scholarly journals Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial

The Lancet ◽  
2014 ◽  
Vol 383 (9936) ◽  
pp. 2213-2221 ◽  
Author(s):  
Jeremy Chataway ◽  
Nadine Schuerer ◽  
Ali Alsanousi ◽  
Dennis Chan ◽  
David MacManus ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Brain Atrophy ◽  
Progressive Multiple Sclerosis ◽  
Secondary Progressive Multiple Sclerosis ◽  
High Dose ◽  
Phase 2 ◽  
Secondary Progressive ◽  
Phase 2 Trial

Repurposing Domperidone in Secondary Progressive MS

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000011863
Author(s):  
Marcus W. Koch ◽  
Kayla Sage ◽  
Sharanjit Kaur ◽  
Janet Kim ◽  
Graziela Cerchiaro ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Adverse Events ◽  
Progressive Multiple Sclerosis ◽  
Secondary Progressive Multiple Sclerosis ◽  
Phase 2 ◽  
Disability Progression ◽  
Two Stage ◽  
Serious Adverse Events ◽  
Secondary Progressive ◽  
Link Type

ObjectiveTo assess whether treatment with the generic drug domperidone can reduce the progression of disability in secondary progressive multiple sclerosis (SPMS), we conducted a phase 2 futility trial following the Simon two-stage design.MethodsWe enrolled patients in an open-label, Simon two-stage, single-center, phase 2, single-arm futility trial at the Calgary MS Clinic if they met the following criteria: age 18–60 years, SPMS, screening EDSS score of 4.0–6.5 and screening T25FW of 9 seconds or more. Patients received domperidone 10 mg QID for one year. The primary outcome was worsening of disability, defined as worsening of the T25FW performance by 20% or more at 12 months compared to at baseline. This trial is registered with ClinicalTrials.gov, number NCT02308137.ResultsBetween February 13, 2015 and January 3, 2020, 110 patients were screened, 81 received treatment, 64 completed follow-up, of whom 62 were analysed. The study did not meet its primary endpoint: 22 of 62 (35%) patients experienced significant worsening of disability, which is close to the expected proportion of 40%, and above the pre-defined futility threshold. Patients with higher prolactin levels during the study had a significantly lower risk of disability progression, which may warrant further investigation. Domperidone treatment was reasonably well tolerated, but adverse events occurred in 84% and serious adverse events in 15% of patients.ConclusionsDomperidone treatment could not reject futility in reducing disability progression in SPMS. The Simon two-stage trial model may be a useful model for phase 2 studies in progressive MS.Classification of evidenceThis study provides Class III evidence that in individuals with secondary progressive multiple sclerosis participating in a futility trial, domperidone treatment could not reject futility in reducing disability progression at 12 months.

Mitoxantrone as a potential therapy for primary progressive multiple sclerosis

2004 ◽  
Vol 10 (3_suppl) ◽  
pp. S58-S61 ◽  
Author(s):  
Olaf Stüve ◽  
Mariko Kita ◽  
Daniel Pelletier ◽  
Robert J Fox ◽  
Jerome Stone ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Western Europe ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Pharmacological Properties ◽  
Phase 2 ◽  
Double Blind ◽  
Primary Progressive ◽  
Secondary Progressive ◽  
Phase 2 Trial

Mitoxantrone (Novantrone®) was the first drug approved in western Europe and North A merica for treatment of secondary progressive multiple sclerosis (SPMS) and progressive relapsing MS (PRMS). Pharmacological properties of mitoxantrone, its role in SPMS, the study rational and design of an ongoing multi-centre, double blind, randomized, placebo -controlled phase 2 trial will be outlined in this article.

TP1-11 MS-STAT2: a phase 3 trial of high dose simvastatin in secondary progressive multiple sclerosis

2019 ◽  
Vol 90 (3) ◽  
pp. e13.1-e13 ◽  
Author(s):  
E Williams ◽  
NA John ◽  
J Blackstone ◽  
W Brownlee ◽  
C Frost ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Unmet Need ◽  
Progressive Multiple Sclerosis ◽  
Secondary Progressive Multiple Sclerosis ◽  
High Dose ◽  
List Type ◽  
Expanded Disability Status Scale ◽  
Phase 3 ◽  
Secondary Progressive ◽  
Disability Status

ObjectivesDisease modifying treatment for secondary progressive multiple sclerosis (SPMS) represents a major unmet need. We outline here the rationale for the MS-STAT2 trial – a phase 3 study of simvastatin in decreasing clinical progression in SPMS. MS-STAT2 will be a landmark study not only for patients with SPMS, but also for the area of drug repurposing and academically led clinical trials as a whole.DesignMulticentre, double blind, parallel group randomised placebo-controlled trial. It follows the positive outcome from the phase 2 MS-STAT1 trial, which demonstrated a 43% reduction in the annualised rate of brain atrophy compared to placebo.1Subjects1180 patients with SPMS with an expanded disability status scale (EDSS) score of 4.0–6.5. Patients need to show evidence of disease progression over the preceding 2 years.MethodsSubject will be recruited at 28 sites across the UK, and randomised to simvastatin 80 mg or matched placebo and assessed every 6 months over the 3 year trial.ResultsThe primary outcome measure is time to 6 month confirmed disability progression, based on change in Expanded Disability Status Scale (EDSS) scores compared to baseline. Secondary outcomes include assessments of cognition, walking, upper limb function and vision. Sub-studies will include advanced imaging outcomes, ocular coherence tomography and fluid biomarkers.ConclusionsMS-STAT2 is set to be a pivotal trial for SPMS. Recruitment has now commenced and further sites are welcome.ReferenceChataway J, et al. MS-STAT. Lancet2014;383:2213–21.

