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Neuroprotective effects of exercise in people with progressive multiple sclerosis (Exercise PRO-MS): study protocol of a phase II trial.

ABSTRACT: BACKGROUND:Neurodegeneration, rather than inflammation, plays a key role in the progressive phase of multiple sclerosis (MS). Current disease modifying treatment options for people with progressive MS (PMS) do not specifically target neurodegeneration. Preliminary evidence suggests that exercise therapy might have neuroprotective effects. However, neuroprotective effect studies of exercise interventions in PMS are scarce and the possible mode of action underlying neuroprotective effects of exercise are unknown and need to be elucidated. The main aim of this phase II trial is to assess whether progressive resistance training (PRT) and high intensity interval training (HIIT), can slow down neurodegeneration in people with PMS. METHODS:In a single-blinded phase II clinical trial with an extended baseline period, 60 people with PMS will be randomly assigned to PRT or HIIT. The participants should have had a relapse onset of MS with confirmed disease progression, however still ambulatory. The duration of the study is 48?weeks, consisting of 16?weeks baseline period (no intervention), 16?weeks intervention and 16?weeks follow-up. Patient-tailored training will be performed 3 times per week for one hour in groups, led by an experienced physiotherapist. The primary outcome measure is neurodegeneration, measured as whole brain atrophy on magnetic resonance imaging (MRI). Secondary outcome parameters will include other biomarkers associated with neurodegeneration (i.e. regional brain atrophy, lesion load, white matter integrity, resting state functional connectivity, blood biomarkers (brain derived neurotrophic factor (BDNF) and serum neurofilament light (sNFL)), patient functioning (physical and cognitive) and cardiovascular risk factors. DISCUSSION:Besides the primary outcome measures, this study will examine a large variety of biomarkers associated with neurodegeneration after an exercise intervention. Combining outcome parameters may help to elucidate the mode of action underlying neuroprotective effects of exercise. TRIAL REGISTRATION:This trial is prospectively registered at the Dutch Trial Registry (number NL8265, date 06-01-2020).

SUBMITTER: Gravesteijn AS

PROVIDER: S-EPMC7212565 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Neuroprotective effects of exercise in people with progressive multiple sclerosis (Exercise PRO-MS): study protocol of a phase II trial.

Gravesteijn A S AS Beckerman H H de Jong B A BA Hulst H E HE de Groot V V

BMC neurology 20200511 1

<h4>Background</h4>Neurodegeneration, rather than inflammation, plays a key role in the progressive phase of multiple sclerosis (MS). Current disease modifying treatment options for people with progressive MS (PMS) do not specifically target neurodegeneration. Preliminary evidence suggests that exercise therapy might have neuroprotective effects. However, neuroprotective effect studies of exercise interventions in PMS are scarce and the possible mode of action underlying neuroprotective effects ...[more]

PMID: 32393193

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Project description:BackgroundWe have co-designed a tailored blended physiotherapy intervention for people with progressive multiple sclerosis (PwPMS) who often struggle to access support for physical activity. Underpinned by self-management principles, the Lifestyle, Exercise and Activity Package for people with Multiple Sclerosis (LEAP-MS) intervention incorporates face-to-face or online physiotherapy coaching sessions with an accompanying online physical activity platform. The LEAP-MS platform is a multi-user system enabling user and physiotherapist to co-create activity plans. The LEAP-MS platform consists of an information and activity suite, interactive components enabling selection of exercises into an activity programme, goal setting and activity logging. The platform also facilitates online remote support from a physiotherapist through an embedded online messaging function. We aim to evaluate the LEAP-MS platform in a feasibility trial.MethodsLEAP-MS will be evaluated within a single-arm feasibility study with embedded process evaluation. After registration and initial eligible screening, 21 participants will be required to complete baseline self-completion measures. This will be followed by an initial home-based or online coaching session with a physiotherapist (who has received tailored self-management and digital resource training) and access to the online intervention for an initial 3-month period. During this period, participants are given the option to request up to five further home-based or online physiotherapy coaching sessions. Follow-up questionnaires and semi-structured interviews will be administered 3 months after baseline with participants and intervention physiotherapists. The LEAP-MS platform will be available to participants for a further 3 months. Usage of the LEAP-MS platform will be tracked during the full 6-month period and final follow-up will be conducted 6 months after baseline.DiscussionFeasibility outcomes (recruitment, retention, intervention uptake and safety) will be reported. The process evaluation will be undertaken to identify possible mechanisms for any observed effects. The data will inform full-scale evaluations of this co-produced, blended physiotherapy intervention.Trial registrationClinicalTrials.gov , NCT03951181 . Registered 15 May 2019.

