Dataset Information

Randomized feasibility trial to assess tolerance and clinical effects of lithium in progressive multiple sclerosis.

ABSTRACT: Background:Disability accumulation in progressive multiple sclerosis (MS) results from inflammatory and neurodegenerative mechanisms. In animal models of MS, lithium acts to reduce inflammatory demyelination, and in models of neurodegenerative diseases, lithium also slows neuronal death. Prospective studies of lithium in MS patients have not been previously undertaken. Objective:To determine the tolerance and feasibility of using low-dose (150-300 mg/daily) lithium as a pharmaceutical intervention in a cohort of subjects with progressive MS, and to gauge preliminary effects of lithium on change in brain volume over time. Methods:Patients with primary or secondary progressive MS were recruited into a 2-year, single-blind crossover trial in which subjects were randomly assigned to take lithium in year 1 or 2. The primary outcomes of interest were tolerance of lithium and percentage brain volume change (PBVC) on vs. off lithium. Secondary outcomes included relapse rates, disability changes, and self-report scales assessing fatigue, mood, and quality of life (QOL). Results:Of 24 screened patients, 23 were randomized to take lithium during year 1 (n = 11) or 2 (n = 12). Two subjects discontinued the trial due to lithium side effects. Other reasons for discontinuation included personal reasons (n = 2), worsening MS (n = 1), and development of multiple myeloma (n = 1). For the 17 who completed the trial, change in PBVC on lithium (+0.107) did not significantly differ from the observation period (-0.355, p = 0.346). Disability measured by Expanded Disability Status Scale and MS Functional Composite did not differ by lithium treatment status. On patient reported measures of mental well-being, subjects reported fewer depressive symptoms on the Beck Depression Inventory (12.3 vs. 15.8, p = 0.016) and more favorably on the mental domains of the MSQOL inventory (56.7 vs. 52.4, p = 0.028). Conclusions:Low-dose lithium is well tolerated in persons with MS. Taking lithium did not result in differences in PBVC, relapses, or disability, but conclusions were limited by study design and sample size. Despite concern for lithium-associated neurological side effects, subjects taking lithium did not report worsened fatigue or physical well-being. On measures of mood and mental health QOL, subjects scored more favorably while taking lithium. Clinicaltrialsgov identifier:NCT01259388.

SUBMITTER: Rinker JR

PROVIDER: S-EPMC7393418 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Randomized feasibility trial to assess tolerance and clinical effects of lithium in progressive multiple sclerosis.

Rinker John R JR Meador William R WR King Peter P

Heliyon 20200728 7

<h4>Background</h4>Disability accumulation in progressive multiple sclerosis (MS) results from inflammatory and neurodegenerative mechanisms. In animal models of MS, lithium acts to reduce inflammatory demyelination, and in models of neurodegenerative diseases, lithium also slows neuronal death. Prospective studies of lithium in MS patients have not been previously undertaken.<h4>Objective</h4>To determine the tolerance and feasibility of using low-dose (150-300 mg/daily) lithium as a pharmaceut ...[more]

PMID: 32760832

Similar Datasets

Project description:BackgroundPrimary progressive multiple sclerosis (PPMS) is the least prevalent multiple sclerosis (MS) phenotype. For persons with PPMS (pwPPMS), pharmacological treatment options are limited. As a complementary non-pharmacological treatment, endurance training improves the health-related quality of life (HRQoL), numerous MS symptoms, and MS-related performance impediments. High-intensity interval training (HIIT) has been shown to induce superior effects compared to moderate-intensity continuous training (MCT). As current evidence is based on MS samples with mixed phenotypes, generalizability to pwPPMS remains unclear.MethodsCYPRO is a parallel-group, single-center, and single-blind randomized controlled superiority trial evaluating the effects of HIIT compared to MCT in pwPPMS. Sixty-one pwPPMS are randomized (1:1) to perform volume-matched HIIT or MCT sessions on bicycle ergometers two to three times per week in addition to standard rehabilitative care during their three-week inpatient stay at Valens rehabilitation clinic, Switzerland. Standard rehabilitative care comprises endurance and strength training, physiotherapy, and occupational therapy. HIIT sessions include six 90-second intervals at 95% peak heart rate (HRpeak), interspersed by 90-second active breaks with unloaded pedaling, aimed to reach 60%HRpeak. MCT represents the standard treatment at Valens rehabilitation clinic and is performed as continuous cycling at 60%HRpeak for the duration of 26 minutes. The primary outcome is cardiorespiratory fitness, assessed as peak oxygen consumption (V̇O2peak) during cardiopulmonary exercise testing (CPET). Secondary outcomes include peak power output during CPET, walking capacity, cognitive performance, HRQoL, fatigue, anxiety and depressive symptoms, and blood-derived biomarkers (e.g., serum neurofilament light chain, glial fibrillary acidic protein, kynurenine pathway metabolites) related to MS pathophysiology. All outcomes are assessed at baseline and discharge after three weeks. Venous blood sampling is additionally performed immediately and two hours after the first HIIT or MCT session.DiscussionCYPRO will expand current knowledge on symptom management and rehabilitation in MS to the subpopulation of pwPPMS, and will contribute to the exploration of potential disease-modifying effects of endurance training in MS. The superiority design of CYPRO will allow deriving explicit recommendations on endurance training design in pwPPMS that can be readily translated into clinical practice.Trial registrationCYPRO has been prospectively registered at ClinicalTrials.gov on 8 February 2022 (NCT05229861).

