no specific proven preventative or restorative interventions and lowering blood pressure only has a very limited effect. 12 – 14 The only phase-3 trial was stopped early because dual antiplatelet therapy with aspirin and clopidogrel caused an increase in deaths in patients with prior lacunar ischaemic stroke. 15 This trial also found that blood pressure lowering did not reduce recurrent stroke 16 or modify cognition. 17 Recently, a phase-2 feasibility trial after lacunar stroke found that isosorbide mononitrate (ISMN), especially when given with cilostazol, improved cognition and functional outcome and reduced recurrent stroke. 18 Given the long, expensive path to new drug development, there is increasing focus on repurposing existing drugs. Repurposing may be “defined as researching new indications for already approved drugs or advancing previously studied but unapproved drugs” 19 and offers the advantages of assessing interventions which already have a wealth of preclinical and clinical data for another indication. Repurposing drugs can be faster, less expensive and risky and carry higher success rates than traditional drug development approaches primarily because researchers can bypass earlier stages of development that establish drug safety. 20 As a result, repurposing reduces research waste. Hence, an increasingly common approach to identifying interventions for testing in neurodegenerative conditions such as cSVD, Alzheimer’s disease, multiple sclerosis and motor neuron disease are structured systematic approaches that identify candidate treatments on the basis of their known mechanisms of action and existing pre-clinical and clinical studies. 12 , 21 – 24 Objectives To update and expand on our previous mechanistic assessment 12 with a wider scoping review of medications that might be repurposed as effective treatments for cSVD with a focus on cognitive outcomes. Methods Background We conducted a rapid multi-stage scoping review 25 to identify potential interventions for preventing cognitive decline in people with cSVD with the aim of testing these in a phase-3 platform trial. Funding calls for platform trials typically specify key criteria to consider when selecting interventions for testing. We based our review on the criteria set out by the UK NIHR Health Technology Assessment programme for “large, collaborative and ambitious platform studies in areas of strategic importance” (number 23/95, call date 27 July 2023, closing date for outline applications 28 November 2023). 26 Key requirements were: i) “a clear process and Independent Scientific Advisory Group (ISAG) for the identification and prioritisation of candidate interventions”; ii) “evaluation of the clinical (and cost) effectiveness of multiple interventions” (implying that interventions should not be expensive); and iii) “each technology [ intervention ] must have sufficient clinical data”, 26 i.e. that there will be a reasonable chance that it would be effective. Further, interventions should have already been tested in a NHS setting; be phase-3 ready; be available to be implemented rapidly if the trial is positive; be immediately useful to service users; treatment length should be commensurate with a platform design; it would be likely that the interventions would be used if supported by the results; and that there should be collective learning, hence the importance of sharing our process of identification and prioritisation of interventions for cSVD, as here. The following processes were designed to identify suitable phase-3-ready interventions that might modify cognition and could be tested in a platform trial and so fit the above call and its requirements. Registration Since this was performed as a rapid scoping review to be completed within two months, we did not create a prior protocol. Additionally, as a scoping review, we did not register it with PROSPERO. Overview The intervention selection strategy is summarised in Figure 1 . Interventions of potential relevance to cSVD from preclinical and clinical searches were merged to form a long-list. From this, interventions were excluded for several reasons including that they were not available in the UK or could not be delivered feasibly. The resulting medium-list was then scored and ten interventions with the highest scores were assessed by an ISAG who identified three that should be taken forward into a potential multi-arm multi-stage platform trial. Searches had no date limits but were primarily limited to English due to the time constraint. Figure 1. Structured identification of potential interventions for treatment of cerebral small vessel disease. Preclinical workpackage Building on our previous work, 27 we (MM) searched PubMed on 14/08/23 (search terms in Figure 1 ), and loaded Titles and Abstracts to R, before text-mining using a series of regular expressions representing over 12000 compounds derived from DrugBank 28 and from the Alzforum Therapeutic Database ( https://www.alzforum.org/therapeutics ) ( Figure 1 , top left). Using a similar approach, we text-mined titles and abstracts using regular expressions to identify publications using rats, mice or primates, to create a list of interventions tested in preclinical models. Our focus was primarily on medications; lifestyle, dietary manipulation and cognitive rehabilitation were not considered in scope. To generate the medium-list, interventions were removed if they would be impossible or impractical to deliver in a phase-3 platform trial based in the UK or another similar socialised healthcare system. A full list of reasons for removal is given in Table 1 and includes drugs that were not listed in the British National Formulary (BNF 29 ) in quarter 3 2023, were considered too expensive for widespread use (threshold BNF price of £30 per month) and interventions that were considered impractical to deliver long-term. Table 1. Reasons for excluding interventions from the long-list identified from preclinical searches. Reason Justification Example(s) Agents in same class Opportunity cost to co-develop agents in same class Isosorbide mononitrate vs isosorbide dinitrate Not in BNF 29 Not available in UK so not available to the trial and could not be implemented rapidly if trial positive AChE-i: phenserine. CCB: nilvadipine. PDE4-i: ibudilast. ROCK-i: Fasudil Impractical to administer Impractical to administer to large populations Electromagnetic stimulation. Hyperbaric oxygen. Remote ischaemic conditioning Intravenous administration Impractical to administer to large populations Alpha-galactosidase. Antipsychotics. Glucagon. Prostacyclin Side effect profile Significant or severe side effect profile where benefit might not outweigh risk Anti-cancer. Anti-convulsant: oxcarbazepine. Pyridone immune-suppressive: perfenidone In widespread use: prescribed Challenging to find patients who are not on the intervention, both for eligibility and avoidance in control group ARA: candesartan, losartan, telmisartan. CCB: amiloride, nifedipine, nimodipine. Statins: atorvastatin In widespread use: over-the-counter or via internet Challenging to find patients who are not on the intervention, both for eligibility and avoidance in control group Fatty acids: omega-3 fatty acids, poly-unsaturated. 13 PDE3-i: sildenafil No evidence to chase No evidence to suggest that might work in cSVD Nootrope: piracetam. PCSK9-synthesis blocker: evolocumab. Xanthine oxidase inhibitor: allopurinol Neutral in another neurological condition Less likely to be effective in cSVD if neutral in another neuro-degenerative condition ARA: losartan neutral for AD. 47 Benzothiazoles: riluzole neutral for MS. 48 CCB: nilvadipine neutral for AD. 46 Potassium-sparing diuretic: amiloride neutral for MS. 48 SSRI: fluoxetine neutral for MS 48 Planned or current testing in cSVD Funder unlikely to support more testing Anti-platelet: cilostazol For short-term use Long-term safety not confirmed Anti-herpes: valaciclovir; valganciclovir Not identified in preclinical search No preclinical data to support clinical use Anti-herpes: valaciclovir; valganciclovir Too expensive for widespread use Unaffordable to NHS for use in large populations GLP-1: Liraglutide, semaglutide Poor adherence Reduced chance of success if intervention is not taken/used GLP-1: Liraglutide, semaglutide Clinical workpackage In parallel, we (EPPM, TQ) screened clinical trials assessing interventions separately for cSVD and VaD ( Figure 1 , top right), again with the prime aim to improve cognition. The searches for cSVD and Vad trials were conducted between October 2021 - January 2022 and June - August 2022, respectively, and updated for both in June 2023. Completed trials were identified from Ovid MEDLINE, EMBASE and PsychInfo (for VaD only) databases for articles in any language from 2012 to the start of the search. Planned and ongoing trials were searched on clinicaltrials.gov , the European Union Clinical Trials Register (EUCTR) and International Clinical Trials Registry Platform (ICTRP) ( Figure 1 ). From these, we merged the identified interventions into two lists, one relevant to cSVD and the other for VaD. Interventions were classified by likely mechanism of action. Interventions were then merged with the preclinical medium-list. Mini-meta-analysis workpackage The aim was to assess whether there was any evidence that individual interventions improved cognition or reduced cognitive decline in any medical indication. Published systematic reviews/meta-analyses of the effect of interventions on cognition were sought (PMB) irrespective of the outcome scale. If none were present, a rapid internal meta-analysis was performed using completed published data from randomised controlled trials or before-after studies identified from searches of the Cochrane Library and PubMed using controlled vocabulary and validated filters to identify RCTs. Data published as graphs rather than in tables were extracted on screen using mean and standard deviation (calculated from standard error if necessary) with screen values scaled for the Y-axis. Data were entered into Cochrane Review Manager (version 5.4.1 for Mac) with the aim of identifying interventions that improved cognition, i.e. meta-analysis odds ratio for a good outcome (OR >>1 suggests benefit). For before-after studies assessing the effect of an intervention within a group of patients, the group size was split equally between the before and after results, a conservative approach. Binary data were analysed directly as an odds ratio (95% CI) using the Mantel-Haenszel method with fixed effects (i.e. assuming that the relative treatment effect was common across all included studies 30 ). Continuous data were analysed as standardised mean difference (SMD) with fixed effects to allow studies using different cognition scales to be integrated. Where necessary, scales were inverted to be compatible with direction of positive cognition, i.e. to reverse the direction of effect for scales that go from high to low. SMD and 95% confidence intervals (95% CI) were converted to an odds ratio (OR, 95% CI) so results from binary and ordinal/continuous results could be compared: 31 , 32 OR = SMD × ∏ / √ 3 = SMD × 1.814 The sample size calculation for the planned UK STEP cSVD platform of N=1,460 was designed to detect an odds ratio of 1.4 (a ‘small’ treatment effect of relevance to a large population of cSVD) with 90% power; hence, short-listed interventions would need meta-analysis evidence that this could be achieved, i.e. OR≥1.4. Scoring of interventions workpackage We developed (PMB) a bespoke scoring system to assess the likelihood that an intervention might successfully alter cognition in people with cSVD ( Table 2 ). The system comprised four parts: mechanisms, meta-analysis, identification of intervention for testing in another phase-3 platform, and feasibility. The first section comprised eight mechanistic targets in cSVD that interventions might modulate in an appropriate direction (e.g. pro-endothelial, anti-inflammatory) to potentially reduce the development and progression of cSVD pathophysiology ( Table 2 ), as used previously 12 (no additional mechanisms having been identified in the intervening nine years); the sectional-score ranges from 0-8. The second section comprised the results of mini rapid meta-analysis based on the odds ratio and lower limit of the 95% confidence interval, the latter to provide information on the precision of the meta-analysis ( Table 2 ); practically, the sectional-score based on the odds ratio ranges from above 0 to less than 100 with an odds ratio of >1 compatible with potential benefit. The third section reviewed whether any of three existing neurodegenerative platforms in the UK ACORD collaboration (MS-SMART, 23 MND-SMART 24 and OCTOPUS 33 , 34 ) were testing the intervention or had plans to do so; the sectional-score ranges from 0-3. The reason for including this information was that it meant that an independent assessment had already identified the same class or intervention (even if this was based on over-lapping information sources). The scores for these three sections were then added to give a sub-score ranging from just above 0 to less than 100. Table 2. Scoring system for assessing whether interventions might work in cSVD. Attribute Score Notes Potential beneficial mechanisms Empirical scoring 12 Tighten blood brain barrier, BBB +1 Pro-endothelial +1 Antiplatelet +1 Smooth muscle cell, proliferative to contractile +1 Anti-leucocyte +1 Anti-fibroblast +1 Anti-inflammation +1 Anti-mitogenic +1 Metaanalysis Odds ratio, OR OR OR for a good outcome: OR >1 means potential benefit OR 95% lower boundary, LB OR 95% LB OR 95% LB: LB >1 means significant benefit Identified for other platforms MS SMART 23 +1 Two separate searching schemes identify same intervention MND SMART 24 +1 Two separate searching schemes identify same intervention OCTOPUS 33 , 34 +1 Two separate searching schemes identify same intervention Sub-score 1 – sum of attributes Range 0 to <~100 Feasibility In British National Formulary (BNF) 29 x1 Essential for a phase-3 trial investigating repurposing Acceptable side effects (from BNF 29 ) x1 Judgement call, essential Limited contraindications (from BNF 29 ) x1 Judgement call, essential Limited existing indication x1 A widely used intervention would not be testable - essential Can be delivered feasibly and long term x1 Essential Cost < £30 per month x1 Judgement call for affordability for widespread use - essential Not already being tested in cSVD x1 Essential Sub-score 2 – multiplier of attributes Either 0 (impossible/impractical) or 1 (feasible) Total score = Sub-score 1 × sub-score 2 Range 0 (infeasible) to <~100 The fourth section identified feasibility (yes = 1, no = 0) and required each and every attribute to be feasible including drug availability in the UK (for whatever indication), acceptable side effects, limited indications (<50% of population) and contraindications, the potential for long-term administration, reasonable treatment cost and not already being tested for cSVD ( Table 2 ). These were multiplied together to create a second sub-score with values or 0 (not feasible) or 1 (feasible). The two sub-scores were then multiplied to give the total score ranging from zero upwards. By example, if anything was considered non-feasible the total score would be zero whatever the results of the first three sections. Otherwise, if everything is feasible, then the final score will be driven by the sum of the first three sectional scores. Intervention CVs/profile workpackage We created ‘CVs’ or profiles (PMB) for each shortlisted intervention comprising information on mechanisms of effect of potential relevance to cSVD (as previously 12 ), evidence of any clinical effect in cSVD, up to three recognised indications (or licensed indications for a drug) and meta-analysis findings (as above). Information from the BNF, 29 or equivalent source if a non-drug, was presented on: dosing; route of administration; NHS cost; adverse event profile; important drug interactions; and cautions, exclusions and contraindications. Information on adherence, score (as above) and any other relevant trials testing it was then given. Finally, a summary of pros and cons resulting from the CV was given. Independent review To compare and rank the shortlisted interventions, an ISAG was created, this comprising experts in stroke or cognition/dementia and trials/platforms; membership comprised RH (chair), JD, PM and SP (academic medics) and GC (patient-public involvement). ‘CVs’ were distributed to the ISAG who then ranked them following open discussion at a video call; PMB was present in a non-voting role to clarify any information. The aim of ISAG was to consider drug summaries for up to 10 drugs, these comprising information of relevance to cSVD on: effects on target cells (e.g. endothelial), existing licensed indications, mini-meta-analysis results of trials in non-cSVD, feasibility of administration, pharmacology (including drug interactions, exclusions), testing in other platforms and overall score ( Table 5 ). Results Preclinical workpackage A search for preclinical references to cSVD (date 14 th August 2023) revealed 36,948 which reduced to 19,654 when limited to those with at least 2 mentions of an intervention included in our drug dictionary ( Figure 2 , top left). 17,628 of 36,948 references included mention of rats, mice or primates, and of these 10,258 had mentions of 1,757 drugs included in our drug dictionary. Figure 2. Flow of data showing number of interventions. Clinical workpackage Searches of registries identified 82 randomised trials of relevance to cSVD with activity status - completed 28, completed with no results 0, suspended/terminated 3, ongoing 3, recruiting 27, to start 13, unknown status 8) ( Figure 2 , top right). Identified interventions included six antihypertensive drugs, two antiplatelets (when given together), five cognitive enhancers/anti-dementia drugs, three involving electromagnetic stimulation, four physiological interventions, nine vasoactive drugs and 13 others of mixed types ( Table 3 ). Table 3. Interventions identified in clinical searches of completed or ongoing trials for cSVD or VaD. For cSVD For VaD Antihypertensives • Amlodipine • Atenolol • Azelnidipine + perindopril • Losartan • Telmisartan • Amlodipine • Nimodipine • Valsartan Antithrombotics • Aspirin + clopidogrel 15 Cognitive enhancers/anti-dementia • Anisodine hydrobromide • Choline alphoscerate • Ginkgo - diterpene lactone or ketoester • Rivastigmine • Almitrine-raubasine (Duxil) • Choline alphoscerate • Citicoline • Donepezil † • Galantamine • Ginkgo biloba • Memantine • Oxiracetam • Rivastigmine • Tandospirone citrate Electro-magnetic stimulation • Repetitive transcranial magnetic stimulation • Theta burst stimulation • Transcranial direct current stimulation • Theta burst stimulation • Transcranial direct current stimulation Physiological • Hyperbaric oxygen treatment • Permissive hypercapnia • Pro-kin visual feedback balance training • Remote ischaemic conditioning (RIC) † • Remote ischaemic conditioning (RIC) † Vasoactive • Alprostadil • Butylphthalide • Cilostazol 18 • Isosorbide mononitrate (ISMN) 18 † • Pentoxifylline • Sarpogrelate hydrochloride • Sildenafil • Tadalafil † • Udenafil • Angiotensin 1-7 • Butylphthalide • Nicergoline • Tadalafil † • Udenafil 41 Others • Allopurinol • Atorvastatin • Carbogen • Equol • Exenatide • Heparin • Maraviroc • Minocycline † • Mixed tocotrienols • Mouse nerve growth factor • Phenylephrine • Polyethylene glycol loxenatide • Rosuvastatin † • Dapagliflozin • Equol (soy-based oestrogen containing supplement) • Ferrous succinate • Fluoxetine • Maraviroc • Methylphenidate • N-acetylcysteine • Olfactory ensheathing cells /Schwann cells/Olfactory receptor neurons • Prospekta (neurotransmitter modulator) • Rosuvastatin † • Urothilin A † Six of the interventions (or within the same class of interventions) shortlisted for consideration by the ISAG were present in both pre-clinical and clinical searches. However, lithium, metformin, semaglutide and vitamins B6/9/12 were shortlisted but not identified in cSVD/Vad clinical studies. A parallel search for interventions of relevance to VaD identified 120 randomised trials with activity status - completed 38, completed with no results 0, suspended or terminated 1, ongoing 3, recruiting 50, to start 20, unknown status 8) ( Figure 2 , top right). Identified interventions included three antihypertensive drugs, no antiplatelets, ten cognitive enhancers/anti-dementia drugs, two involving electromagnetic stimulation, one physiological intervention, five vasoactive drugs and 11 others of mixed types ( Table 3 ). Exclusion of interventions from long-list Interventions from the preclinical and clinical searches were merged and de-duplicated to create a long-list. The long-list of potential interventions for cSVD was reduced to a medium-list by removing interventions that were impossible or impractical to study in a phase-3 platform trial running in the UK. Reasons and their explanations are given in Table 1 with the most common including drugs that are not listed in the British National Formulary and so not available to the trial (62 classes of intervention), drugs that need parenteral administration which would be impractical for widespread use (22 classes), interventions with a significant side-effect profile (15 classes), interventions without good existing preclinical or clinical evidence that the intervention might work (15 classes) and existing widespread use of the drug or class of drugs (13 classes). Mini-meta-analysis workpackage The results of the mini-meta-analyses based on randomised controlled trials and before-after studies for the shortlisted interventions are shown in Table 4 . Interventions varied in their potential to improve cognition for any indication; interventions with a large SMD/high OR were phosphodiesterase5-inhibitors whilst there was no evidence of efficacy for vitamin B12 (see Scoring spreadsheet, Data availability, CC-BY 4.0). Table 4. Summary of meta-analyses for shortlisted candidate interventions for cSVD. Outcome S N SMD (95% CI) OR (95% CI) [ 1 , 2 ] AChE-i, any 41 Continuous 8 3796 0.23 (0.17, 0.30) 1.52 (1.36-1.72) Donepezil 05mg 3 1556 0.20 (0.10, 0.31) 1.44 (1.20-1.76) Donepezil 10mg 2 576 0.37 (0.19, 0.55) 1.96 (1.41-2.71) Galantamine 2 966 0.26 (0.13, 0.39) 1.60 (1.27-2.03) Rivastigmine 1 698 0.15 (0.01, 0.30) 1.31 (1.02-1.72) Biguanide, metformin ( Figure 3a ) Continuous 6 650 0.44 (0.28, 0.58) 2.22 (1.66-2.92) GLP-1, any Binary 3 15820 - 2.04 (1.11-3.70) Liraglutide 1 9340 - 2.00 (1.00-4.00) Semaglutide 2 6480 - 2.13 (0.60-7.69) GSK3-i, lithium Continuous 5 289 0.51 (0.27, 0.75) 2.52 (1.63-3.90) NMDA antagonist, memantine Continuous 2 826 0.37 (0.23, 0.50) 1.96 (1.52-2.48) NOD, isosorbide mononitrate 18 Ordinal 1 308 - 1.82 (1.16-2.78) NOD + PDE3-i: ISMN + cilostazol 18 Ordinal 1 156 - 2.27 (1.18-4.35) PDE5-i, any ( Figure 3b ) Continuous 4 110 1.14 (0.73, 1.55) 7.91 (3.76-16.63) Tadalafil 2 34 1.21 (0.45, 1.96) 8.98 (2.26-34.99) Udenafil [ 3 ] 2 76 1.11 (0.62, 1.60) 7.49 (3.08-18.21) RIC, per/post-conditioning Continuous 9 396 0.56 (0.36, 0.77) 2.76 (1.92-4.04) Statin Continuous 6 1599 0.20 (0.10, 0.30) 1.44 (1.20, 1.72) Atorvastatin 5 923 0.20 (0.07, 0.33) 1.44 (1.14-1.82) Rosuvastatin 1 676 0.20 (0.05, 0.35) 1.44 (1.10, 1.89) Tetracycline, minocycline Continuous 7 547 0.28 (0.11, 0.46) 1.66 (1.22-2.30) Vitamin B12, post stroke Continuous 2 6064 -0.03 (-0.08, 0.02) 0.95 (0.87-1.04) 1 Odds ratio (OR) calculated from standardised mean difference: OR = SMD x ∏/√3. 31 , 32 2 For drug classes with more than one constituent and sufficient data, only the drug with most data was assessed by the ISAG, e.g. donepezil was assessed but galantamine and rivastigmine were not. 3 Not available in UK. Figure 3. Forest plots for a) metformin, and b) phosphodiesterase-inhibitors (including tadalafil). Positive scores imply better cognition. Intervention CVs/profile workpackage Summaries or “CVs” for 10 interventions were developed, as précised in Table 5 . Table 5. Characteristics of 10 shortlisted drugs as reviewed by Independent Scientific Advisory Group (ISAG). Characteristics shown here are a precis of the drug CV reviewed by ISAG. Intervention Cognition meta-analysis, cost, score and ranking For testing Against testing Ranked Metformin (biguanide). No alternatives. OR 2.22 (95% CI 1.66-2.92) n=650. Cost £2.17 pm. Score 21.5. Ranked 1. Licensed first therapy in type 2 diabetes and for prevention of diabetes in pre-diabetes (500-1000 mg SR bd). Reduced cognitive impairment and cSVD burden in type 2 diabetes. 59 Epidemiology: reduced dementia in T2DM. 60 , 61 Positive Mendelian randomisation study for AD. 54 Adherence 90.9% at 6+ months. 62 Being tested in OCTOPUS platform. 33 , 34 Excludes diabetics on metformin. High dose (1g bd) associated with gastrointestinal side effects. Tadalafil (phospho-diesterase5-inhibitor, PDE5-i). Alternatives: avanafil, sildenafil, vardenafil. OR 7.91 (95% CI 3.76-16.63), N=110. Cost £1.93 pm. Score 47.1. Ranked 2. Licensed for erectile dysfunction (5 mg prn), pulmonary hypertension (40 mg od), benign prostatic hypertrophy (5mg od). Adherence 88.7% at 24 weeks. Compatible with positive isosorbide finding in LACI-2 trial. 18 Meta-analysis positive on cognition in experimental AD. 63 Small single-dose studies show improvement in cerebral perfusion and blood flow. 64 , 65 Medication-wide association study compatible with reduced dementia. 56 OR and hence score are very high - likely to be an over-estimate bearing in mind low sample size and 3 of 4 studies were before-after in design. Isosorbide mononitrate (ISMN, nitric oxide donor, NOD). Alternatives: isosorbide dinitrate, glyceryl trinitrate. OR 1.82 (95% CI 1.16-2.78), N=308. 18 Cost £ 6.75 pm. Score 18.7. Ranked 3. Licensed for prophylaxis of angina and as an adjunct in congestive heart failure. Positive after lacunar stroke subtype of cSVD (LACI-2). 18 Adherence 86.2% at 12 months. Effect enhanced when given with cilostazol. 18 So could use combined ISMN & cilostazol. Evidence for cognition in cSVD based on only one phase-2 trial, LACI-2. 18 Post ISAG meeting notes: 1. Since this study, LACI-3 has been funded by NIHR HTA and will study safety and efficacy of ISMN and/or cilostazol after lacunar stroke. 2. CVD-Cog, if funded by Alzheimer’s Society, will study ISMN and/or cilostazol in non-lacunar ischaemic stroke with radiological cSVD. 3. SVD-Cog will be submitted for funding and will study ISMN and/or cilostazol in patients attending a memory-dementia clinic who have radiological cSVD. Hence, ISMN would now be inappropriate to study in a platform Unranked Atorvastatin (hydroxymethylglutaryl-CoA reductase-inhibitor). Alternative: rosuvastatin. OR 1.44 (1.20, 1.72), N=923. Cost £1.32 pm. Score 16.4. Unranked since “would need more than just a statin”. Licensed for primary and secondary prevention after vascular disease, including ischaemic stroke (80 mg od). Reduced stroke recurrence (N=4731). 66 No effect on impaired cerebrovascular reactivity or endothelial function in cSVD (N=94). 67 Improved digit symbol substitution test and reduced dementia. 68 Widely used after stroke but dementia/geriatric patients could be randomised. Donepezil (acetyl cholinesterase-inhibitor, AChE-i). Alternatives: galantamine, rivastigmine OR 1.52 (1.36-1.72), N=2354. Cost £1.22 pm. Score 16.3. Unranked since “no convincing mechanism or efficacy data”. Licensed for early/medium AD (5 mg od). Reduced cognitive impairment in schizophrenia. 69 Meta-analyses compatible with improved cognition in VaD. 41 , 43 All AChE-I VaD trials done only out to 6 months; no 18-month data. Metaanalysis influenced by a neutral CADASIL trial 70 although unclear how relevant monogenic cSVD treatments might be to sporadic cSVD? Cannot be trialled in mixed dementia since many will be on an AChE-I. Unclear whether AChE-Is have any neuroprotective role. 44 Lithium (glycogen synthase kinase 3-inhibitor, GSK3-i). No alternatives. OR 2.52 (95% CI 1.63-3.90), N=289. Cost £7.50 pm. Score 15.7. Unranked “in view of monitoring requirements”. Licensed for treatment and prophylaxis of mania, bipolar disorder and recurrent depression (1.0-1.5 gm od). No cSVD data. Adherence 85.6% at ? months. 71 Need to manage dose by plasma levels so multiple visits so adding complexity/expense. Minocycline (tetracycline antibiotic). Alternative: doxycycline. OR 1.66 (95% CI 1.22-2.30), N=547. Cost £13.02 pm. Score 16.2. Unranked because “unconvinced by earlier efficacy trials”. Licensed antibiotic. Reduced cognitive impairment in schizophrenia. 69 Candidate treatment for AD. 21 , 22 Adherence unreported for long-term therapy. No effect on cognition in AD (Nb avoid 200mg bd). 45 SLE (risk 2.6-8.5 fold) and liver dysfunction (risk 2.1 fold) increased if given for >1 year. 72 Remote ischaemic conditioning (RIC). No alternatives. OR 2.76 (1.92-4.04), N=228. Cost unclear but likely to be significant. Score 24.9. Unranked since “not ready for large scale long-term use”. Some devices have CE Mark. Reduces WMH/cSVD features. 73 – 76 Improved cognition after ischaemic stroke. 77 Burden of self-administered long-term twice daily treatment. Poor adherence (46.5%) at 1 year. 78 Limited availability of MHRA-approved devices. Semaglutide (glucagon-like peptide-1 receptor agonist, GLP-1ra). Alternative: liraglutide). OR 2.04 (1.11-3.70), N=6480. Cost £78.48. Score 9.0. Unranked since trials funded for AD. Licensed for type-2 diabetes. (Other GPL1ra are licensed for adjunct in weight loss). GLP-1ra reduce dementia in type-2 diabetes. 79 Cognition meta-analysis for any GLP1: OR 1.82 (0.95-3.50), N=7732. 80 No cSVD data. Adherence 69.7% at 12 months. 81 Too expensive so trial would need commercial support. Poor adherence rates. Vitamin B6 & B9 (folic acid) & B12. OR 0.95 (95% CI 0.87-1.04), N=6064. Cost unclear since VITATOPS/VISP drug doses are not available in UK. Score 14.7. Unranked since “large neutral trials already”. Licensed for vitamin deficiencies, e.g. B12 deficiency. Periventricular white matter lucencies are related to low B12 levels in small vessel disease stroke. 82 Adherence 89.3% at 12 months. Positive mendelian randomisation study for stroke. 53 Neutral studies on recurrence after stroke (VISP, 83 VITATOPS 84 ). Neutral studies on cognition after stroke (VISP, 83 VITATOPS 85 ) and meta-analysis. Not available at the VITATOPS/VISP doses (over the counter doses are much lower). Would require 3 tablets Independent review of 10 shortlisted drugs The ISAG reviewed the summaries for 10 interventions. Three drugs were ranked: 1) metformin (biguanide, a metabolic modulator), 2) tadalafil (phosphodiesterase5-inhibitor causing vasodilation), and 3) isosorbide mononitrate (nitric oxide donor causing vasodilation). The other seven interventions were not considered to be relevant to study in a large trial for reasons that are given in Table 5 , and so were not ranked: atorvastatin (hydroxymethylglutaryl-CoA reductase-inhibitor), donepezil (acetyl cholinesterase-inhibitor, AChE-i), lithium (glycogen synthase kinase 3-inhibitor, GSK3-i), minocycline (tetracycline antibiotic), remote ischaemic conditioning (RIC), semaglutide (glucagon-like peptide-1 receptor agonist, GLP-1ra) and vitamin B6/9/12. Comparisons with recommendations for assessing interventions in other neurodegenerative conditions (AD, MND, MS) are given in Table 6 . Some of the chosen interventions were not identified here for cSVD since they: are not in the BNF (e.g. fasudil, ibudilast, phenserine), 29 have significant side-effects (e.g. oxcarbazepine, perfenidone), were infrequently identified in preclinical screening (e.g. trazodone - only 4 mentions), lack safety information for long-term administration (e.g. anti-herpes drugs), are in widespread use 35 so would lead to a significant number of exclusions (angiotensin receptor antagonists, calcium channel blockers), have neutral effects in other neurodegenerative conditions (amiloride, fluoxetine, losartan, memantine, riluzole, trazodone), can be bought over the counter so potentially contaminating the control group (fatty acids, tadalafil, sildenafil, vitamins), or are already being tested (glucagon-like peptide-1 receptor agonists). Table 6. Interventions prioritised for testing in neurological diseases following systematic assessment. Drug class: examples Alzheimer’s disease (AD) Motor neurone disease (MND) Multiple sclerosis (MS) This review in cerebral small vessel disease (cSVD) AChE-i: phenserine Recommended for testing. 22 Not shortlisted here – not in BNF. 29 Anticonvulsant: Oxcarbazepine Recommended for testing. 23 Not shortlisted here – significant side-effects. Antidepressant: trazodone Recommended for testing. 24 Neutral in MND-SMART (N=371). 42 Not shortlisted here – infrequently identified in preclinical screening (4 mentions), neutral in MND. 42 Anti-herpes: valaciclovir; valganciclovir Recommended for testing. 22 Not shortlisted here – for short term use, not identified in pre-clinical search. ARA: candesartan, losartan, telmisartan Recommended for testing. 21 Losartan neutral (N=221). 47 Not shortlisted here – in widespread use; losartan neutral for AD. 47 Benzothiazoles: riluzole Recommended for testing. 23 Neutral in MS-SMART (N=223). 48 Not shortlisted here – neutral in MS. 48 Biguanide: metformin Recommended for testing. OCTOPUS is testing. 33 , 34 Recommended here for testing. CCB: amlodipine, nilvadipine Recommended for testing. 21 Neutral (N=498). 46 Not shortlisted here – in widespread use; amlodipine (AFFECT) failed to recruit in cSVD; 86 nilvadipine not in BNF. 29 Fatty acids: linoleic acid, lipoic acid, omega-3 fatty acid Recommended for testing. 23 OCTOPUS is testing R/S-alpha lipoic acid. 33 , 34 Not shortlisted here – can be bought over the counter, omega-3 fatty acids. NOD: ISMN Recommended for testing here. 12 Positive, especially when co-administered with cilostazol. 18 To be tested in LACI-3. GLP-1: liraglutide, semaglutide Recommended for testing. 21 , 22 ELAD is testing liraglutide. 87 Shortlisted but not ranked – already being tested, expensive and poor adherence. NMDA-ra: memantine Recommended for testing. 24 Neutral in MND-SMART (N=369). 42 Not shortlisted here – neutral in MND. 42 Pyridone immune-suppressive: perfenidone Recommended for testing. 23 Not shortlisted here – severe side effects requiring specialist supervision. 29 PDE3-i: cilostazol Recommended for testing. 12 Neutral in cSVD/positive if given with ISMN. 18 PDE4-i: ibudilast Recommended for testing. 23 Not shortlisted here – not in BNF. 29 PDE5-i: tadalafil Recommended here for testing. Potassium-sparing diuretic: amiloride Recommended for testing. 23 Neutral in MS-SMART (N=223). 48 Not shortlisted here – neutral in MS. 48 ROCK-i: fasudil Recommended for testing. 22 Not shortlisted here – not in BNF. 29 SSRI: citalopram, fluoxetine, fluvoxamine, sertraline Recommended for testing. 23 Fluoxetine neutral in MS-SMART (N=223). 48 Not shortlisted here – fluoxetine neutral in MS. 48 Tetracycline antibiotic: minocycline Recommended for testing. 21 Neutral (N=544). 45 Shortlisted but not ranked – neutral for AD. 45 Discussion Summary of evidence Following screening of pre-clinical and clinical studies, we identified more than 1700 interventions that might be candidate treatments for cSVD. These were filtered down to ten by removing duplicates and interventions that were not possible or practical to assess in a phase-3 platform trial environment or that showed inadequate evidence of efficacy. The ten interventions comprised nine drugs (atorvastatin, donepezil, ISMN, lithium, metformin, minocycline, semaglutide and combined vitamin B6/9/12) and one device (remote ischaemic conditioning) ( Table 5 ). These were then ranked by an ISAG with three prioritised: a metabolic modulator (metformin) and two vasoactive agents (tadalafil, ISMN), all of which have some evidence that they may improve cognition in other conditions although none are licensed for this purpose. The first ranked drug, metformin, a biguanide, is licensed for the treatment of type-2 diabetes mellitus (BNF 29 ) and guidelines recommend it for first-line therapy for this indication. It is also licensed for the prevention of diabetes in people with pre-diabetes. The meta-analysis showed that both the odds ratio (2.22) and lower 95% CI (1.66) were well above the target platform odds ratio of 1.40. Metformin has been identified for assessment in other neurological diseases and is being tested in the OCTOPUS platform trial in multiple sclerosis ( Table 6 ). 33 , 34 However, a systematic review done for a guideline did not identify evidence supporting the use of antidiabetic drugs for treating cSVD although this recommendation was not specific to metformin. 36 The second ranked drug, tadalafil, is a phosphodiesterase5 inhibitor (PDE5-i) that maintains cyclic guanosine monophosphate levels, the second messenger for nitric oxide. It is licensed for the treatment of erectile dysfunction, benign prostatic hypertrophy and pulmonary hypertension (BNF 29 ) and has recently become available over the counter. The meta-analysis showed that both the odds ratio (7.91) and lower 95% CI (3.76) for PDE5-i were well above the target platform odds ratio of 1.40. However, the meta-analysis was based on a small dataset of 110 participants, mostly from before-after studies. Nevertheless, the positive findings for the third ranked drug, ISMN, a nitric oxide donor (NOD), in the LACI-2 trial 18 are supportive in view of the related mechanism of action for NOD and PDE5-i. ISMN is licensed for the prophylaxis of angina and as an adjunct in congestive heart failure (BNF 29 ). Of the three drugs, ISMN is the only one to have been tested in cSVD, specifically in patients with previous lacunar infarction. The LACI-1 and LACI-2 trials showed that ISMN was feasible to take (given with or without cilostazol) for up to a year, was safe and improved cognition and functional outcome and reduced recurrent stroke, especially when given with cilostazol. 18 , 37 – 39 Recently, NIHR HTA funded the LACI-3 trial which will test the safety and efficacy of ISMN and cilostazol in patients with previous lacunar stroke in a 2x2 partial factorial design. Hence, it would now be inappropriate to test either of these drugs in a UK platform. Practically, the only other short-listed intervention ( Table 5 ) that could readily be tested in a phase-3 platform for cSVD is one of the licensed oral AD drugs, as identified for VCI. 40 Eight short-term small-to-medium sized trials of AChE-i have been performed in VaD and they showed efficacy with an odds ratio (1.52) which exceeds the platform target odds ratio of 1.4; 41 the lower 95% CI boundary (1.36) just misses this. Donepezil at 10 mg daily would probably be the drug of choice since it appears to be more efficacious than when given at 5 mg daily ( Table 4 ). Memantine is also a possibility although it was neutral in MND-SMART. 42 A recent network metanalysis provides mixed results as to whether AChE-I improve cognition in VCI/VaD. 43 However, it remains unclear whether AChE-i and memantine only modulate symptoms in AD, also have some disease modifying/neuroprotective properties or even address AD pathology which may often be present in VCI/VaD. 44 In this respect, cSVD would be an interesting target for testing whether AChE-Is do have disease-modifying effects in view of the longer natural history for cognitive decline in cSVD. The present study extended the methodology used previously for identifying candidate treatments for cSVD 12 by adding preclinical and clinical screening, mini-meta-analyses to assess whether an intervention might affect cognition in other disease areas and a scoring system. These approaches are broadly similar but not identical to those used for AD, MND and MS. 21 – 24 Some relevant pathways and hence licenced drugs may have been missed due to restrictions on search terms – a future search should include other relevant pathways in other neurological diseases even if these have not yet been tested in animal models of cSVD. In retrospect, adding OR>1.40 or even the 95% lower CI >1.40 as a multiplier in scoring would have excluded short-listed interventions with little likelihood of success such as vitamin B12 ( Table 5 ). Structured systematic approaches to identifying candidate treatments are not a guarantee that any identified and highly scored intervention will definitely work. For example, five classes of compounds were identified for repurposing as treatments of AD 21 and yet trials of minocycline, 45 nilvadipine 46 and losartan 47 were all neutral on clinical outcomes. 22 Similarly, of seven drugs identified for testing in MS, 23 amiloride, fluoxetine and riluzole were assessed at phase-2b and found to have no effect on MRI brain volume change between baseline and 96 weeks. 48 Recently, memantine and trazodone were found to be ineffective for MND. 42 Interestingly, all of these trials were much smaller than the planned UK STEP platform trial in cSVD and so underpowered for finding small but potentially useful clinical benefits at the population level providing the intervention is cost-effective. Further, some trials for neurogenerative conditions have relied on intermediate imaging endpoints which may be insensitive to changes in clinical endpoints; the incongruent relationship between neuroimaging intermediate outcomes at phase-2 and clinical functional outcomes at phase-3 has been highlighted for interventions such as citicoline for acute ischaemic stroke and blood pressure lowering for acute intracerebral haemorrhage. The framework for clinical trials in cSVD (FINESSE) recommends that clinical outcomes should be used as the main endpoint in cSVD trials although brain imaging changes may also be collected. 49 In this respect, LACI-2 showed that whilst clinical outcomes were positive, imaging outcomes were mostly neutral, suffered from larger data losses and come with increased costs and the need for participants to visit hospitals. 50 Strengths and limitations The main strength of this study is the triangulation of information from preclinical and clinical cSVD and VCI studies in the search for candidate treatments for cSVD, mini meta-analyses of potentially interesting interventions with scoring and then independent prioritisation and ranking. That only six of the ten shortlisted interventions were identified in clinical searches of completed, ongoing or planned trials shows the importance of also assessing the preclinical literature. Taken together, our approach offers a robust, efficient and reproducible approach to drug repurposing selection that could be used for other indications or target diseases. However, there are also several limitations to the study. First, the intention was to identify potential interventions that could be tested at phase-3 by repurposing existing and inexpensive UK-licensed drugs. This meant we excluded drugs that are not available in the UK, could not logistically be administered long-term, were not ready for phase-3 trial assessment or were too expensive for widespread use. Hence, there will be novel interventions that could be tested at phase-2 and others that are available for repurposing outside of the UK. We excluded members of 62 classes of drugs that are not available in the UK; examples of drugs with potential relevance to cSVD include azelnidipine (calcium channel antagonist), beraprost (prostacyclin analogue), butylphthalide (neuroprotection and vasodilation), choline alphoscerate (neurotransmitter precursor), equol (oestrogen mimic), fasudil (rho-kinase inhibitor), ginkgo biloba (uncertain mechanisms), nerve growth factor and oxiracetam (nootrope), These are available in various parts of the world including low-middle income countries and some are in trial for cSVD ( Table 3 ). Equally, there will be drugs that are available in the UK but not in some other countries (such as isosorbide mononitrate). Second, the review was performed rapidly to identify interventions that could be tested in a platform trial in response to a platform trial funding call. Although the time between call and grant submission was four months, the intervention identification phase only lasted two months since the platform design and its costing necessarily needed to know what interventions would be assessed initially. Further, electronic searches were limited to English language. As a result, it is likely that we have missed some studies and interventions although many were found as duplicates in searches. We are now extending the process to perform a deeper dive into phosphodiesterase inhibitors and acetylcholinesterase inhibitors/memantine and assess their effects on cognition in non-cSVD indications. Third, the pre-clinical search focussed on models of relevance to cSVD and it is possible that this approach is too restrictive. Fourth, although the scoring system was based on one used previously, 12 it was expanded for use here without prior validation although it appears to have face validity. Fifth, we did not, in the main, account for dose in the meta-analyses. For the platform, we planned to initiate drugs at a low-medium dose and then escalate to near maximal, as we did in LACI-1/2 18 , 38 and will do in LACI-3. 