Project description:BackgroundNeurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource.MethodsWe did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259.FindingsBetween Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI -0·4 to 0·5; p=0·99]; fluoxetine vs placebo -0·1% [-0·5 to 0·3; p=0·86]; riluzole vs placebo -0·1% [-0·6 to 0·3; p=0·77]). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes.InterpretationThe absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine.FundingEfficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.

Project description:IntroductionThe major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society Clinical Trials Network (CTN) was initiated in 2007 with the purpose of developing a national, efficient, multiarm trial of repurposed drugs. Key underpinning work was commissioned by the CTN to inform the design, outcome selection and drug choice including animal models and a systematic review. This identified seven leading oral agents for repurposing as neuroprotective therapies in secondary progressive MS (SPMS). The purpose of the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) will be to evaluate the neuroprotective efficacy of three of these drugs, selected with distinct mechanistic actions and previous evidence of likely efficacy, against a common placebo arm. The interventions chosen were: amiloride (acid-sensing ion channel antagonist); fluoxetine (selective serotonin reuptake inhibitor) and riluzole (glutamate antagonist).Methods and analysisPatients with progressing SPMS will be randomised 1:1:1:1 to amiloride, fluoxetine, riluzole or matched placebo and followed for 96 weeks. The primary outcome will be the percentage brain volume change (PBVC) between baseline and 96 weeks, derived from structural MR brain imaging data using the Structural Image Evaluation, using Normalisation, of Atrophy method. With a sample size of 90 per arm, this will give 90% power to detect a 40% reduction in PBVC in any active arm compared with placebo and 80% power to detect a 35% reduction (analysing by analysis of covariance and with adjustment for multiple comparisons of three 1.67% two-sided tests), giving a 5% overall two-sided significance level. MS-SMART is not powered to detect differences between the three active treatment arms. Allowing for a 20% dropout rate, 110 patients per arm will be randomised. The study will take place at Neuroscience centres in England and Scotland.Ethics and disseminationMS-SMART was approved by the Scotland A Research Ethics Committee on 13 January 2013 (REC reference: 13/SS/0007). Results of the study will be submitted for publication in a peer-reviewed journal.Trial registration numbersNCT01910259; 2012-005394-31; ISRCTN28440672.

Project description:BACKGROUND:Cognitive dysfunction affects up to 70% of people with progressive MS (PMS). It can exert a deleterious effect on activities of daily living, employment and relationships. Preliminary evidence suggests that performance can improve with cognitive rehabilitation (CR) and aerobic exercise (EX), but existing data are predominantly from people with relapsing-remitting MS without cognitive impairment. There is therefore a need to investigate whether this is also the case in people with progressive forms of the disease who have objectively identified cognitive impairment. It is hypothesized that CR and EX are effective treatments for people with PMS who have cognitive impairment, in particular processing speed (PS) deficits, and that a combination of these two treatments is more effective than each individual treatment given alone. We further hypothesize that improvements in PS will be associated with modifications of functional and/or structural plasticity within specific brain networks/regions involved in PS measured with advanced MRI techniques. METHODS:This study is a multisite, randomized, double-blinded, sham controlled clinical trial of CR and aerobic exercise. Three hundred and sixty subjects from 11 sites will be randomly assigned into one of four groups: CR plus aerobic exercise; CR plus sham exercise; CR sham plus aerobic exercise and CR sham plus sham exercise. Subjects will participate in the assigned treatments for 12 weeks, twice a week. All subjects will have a cognitive and physical assessment at baseline, 12 weeks and 24 weeks. In an embedded sub-study, approximately 30% of subjects will undergo structural and functional MRI to investigate the neural mechanisms underlying the behavioral response. The primary outcome is the Symbol Digit Modalities Test (SDMT) measuring PS. Secondary outcome measures include: indices of verbal and non-verbal memory, depression, walking speed and a dual cognitive-motor task and MRI. DISCUSSION:The study is being undertaken in 6 countries (11 centres) in multiple languages (English, Italian, Danish, Dutch); with testing material validated and standardized in these languages. The rationale for this approach is to obtain a robustly powered sample size and to demonstrate that these two interventions can be given effectively in multiple countries and in different languages. TRIAL REGISTRATION:The trial was registered on September 20th 2018 at www.clinicaltrials.gov having identifier NCT03679468. Registration was performed before recruitment was initiated.

Project description:BACKGROUND:There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS:We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (?100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS:Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS:In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Project description:IntroductionAlthough physical activity may reduce disease burden, fatigue and disability, and improve quality of life among people with multiple sclerosis (MS), many people with MS are physically inactive and spend significant time in sedentary behaviour. Behaviour change interventions may assist people with MS to increase physical activity and reduce sedentary behaviour. However, few studies have investigated their effectiveness using objective measures of physical activity, particularly in the long term. Further, interventions that have proven effective in the short term may not be feasible in clinical practice because of the large amount of support provided. The iStep-MS trial aims to determine the safety, feasibility and acceptability of a behaviour change intervention to increase physical activity and reduce sedentary behaviour among people with MS.Methods and analysisSixty people with MS will be randomised (1:1 ratio) to receive a 12-week intervention or usual care only. The intervention consists of four physical activity consultations with a physiotherapist supported by a handbook and pedometer. Outcomes assessed at baseline, 12 weeks and 9 months are physical activity (ActiGraph wGT3X-BT accelerometer), sedentary behaviour (activPAL3µ), self-reported activity and sitting time, walking capability, fatigue, self-efficacy, participation, quality of life and health service use. The safety of the intervention will be determined by assessing change in pain and fatigue and the incidence of adverse events during the follow-up period. A parallel process evaluation will assess the feasibility and acceptability of the intervention through assessment of fidelity to the programme and semistructured interviews exploring participants' and therapists' experiences of the intervention. The feasibility of conducting an economic evaluation will be determined by collecting data on quality of life and resource use.Ethics and disseminationResearch ethics committee approval has been granted from Brunel University London. Results of the trial will be submitted for publication in journals and distributed to people with MS and physiotherapists.Trial registration numberISRCTN15343862 (doi 10.1186/ISRCTN15343862). Protocol version: 1.0; Pre-results.

Project description:IntroductionPeople with multiple sclerosis (PwMS) experience a range of physical, cognitive, and affective symptoms. Behavioral interventions targeting increased physical activity show promising support as low-cost methods to improve working memory, episodic memory, and processing speed in PwMS. In this randomized controlled trial, we will examine the efficacy of a pedometer-tracking intervention, designed to increase low-to-moderate levels of physical activity, for improving working memory in PwMS.Methods and analysisEighty-seven PwMS, between the ages of 30-59, have been recruited for the study. Seventy-five of the eligible and interested individuals were randomized to six-month health behavior monitoring groups: a Step-track group or a Water-track group (serving as the active control). Neuropsychological measures, assessing the primary outcome of the study, were administered at pre, midpoint, and post-intervention. Exploratory factor analysis of neuropsychological measures resulted in three factors: a working memory/processing speed factor, a visual episodic memory factor, and a verbal episodic memory factor. Changes in this latent measure of working memory/processing speed is the primary outcome of the current study. Functional MRI data will be analyzed to examine changes in the functional connectivity of the neural network supporting working memory.Ethics and disseminationThe institutional review board granted approval for the study and all participants provided written informed consent. The results of this study will provide support showing that step-tracking increases overall levels of physical activity, improves working memory and processing speed, and strengthens the neural circuitry that supports better cognition. Evidence from this study will thus offer promising support for the routine use of step-tracking devices to improve cognitive functioning in PwMS. Study results will be disseminated through peer-reviewed publications and presentations at scientific conferences.

Dataset Information

Neuroprotective effects of exercise in people with progressive multiple sclerosis (Exercise PRO-MS): study protocol of a phase II trial.

Publications

Neuroprotective effects of exercise in people with progressive multiple sclerosis (Exercise PRO-MS): study protocol of a phase II trial.

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