Project description:To study whether dimethyl fumarate is superior to placebo in decreasing CSF concentrations of neurofilament light chain (NFL) in patients with primary progressive MS (PPMS). In the double-blind, placebo-controlled phase 2 study dimethyl FUMArate treatment in Progressive Multiple Sclerosis (FUMAPMS), patients with PPMS were randomly assigned to treatment with 240 mg dimethyl fumarate or placebo in a 1:1 ratio for 48 weeks. The primary endpoint was change in concentration of NFL in the CSF. Secondary endpoints included other CSF biomarkers and clinical and MRI measures. Efficacy was evaluated for the full data set by multiple imputations to account for missing data. Safety was assessed for the full data set. Fifty-four patients (mean age 54.9 years [SD 6.1], median Expanded Disability Status Scale 4.0 [nterquartile range 4.0-6.0], disease duration 14.1 [SD 9.4], and 21 [39%] female) were randomized to either placebo (n = 27) or dimethyl fumarate (n = 27) therapy. At screening CSF concentrations, adjusted for age and sex, of NFL, myelin basic protein (MBP), soluble CD27, chitinase 3-like 1, and B-cell maturation antigen were higher than in a group of symptomatic controls. Twenty-six patients (96%) in the dimethyl fumarate group and 24 patients (89%) in the placebo group completed the randomized phase. Mean change in CSF concentrations of NFL did not differ between groups (mean difference 99 ng/L; 95% CI -292 to 491 ng/L). MBP in CSF decreased in the treatment group (-182 ng/L, 95% CI -323 to -41 ng/L compared with placebo). The difference observed in the multiple imputation data set was not significant in a per protocol analysis. This was nominally significant in the multiple imputation data set but not in the per protocol analysis This was not found in the per protocol analysis Other secondary and tertiary outcomes were not affected. Various infections, lymphopenia, flushing, and gastrointestinal side effects were more frequent in the dimethyl fumarate group. Serious adverse events were similar between groups. Dimethyl fumarate treatment for 48 weeks had no effect on any of the investigated efficacy measures in patients with PPMS. We did not observe adverse events not anticipated for dimethyl fumarate treatment. Clinicaltrials.gov identifier NCT02959658. This study provides Class I evidence that for patients with PPMS, dimethyl fumarate treatment has no effect on CSF NFL levels compared with placebo treatment.

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:Background and objectivesImproved biomarkers of neuroprotective treatment are needed in progressive multiple sclerosis (PMS) to facilitate more efficient phase 2 trial design. The MS-STAT randomized controlled trial supported the neuroprotective potential of high-dose simvastatin in secondary progressive MS (SPMS). Here, we analyze serum from the MS-STAT trial to assess the extent to which neurofilament light (NfL) and neurofilament heavy (NfH), both promising biomarkers of neuroaxonal injury, may act as biomarkers of simvastatin treatment in SPMS.MethodsThe MS-STAT trial randomized patients to 80 mg simvastatin or placebo. Serum was analyzed for NfL and NfH using Simoa technology. We used linear mixed models to investigate the treatment effects of simvastatin compared with placebo on NfL and NfH. Additional models examined the relationships between neurofilaments and MRI and clinical measures of disease severity.ResultsA total of 140 patients with SPMS were included. There was no evidence for a simvastatin treatment effect on NfL or NfH: compared with placebo, NfL was 1.2% lower (95% CI 10.6% lower to 9.2% higher; p = 0.820) and NfH was 0.4% lower (95% CI 18.4% lower to 21.6% higher; p = 0.969) in the simvastatin treatment group. Secondary analyses suggested that higher NfL was associated with greater subsequent whole brain atrophy, higher T2 lesion volume, and more new/enlarging T2 lesions in the previous 12 months, as well as greater physical disability. There were no significant associations between NfH and MRI or clinical variables.DiscussionWe found no evidence of a simvastatin treatment effect on serum neurofilaments. While confirmation of the neuroprotective benefits of simvastatin is awaited from the ongoing phase 3 study (NCT03387670), our results suggest that treatments capable of slowing the rate of whole brain atrophy in SPMS, such as simvastatin, may act via mechanisms largely independent of neuroaxonal injury, as quantified by NfL. This has important implications for the design of future phase 2 clinical trials in PMS.Trial registration informationMS-STAT: NCT00647348.Classification of evidenceThis study provides class I evidence that simvastatin treatment does not have a large impact on either serum NfL or NfH, as quantified in this study, in SPMS.

Dataset Information

Randomized feasibility trial to assess tolerance and clinical effects of lithium in progressive multiple sclerosis.

Publications

Randomized feasibility trial to assess tolerance and clinical effects of lithium in progressive multiple sclerosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets