scholarly journals Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis

BMJ Open ◽  
2018 ◽  
Vol 8 (8) ◽  
pp. e021944 ◽  
Author(s):  
Peter Connick ◽  
Floriana De Angelis ◽  
Richard A Parker ◽  
Domenico Plantone ◽  
Anisha Doshi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Unmet Need ◽  
Dropout Rate ◽  
Analysis Of Covariance ◽  
Controlled Clinical Trial ◽  
Imaging Data ◽  
Secondary Progressive ◽  
Link Type ◽  
Oral Agents ◽  
Neuroprotective Therapies

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.

scholarly journals Randomised phase II trial of olaparib, chemotherapy or olaparib and cediranib in patients with platinum-resistant ovarian cancer (OCTOVA): a study protocol

BMJ Open ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. e041463
Author(s):  
Anita Mansouri ◽  
Naomi McGregor ◽  
Rachel Dunn ◽  
Sam Dobbie ◽  
Jane Holmes ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Antiangiogenic Therapy ◽  
Single Agent ◽  
Unmet Need ◽  
Dropout Rate ◽  
Weekly Paclitaxel ◽  
Type I ◽  
Link Type ◽  
Platinum Based Chemotherapy

IntroductionPatients relapsing within 12 months of platinum-based chemotherapy usually have a poorer response to subsequent treatments. To date, extensive research into the mechanism of resistance to platinum agents in the treatment of ovarian cancer has not resulted in improved responses or longer survival. Further experimental work and clinical trials with novel agents are therefore justified to address this unmet need.Patients with ovarian, fallopian tube or primary peritoneal cancer that has relapsed within 12 months of platinum-based chemotherapy will be randomised with stratification for BReast CAncer gene (BRCA) status, prior poly (ADP-ribose) polymerase (PARP) exposure and prior antiangiogenic therapy into weekly paclitaxel (chemotherapy), olaparib or the combination of cediranib and olaparib. They will be followed until disease progression or unacceptable toxicity develops. Our trial design permits two investigations. We will compare the efficacy and tolerability of single-agent olaparib with weekly paclitaxel. We will also compare the efficacy and tolerability of olaparib with the combination of olaparib and cediranib. The required sample size of 138 participants (46 per arm) was calculated using a 20% one-sided type I error, 80% power and 15% dropout rate. Recruitment will last 34 months with a follow-up of 18 months.Methods and analysisEthics and disseminationThis study will be conducted under a UK Medicines and Healthcare Products Regulatory Agency Clinical Trials Authorisation. Approval to conduct the study was obtained from the responsible authority before beginning the study. The sponsor will retain ownership of all data arising from the trial. We aim to publish this research in a specialist peer-reviewed scientific journal on study completion. EudraCT number: 2016-000559-28, ethics reference number: 16/LO/2150.Trial registration numberISRCTN: ISRCTN14784018, clinicaltrials.gov: NCT03117933; Pre-results.

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.

scholarly journals Brain connectivity and motor improvements after ballet intervention in multiple sclerosis: pilot

2021 ◽  
Author(s):  
Paul B. Camacho ◽  
Brad P. Sutton ◽  
Citlali López-Ortiz
Keyword(s):  
Multiple Sclerosis ◽  
Rating Scale ◽  
Brain Connectivity ◽  
Structural Connectivity ◽  
Clustering Coefficient ◽  
Controlled Clinical Trial ◽  
Imaging Data ◽  
Resting State Functional Connectivity ◽  
Post Intervention ◽  
Smoothness Index

AbstractBackground and PurposeA pilot study to determine feasibility of detecting changes in structural connectivity (SC) and resting-state functional connectivity (RSFC) occur alongside motor improvements after participation in the Targeted Ballet Program (TBP) in adults with relapsing-remitting multiple sclerosis (RRMS).MethodsFive participants (four female) with RRMS between the ages of 38-64 with the following characteristics at baseline: Expanded Disability Status Scale 2.0-6.0, International Cooperative Ataxia Rating Scale (ICARS) > 7, Symbol-Digit Modality Test > 22, and no relapses or initiation of medications indicated to affect mobility within the past 30 days. Participants were asked to complete 12 weeks (one hour, twice per week) of the TBP. Magnetic resonance imaging data was collected pre- and post-intervention for SC and RSFC network analysis.ResultsIncreases in two RRMS-related graph theoretical measures (mean strength and mean clustering coefficient) for RSFC (p < 0.05) are detectable alongside significant reduction in ataxia (ICARS: p = 0.01012, Smoothness Index: p = 0.04995), and increase in balance (Mini-BESTest: p = 0.01474) following participation in the well-tolerated TBP.Discussion and ConclusionsSignificant increases in mean strength and mean clustering coefficient of RSFC suggest functional neurological improvements after participation in the TBP. The relationship between these network changes and clinical improvements in balance and amelioration of ataxia after participation in the TBP requires a larger randomized-controlled clinical trial of the TBP in persons with RRMS.

scholarly journals Tolerogenic dendritic cell-based treatment for multiple sclerosis (MS): a harmonised study protocol for two phase I clinical trials comparing intradermal and intranodal cell administration

BMJ Open ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. e030309 ◽  
Author(s):  
Barbara Willekens ◽  
Silvia Presas-Rodríguez ◽  
MJ Mansilla ◽  
Judith Derdelinckx ◽  
Wai-Ping Lee ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Phase I ◽  
Unmet Need ◽  
Primary Objective ◽  
Attractive Alternative ◽  
Phase I Clinical Trials ◽  
Two Phase ◽  
Link Type

IntroductionBased on the advances in the treatment of multiple sclerosis (MS), currently available disease-modifying treatments (DMT) have positively influenced the disease course of MS. However, the efficacy of DMT is highly variable and increasing treatment efficacy comes with a more severe risk profile. Hence, the unmet need for safer and more selective treatments remains. Specifically restoring immune tolerance towards myelin antigens may provide an attractive alternative. In this respect, antigen-specific tolerisation with autologous tolerogenic dendritic cells (tolDC) is a promising approach.Methods and analysisHere, we will evaluate the clinical use of tolDC in a well-defined population of MS patients in two phase I clinical trials. In doing so, we aim to compare two ways of tolDC administration, namely intradermal and intranodal. The cells will be injected at consecutive intervals in three cohorts receiving incremental doses of tolDC, according to a best-of-five design. The primary objective is to assess the safety and feasibility of tolDC administration. For safety, the number of adverse events including MRI and clinical outcomes will be assessed. For feasibility, successful production of tolDC will be determined. Secondary endpoints include clinical and MRI outcome measures. The patients’ immune profile will be assessed to find presumptive evidence for a tolerogenic effect in vivo.Ethics and disseminationEthics approval was obtained for the two phase I clinical trials. The results of the trials will be disseminated in a peer-reviewed journal, at scientific conferences and to patient associations.Trial registration numbersNCT02618902andNCT02903537; EudraCT numbers: 2015-002975-16 and 2015-003541-26.

Early Mitoxantrone-Induced Cardiotoxicity Detected in Secondary Progressive Multiple Sclerosis

2011 ◽  
Vol 3 ◽  
pp. CMT.S7586
Author(s):  
M.P. Namaka ◽  
D.A. Turcotte ◽  
M. Klowak ◽  
C.M. Leong ◽  
A. Grossberndt ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Randomized Study ◽  
Dropout Rate ◽  
Progressive Multiple Sclerosis ◽  
Secondary Progressive Multiple Sclerosis ◽  
Open Label ◽  
Ventricular Ejection Fraction ◽  
Secondary Progressive ◽  
High Dropout Rate ◽  
Gated Acquisition

Background and purpose Mitoxantrone (MX) (Novantrone®) is approved in Canada for certain refractory cancers and acute non-lymphocytic leukemias. It has FDA approval as an immunomodulatory agent for use in secondary progressive multiple sclerosis (SPMS). The general aim of this study is to evaluate the efficacy, safety, and tolerability of MX in SPMS. Experimental approach A single-centre, open-label, non-randomized study was conducted in patients with a ≥6 month history of SPMS. The primary parameters used to assess efficacy and safety were EDSS scores and the multiple-gated acquisition scan (MUGA) scores, respectively. Key results The MX-treatment group experienced a high dropout rate due to significantly reduced ventricular ejection fraction. EDSS scores from baseline to follow-up revealed no statistical difference between active control and MX-treatment groups. Conclusion: MX treatment may not slow disease progression in certain forms of SPMS and may be associated with a high risk of cardiotoxicity.

scholarly journals A 10-year follow-up of the European multicenter trial of interferon β-1b in secondary-progressive multiple sclerosis

2015 ◽  
Vol 22 (4) ◽  
pp. 533-543 ◽  
Author(s):  
J Kuhle ◽  
M Hardmeier ◽  
G Disanto ◽  
K Gugleta ◽  
M Ecsedi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Controlled Trial ◽  
Progressive Multiple Sclerosis ◽  
Secondary Progressive Multiple Sclerosis ◽  
Analysis Of Covariance ◽  
Long Term Effects ◽  
Long Term Outcome ◽  
Secondary Progressive

Objectives: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). Methods: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. Results: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R2: 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited ( R2: 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. Conclusions: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed.

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.

scholarly journals A Profiling Study of People with Multiple Sclerosis Who Access Physiotherapy Services in Ireland

2010 ◽  
Vol 12 (3) ◽  
pp. 115-121 ◽  
Author(s):  
Susan Coote ◽  
Grainne McKeown ◽  
Michelle Shannon ◽  
Keyword(s):  
Multiple Sclerosis ◽  
Data Collection ◽  
Lower Extremity ◽  
Functional Status ◽  
Unmet Need ◽  
Secondary Progressive ◽  
Disability Scale ◽  
Walking Aids ◽  
Data Collection Sheet ◽  
Relapsing Remitting

In a survey of its members conducted by the MS Society of Ireland, access to physiotherapy was reported as the greatest unmet need. This national multicenter profiling study surveyed people with multiple sclerosis (MS) receiving physiotherapy services at a range of locations to determine their characteristics and the amount of intervention received. A standardized data-collection sheet was developed, and data were collected over a 3-month period. The lower-extremity section of the Guys Neurological Disability Scale was used to classify mobility level, which varied widely. A total of 295 people received physiotherapy at 17 services during the 3-month period. Of these, 72% were female, and most had relapsing-remitting (43%) or secondary progressive MS (39%). Those using walking aids made up the largest proportion of participants (47.5%). On average, participants received 3.6 hours of physiotherapy over the 3-month period, with 36% of participants receiving 1 hour or less and 9.5% of participants receiving more than 8 hours. The main problems cited were balance, fatigue, walking, mobility, and strength. Further research is required to determine whether the small amount of physiotherapy being received by MS patients in Ireland is sufficient to bring about improvement or prevent further deterioration in functional status.

Remyelination: what are the prospects for regenerative therapies in multiple sclerosis?

2021 ◽  
Author(s):  
Jonathan D. Moore
Keyword(s):  
Multiple Sclerosis ◽  
Immune System ◽  
Unmet Need ◽  
Good Control ◽  
Small Companies ◽  
Myelin Sheaths ◽  
Working Age ◽  
Regenerative Therapies ◽  
Neuroprotective Therapies

Multiple sclerosis (MS) involves the immune system attacking the myelin sheaths surrounding axons and is a major cause of disability in working-age adults. Various approved therapies now provide reasonably good control over MS neuroinflammation, but none have a pronounced impact on the neurodegeneration associated with the disease. One prominent approach to fulfilling the unmet need for neuroprotective therapies, is the search for agents that promote ‘remyelination', namely the generation of new oligodendrocytes that can form replacement myelin sheaths around denuded axons. In this article, I discuss some emerging targets for remyelinating therapies, mainly being pursued by recently formed small companies translating academic findings.

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