High-dose erythropoietin in patients with progressive multiple sclerosis: A randomized, placebo-controlled, phase 2 trial

2016 ◽  
Vol 23 (5) ◽  
pp. 675-685 ◽  
Author(s):  
Karen Schreiber ◽  
Melinda Magyari ◽  
Finn Sellebjerg ◽  
Pernille Iversen ◽  
Ellen Garde ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Primary Outcome ◽  
Progressive Multiple Sclerosis ◽  
High Dose ◽  
Phase 2 ◽  
Double Blind ◽  
Intention To Treat ◽  
Phase 2 Trial ◽  
Hand Dexterity ◽  
Magnetic Resonance Imaging Mri

Background: Erythropoietin (EPO) is a part of an endogenous neuroprotective system in the brain and may address pathophysiological mechanisms in progressive multiple sclerosis (MS). Objective: To evaluate a treatment effect of EPO on progressive MS. Methods: This was a single-center, randomized, double-blind, placebo-controlled phase 2 trial, in which 52 patients with secondary or primary progressive MS were allocated to treatment with recombinant EPO (48,000 IU) or placebo, administered intravenously 17 times during 24 weeks. Patients had an Expanded Disability Status Score (EDSS) from 4 to 6.5 and clinical progression without relapses in the 2 preceding years. The primary outcome was the change in a composite measure of maximum gait distance, hand dexterity, and cognition from baseline to 24 weeks. Results: A total of 50 patients completed the study. Venesection was performed often but no thromboembolic events occurred. We found no difference in the primary outcome between the EPO and the placebo group using the intention-to-treat principle ( p = 0.22). None of the secondary outcomes, neither clinical nor magnetic resonance imaging (MRI) measures showed any significant differences. Conclusion: This study provides class II evidence that treatment with high-dose EPO is not an effective treatment in patients with moderately advanced progressive MS.

scholarly journals Free serum haemoglobin is associated with brain atrophy in secondary progressive multiple sclerosis

2016 ◽  
Vol 1 ◽  
pp. 10 ◽  
Author(s):  
Alex Lewin ◽  
Shea Hamilton ◽  
Aviva Witkover ◽  
Paul Langford ◽  
Richard Nicholas ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mass Spectrometry ◽  
Tandem Mass Spectrometry ◽  
Brain Atrophy ◽  
Progressive Multiple Sclerosis ◽  
Secondary Progressive Multiple Sclerosis ◽  
Serum Lactate Dehydrogenase ◽  
Tandem Mass ◽  
Secondary Progressive ◽  
Free Serum

Background: A major cause of disability in secondary progressive multiple sclerosis (SPMS) is progressive brain atrophy, whose pathogenesis is not fully understood. The objective of this study was to identify protein biomarkers of brain atrophy in SPMS. Methods: We used surface-enhanced laser desorption-ionization time-of-flight mass spectrometry to carry out an unbiased search for serum proteins whose concentration correlated with the rate of brain atrophy, measured by serial MRI scans over a 2-year period in a well-characterized cohort of 140 patients with SPMS.  Protein species were identified by liquid chromatography-electrospray ionization tandem mass spectrometry. Results: There was a significant (p<0.004) correlation between the rate of brain atrophy and a rise in the concentration of proteins at 15.1 kDa and 15.9 kDa in the serum.  Tandem mass spectrometry identified these proteins as alpha-haemoglobin and beta-haemoglobin, respectively.  The abnormal concentration of free serum haemoglobin was confirmed by ELISA (p<0.001).  The serum lactate dehydrogenase activity was also highly significantly raised (p<10-12) in patients with secondary progressive multiple sclerosis.  Conclusions: The results are consistent with the following hypothesis. In progressive multiple sclerosis, low-grade chronic intravascular haemolysis releases haemoglobin into the serum; the haemoglobin is subsequently translocated into the central nervous system (CNS) across the damaged blood-brain barrier.  In the CNS, the haemoglobin and its breakdown products, including haem and iron, contribute to the neurodegeneration and consequent brain atrophy seen in progressive disease. We postulate that haemoglobin is a source of the iron whose deposition along blood vessels in multiple sclerosis plaques is associated with neurodegeneration.  If so, then chelators of haemoglobin, rather than chelators of free serum iron, may be effective in preventing this neurodegeneration.

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