51 Sixth, we did not seek evidence that interventions would alter mechanistic efficacy biomarkers. Seventh, the conversion of standardised mean difference to odds ratio for use in the mini-meta-analyses may have introduced bias or imprecision in effect estimates. And last, there are additional approaches that may be useful in identifying candidate drugs that we did not incorporate, for example Mendelian randomisation assessments 52 – 55 and medication-wide association studies. 56 Conclusions In summary, we performed a rapid structured systematic search for interventions that might be relevant to treating or preventing cSVD. We identified interventions that could be repurposed and three were ranked by an ISAG; each of metformin, tadalafil and ISMN could readily be tested at phase-3 in the UK and be used routinely in clinical practice if found to be effective. Although our UK STEP grant application to test these in a platform environment was unsuccessful, we will be assessing ISMN as well as cilostazol in the recently funded LACI-3 trial. Ethics and consent Ethics and consent were not required. Author contributions • Philip M Bath: Conceptualisation, Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing – original draft preparation • Elizabeth P M Phan: Data curation, Formal analysis, Writing – review & editing • Gwynneth Clay: Conceptualisation, Supervision, Writing – review & editing • Jesse Dawson: Supervision, Writing – review & editing • Paresh Malhotra: Supervision, Writing – review & editing • Rob Howard: Supervision, Writing – review & editing • Suvankar Pal: Supervision, Writing – review & editing • Joanna M Wardlaw: Conceptualisation, Validation, Writing – review & editing • Terry Quinn: Conceptualisation, Methodology, Supervision, Writing – review & editing • Malcolm MacLeod: Conceptualisation, Data curation, Formal analysis, Investigation, Methodology, Resources, Writing – review & editing Units, symbols and mathematical scripts There are no special units, symbols or mathematical scripts. Data availability Scoring of interventions for cerebral small vessel disease. http://doi.org/10.17639/nott.7493 . 57 Attribution 4.0 International Deed license CC-BY 4.0 This project contains the following underlying data: • Data file 1, Excel sheet giving scoring calculations: Scoring spreadsheet • Data file 2, Data dictionary for spreadsheet: Data Dictionary • Data file 3, PRISMA ScR checklist: PRISMA-ScR Checklist Reporting guidelines The report follows the checklist for the PRISMA extension for scoping reviews (PRISMA-ScR) guideline 58 adapted to account for the structure of this project and its multiple work packages. http://doi.org/10.17639/nott.7493 . 57 Attribution 4.0 International Deed license CC-BY 4.0 Acknowledgements PMB is Stroke Association Professor of Stroke Medicine, an emeritus NIHR Senior Investigator and is a member of the Vascular Experimental Medicine (VEM) group of Dementia Platform UK (DPUK). 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PubMed Abstract | Publisher Full Text | Free Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 20 Dec 2024 ADD YOUR COMMENT Comment Author details Author details 1 Stroke Trials Unit, University of Nottingham, Nottingham, England, NG7 2UH, UK 2 Stroke, Nottingham University Hospitals NHS Trust, Nottingham, England, NG7 2UH, UK 3 School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, G4 0SF, UK 4 School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, G51 4TF, UK 5 Division of Neurology, Imperial College, London, W6 8RP, UK 6 Maple House, University College London, London, England, W1T 7NF, UK 7 Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, Midlothian, EH16 4SB, UK 8 Dementia Research Institute Centre, University of Edinburgh, Edinburgh, Midlothian, EH16 4SB, UK 9 CAMARADES Group, University of Edinburgh, Edinburgh, Midlothian, EH16 4SB, UK Philip M Bath Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Writing – Original Draft Preparation Elizabeth P Phan Roles: Data Curation, Formal Analysis, Writing – Review & Editing Gwynneth Clay Roles: Conceptualization, Supervision, Writing – Review & Editing Jesse Dawson Roles: Supervision, Writing – Review & Editing Paresh Malhotra Roles: Supervision, Writing – Review & Editing Rob Howard Roles: Supervision, Writing – Review & Editing Suvankar Pal Roles: Supervision, Writing – Review & Editing Joanna M Wardlaw Roles: Conceptualization, Validation, Writing – Review & Editing Terry Quinn Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing Malcolm Macleod Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (2) version 2 Revised Published: 10 Sep 2025, 13:1546 https://doi.org/10.12688/f1000research.157890.2 version 1 Published: 20 Dec 2024, 13:1546 https://doi.org/10.12688/f1000research.157890.1 Copyright © 2025 Bath PM et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Bath PM, Phan EP, Clay G et al. Developing treatments for cerebral small vessel disease: a scoping review of licensed interventions for potential repurposing [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1546 ( https://doi.org/10.12688/f1000research.157890.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 20 Dec 2024 Views 0 Cite How to cite this report: Zotin MCZ. Reviewer Report For: Developing treatments for cerebral small vessel disease: a scoping review of licensed interventions for potential repurposing [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1546 ( https://doi.org/10.5256/f1000research.173409.r392606 ) The direct URL for this report is: https://f1000research.com/articles/13-1546/v1#referee-response-392606 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 09 Aug 2025 Maria Clara Zanon Zotin , Universidade de Sao Paulo, São Paulo, State of São Paulo, Brazil Approved VIEWS 0 https://doi.org/10.5256/f1000research.173409.r392606 This is a rapid multi-stage scoping review and mini-meta-analysis aimed at identifying potential interventions for preventing cognitive decline in patients with cSVD which could be tested in a phase-3 platform trial. Pre-clinical and clinical studies were screened. Potential interventions were ... Continue reading READ ALL This is a rapid multi-stage scoping review and mini-meta-analysis aimed at identifying potential interventions for preventing cognitive decline in patients with cSVD which could be tested in a phase-3 platform trial. Pre-clinical and clinical studies were screened. Potential interventions were filtered down to 10 by removing duplicates and those interventions deemed ineffective (including non-cost-effective ones) or unavailable. The shortlisted candidate interventions for cSVD were assessed in mini-meta-analyses, and phosphodiesterase5-inhibitors showed higher OR. These ten shortlisted interventions were further narrowed down to three by an independent scientific advisory committee that prioritised metformin, tadalafil, and ISMN. This is a well-structured and well-written straight-forward and practical scoping review of experts in the field of CSVD and vascular dementia, aimed at guiding future research and fostering purposeful clinical trials. This review contributes significantly to the field by focusing on repurposing existing drugs, which may lead to faster and more cost-effective future trials. I have only a minor questions/comment: The authors clearly state that the study aims to identify promising drugs suitable for phase-3 testing in the UK and acknowledge this location-specificity as a limitation, given that drugs available elsewhere may be excluded. Could the authors comment on how restricting the analysis to UK-authorized drugs and excluding “impossible or impractical interventions” might affect the generalizability of the findings to other countries, particularly low- and middle-income settings where CSVD burden is highest? From my perspective, these restrictions may not diminish, and could potentially enhance, the applicability of the results to resource-limited contexts with constrained research funding and healthcare infrastructure. The authors’ insights on this would be valuable. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Yes Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Neuroradiology. Vascular Neurology. Cerebral Small Vessel Diseases. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Zotin MCZ. Reviewer Report For: Developing treatments for cerebral small vessel disease: a scoping review of licensed interventions for potential repurposing [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1546 ( https://doi.org/10.5256/f1000research.173409.r392606 ) The direct URL for this report is: https://f1000research.com/articles/13-1546/v1#referee-response-392606 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Taylor JL. Reviewer Report For: Developing treatments for cerebral small vessel disease: a scoping review of licensed interventions for potential repurposing [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1546 ( https://doi.org/10.5256/f1000research.173409.r392611 ) The direct URL for this report is: https://f1000research.com/articles/13-1546/v1#referee-response-392611 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 22 Jul 2025 Jade L. Taylor , University of California Davis, Davis, California, USA Approved VIEWS 0 https://doi.org/10.5256/f1000research.173409.r392611 The systematic review by Bath et al. presents a well-designed and thoughtfully executed synthesis of both clinical and preclinical trials investigating potential therapies for cerebral small vessel disease (cSVD). The authors employ a robust multi-scale approach, integrating preclinical screening, feasibility ... Continue reading READ ALL The systematic review by Bath et al. presents a well-designed and thoughtfully executed synthesis of both clinical and preclinical trials investigating potential therapies for cerebral small vessel disease (cSVD). The authors employ a robust multi-scale approach, integrating preclinical screening, feasibility scoring, and evaluation by an independent scientific advisory group (ISAG), which collectively enhance the strength and credibility of the report. Practical considerations, such as cost and long-term tolerability of interventions, are sensibly incorporated, increasing the likelihood that identified candidate therapies will be viable in clinical practice. Importantly, the authors are transparent about the absence of a pre-registered protocol (e.g., PROSPERO), acknowledging the limitation this poses in terms of replicability. Given the current lack of effective disease-modifying treatments for cSVD, this review represents a timely and valuable contribution to the field. Areas for revision or clarification: Page 2, Paragraph 2 (Results section of the abstract): The phrase “those that were not available in the UK” should be corrected to “those that were available in the UK.” ISAG Criteria: The criteria employed by the ISAG should be introduced earlier in the manuscript—preferably in the methods section—and clearly linked to Table 5 for clarity. The inclusion of only English-language studies should be explicitly acknowledged as a limitation, as it may have resulted in the exclusion of relevant non-English literature. The limitations of converting standardized mean differences from before-after studies to odds ratios for comparison purposes should be discussed, as this transformation may introduce bias or imprecision in effect estimates. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) No Competing Interests: No competing interests were disclosed. Reviewer Expertise: cerebral blood vessel physiology and pathophysiology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Taylor JL. Reviewer Report For: Developing treatments for cerebral small vessel disease: a scoping review of licensed interventions for potential repurposing [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1546 ( https://doi.org/10.5256/f1000research.173409.r392611 ) The direct URL for this report is: https://f1000research.com/articles/13-1546/v1#referee-response-392611 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 10 Sep 2025 Philip Bath , Stroke Trials Unit, University of Nottingham, Nottingham, NG7 2UH, UK 10 Sep 2025 Author Response We thank Dr Taylor for their helpful comments. Page 2, Paragraph 2 (Results section of the abstract): The phrase “those that were not available in the UK” should be corrected to ... Continue reading We thank Dr Taylor for their helpful comments. Page 2, Paragraph 2 (Results section of the abstract): The phrase “those that were not available in the UK” should be corrected to “those that were available in the UK.” Thank you – we have corrected this in Abstract/Results.. CHANGE ISAG Criteria: The criteria employed by the ISAG should be introduced earlier in the manuscript—preferably in the methods section—and clearly linked to Table 5 for clarity. Thank you – we have expanded on the criteria assessed by ISAG in the Methods/Independent review section with a link to Table 5. We have also corrected the use of Independent Scientific Advisory Committee (ISAC) by changing to … Group (ISAG) in the Header of Table 5 and text (sections Overview, Table 3 and Independent review…) for consistency with the original NIHR research call. CHANGE The inclusion of only English-language studies should be explicitly acknowledged as a limitation, as it may have resulted in the exclusion of relevant non-English literature. Thank you – we have added this point to the Discussion/limitations section (added to limitation 2. CHANGE The limitations of converting standardized mean differences from before-after studies to odds ratios for comparison purposes should be discussed, as this transformation may introduce bias or imprecision in effect estimates. Thank you – we have added this point to the Discussion/limitations section (new limitation 7). CHANGE We thank Dr Taylor for their helpful comments. Page 2, Paragraph 2 (Results section of the abstract): The phrase “those that were not available in the UK” should be corrected to “those that were available in the UK.” Thank you – we have corrected this in Abstract/Results.. CHANGE ISAG Criteria: The criteria employed by the ISAG should be introduced earlier in the manuscript—preferably in the methods section—and clearly linked to Table 5 for clarity. Thank you – we have expanded on the criteria assessed by ISAG in the Methods/Independent review section with a link to Table 5. We have also corrected the use of Independent Scientific Advisory Committee (ISAC) by changing to … Group (ISAG) in the Header of Table 5 and text (sections Overview, Table 3 and Independent review…) for consistency with the original NIHR research call. CHANGE The inclusion of only English-language studies should be explicitly acknowledged as a limitation, as it may have resulted in the exclusion of relevant non-English literature. Thank you – we have added this point to the Discussion/limitations section (added to limitation 2. CHANGE The limitations of converting standardized mean differences from before-after studies to odds ratios for comparison purposes should be discussed, as this transformation may introduce bias or imprecision in effect estimates. Thank you – we have added this point to the Discussion/limitations section (new limitation 7). CHANGE Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 10 Sep 2025 Philip Bath , Stroke Trials Unit, University of Nottingham, Nottingham, NG7 2UH, UK 10 Sep 2025 Author Response We thank Dr Taylor for their helpful comments. Page 2, Paragraph 2 (Results section of the abstract): The phrase “those that were not available in the UK” should be corrected to ... Continue reading We thank Dr Taylor for their helpful comments. Page 2, Paragraph 2 (Results section of the abstract): The phrase “those that were not available in the UK” should be corrected to “those that were available in the UK.” Thank you – we have corrected this in Abstract/Results.. CHANGE ISAG Criteria: The criteria employed by the ISAG should be introduced earlier in the manuscript—preferably in the methods section—and clearly linked to Table 5 for clarity. Thank you – we have expanded on the criteria assessed by ISAG in the Methods/Independent review section with a link to Table 5. We have also corrected the use of Independent Scientific Advisory Committee (ISAC) by changing to … Group (ISAG) in the Header of Table 5 and text (sections Overview, Table 3 and Independent review…) for consistency with the original NIHR research call. CHANGE The inclusion of only English-language studies should be explicitly acknowledged as a limitation, as it may have resulted in the exclusion of relevant non-English literature. Thank you – we have added this point to the Discussion/limitations section (added to limitation 2. CHANGE The limitations of converting standardized mean differences from before-after studies to odds ratios for comparison purposes should be discussed, as this transformation may introduce bias or imprecision in effect estimates. Thank you – we have added this point to the Discussion/limitations section (new limitation 7). CHANGE We thank Dr Taylor for their helpful comments. Page 2, Paragraph 2 (Results section of the abstract): The phrase “those that were not available in the UK” should be corrected to “those that were available in the UK.” Thank you – we have corrected this in Abstract/Results.. CHANGE ISAG Criteria: The criteria employed by the ISAG should be introduced earlier in the manuscript—preferably in the methods section—and clearly linked to Table 5 for clarity. Thank you – we have expanded on the criteria assessed by ISAG in the Methods/Independent review section with a link to Table 5. We have also corrected the use of Independent Scientific Advisory Committee (ISAC) by changing to … Group (ISAG) in the Header of Table 5 and text (sections Overview, Table 3 and Independent review…) for consistency with the original NIHR research call. CHANGE The inclusion of only English-language studies should be explicitly acknowledged as a limitation, as it may have resulted in the exclusion of relevant non-English literature. Thank you – we have added this point to the Discussion/limitations section (added to limitation 2. CHANGE The limitations of converting standardized mean differences from before-after studies to odds ratios for comparison purposes should be discussed, as this transformation may introduce bias or imprecision in effect estimates. Thank you – we have added this point to the Discussion/limitations section (new limitation 7). CHANGE Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 20 Dec 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 2 (revision) 10 Sep 25 Version 1 20 Dec 24 read read Jade L. Taylor , University of California Davis, Davis, USA Maria Clara Zanon Zotin , Universidade de Sao Paulo, São Paulo, Brazil Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Zotin M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 09 Aug 2025 | for Version 1 Maria Clara Zanon Zotin , Universidade de Sao Paulo, São Paulo, State of São Paulo, Brazil 0 Views copyright © 2025 Zotin M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This is a rapid multi-stage scoping review and mini-meta-analysis aimed at identifying potential interventions for preventing cognitive decline in patients with cSVD which could be tested in a phase-3 platform trial. Pre-clinical and clinical studies were screened. Potential interventions were filtered down to 10 by removing duplicates and those interventions deemed ineffective (including non-cost-effective ones) or unavailable. The shortlisted candidate interventions for cSVD were assessed in mini-meta-analyses, and phosphodiesterase5-inhibitors showed higher OR. These ten shortlisted interventions were further narrowed down to three by an independent scientific advisory committee that prioritised metformin, tadalafil, and ISMN. This is a well-structured and well-written straight-forward and practical scoping review of experts in the field of CSVD and vascular dementia, aimed at guiding future research and fostering purposeful clinical trials. This review contributes significantly to the field by focusing on repurposing existing drugs, which may lead to faster and more cost-effective future trials. I have only a minor questions/comment: The authors clearly state that the study aims to identify promising drugs suitable for phase-3 testing in the UK and acknowledge this location-specificity as a limitation, given that drugs available elsewhere may be excluded. Could the authors comment on how restricting the analysis to UK-authorized drugs and excluding “impossible or impractical interventions” might affect the generalizability of the findings to other countries, particularly low- and middle-income settings where CSVD burden is highest? From my perspective, these restrictions may not diminish, and could potentially enhance, the applicability of the results to resource-limited contexts with constrained research funding and healthcare infrastructure. The authors’ insights on this would be valuable. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Yes Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Neuroradiology. Vascular Neurology. Cerebral Small Vessel Diseases. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Zotin MCZ. Peer Review Report For: Developing treatments for cerebral small vessel disease: a scoping review of licensed interventions for potential repurposing [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1546 ( https://doi.org/10.5256/f1000research.173409.r392606) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-1546/v1#referee-response-392606 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Taylor J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 22 Jul 2025 | for Version 1 Jade L. Taylor , University of California Davis, Davis, California, USA 0 Views copyright © 2025 Taylor J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The systematic review by Bath et al. presents a well-designed and thoughtfully executed synthesis of both clinical and preclinical trials investigating potential therapies for cerebral small vessel disease (cSVD). The authors employ a robust multi-scale approach, integrating preclinical screening, feasibility scoring, and evaluation by an independent scientific advisory group (ISAG), which collectively enhance the strength and credibility of the report. Practical considerations, such as cost and long-term tolerability of interventions, are sensibly incorporated, increasing the likelihood that identified candidate therapies will be viable in clinical practice. Importantly, the authors are transparent about the absence of a pre-registered protocol (e.g., PROSPERO), acknowledging the limitation this poses in terms of replicability. Given the current lack of effective disease-modifying treatments for cSVD, this review represents a timely and valuable contribution to the field. Areas for revision or clarification: Page 2, Paragraph 2 (Results section of the abstract): The phrase “those that were not available in the UK” should be corrected to “those that were available in the UK.” ISAG Criteria: The criteria employed by the ISAG should be introduced earlier in the manuscript—preferably in the methods section—and clearly linked to Table 5 for clarity. The inclusion of only English-language studies should be explicitly acknowledged as a limitation, as it may have resulted in the exclusion of relevant non-English literature. The limitations of converting standardized mean differences from before-after studies to odds ratios for comparison purposes should be discussed, as this transformation may introduce bias or imprecision in effect estimates. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) No Competing Interests No competing interests were disclosed. Reviewer Expertise cerebral blood vessel physiology and pathophysiology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (1) Author Response 10 Sep 2025 Philip Bath, Stroke Trials Unit, University of Nottingham, Nottingham, NG7 2UH, UK We thank Dr Taylor for their helpful comments. Page 2, Paragraph 2 (Results section of the abstract): The phrase “those that were not available in the UK” should be corrected to “those that were available in the UK.” Thank you – we have corrected this in Abstract/Results.. CHANGE ISAG Criteria: The criteria employed by the ISAG should be introduced earlier in the manuscript—preferably in the methods section—and clearly linked to Table 5 for clarity. Thank you – we have expanded on the criteria assessed by ISAG in the Methods/Independent review section with a link to Table 5. We have also corrected the use of Independent Scientific Advisory Committee (ISAC) by changing to … Group (ISAG) in the Header of Table 5 and text (sections Overview, Table 3 and Independent review…) for consistency with the original NIHR research call. CHANGE The inclusion of only English-language studies should be explicitly acknowledged as a limitation, as it may have resulted in the exclusion of relevant non-English literature. Thank you – we have added this point to the Discussion/limitations section (added to limitation 2. CHANGE The limitations of converting standardized mean differences from before-after studies to odds ratios for comparison purposes should be discussed, as this transformation may introduce bias or imprecision in effect estimates. Thank you – we have added this point to the Discussion/limitations section (new limitation 7). CHANGE View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Taylor JL. Peer Review Report For: Developing treatments for cerebral small vessel disease: a scoping review of licensed interventions for potential repurposing [version 2; peer review: 2 approved] . F1000Research 2025, 13 :1546 ( https://doi.org/10.5256/f1000research.173409.r392611) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. 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