scholarly journals Imaging outcome measures for progressive multiple sclerosis trials

2017 ◽  
Vol 23 (12) ◽  
pp. 1614-1626 ◽  
Author(s):  
Marcello Moccia ◽  
Nicola de Stefano ◽  
Frederik Barkhof
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Diffusion Tensor ◽  
Brain Lesion ◽  
Sample Size Calculation ◽  
Progressive Multiple Sclerosis ◽  
Imaging Biomarkers ◽  
Magnetization Transfer Ratio ◽  
Position Emission Tomography ◽  
Markers Of Inflammation

Imaging markers that are reliable, reproducible and sensitive to neurodegenerative changes in progressive multiple sclerosis (MS) can enhance the development of new medications with a neuroprotective mode-of-action. Accordingly, in recent years, a considerable number of imaging biomarkers have been included in phase 2 and 3 clinical trials in primary and secondary progressive MS. Brain lesion count and volume are markers of inflammation and demyelination and are important outcomes even in progressive MS trials. Brain and, more recently, spinal cord atrophy are gaining relevance, considering their strong association with disability accrual; ongoing improvements in analysis methods will enhance their applicability in clinical trials, especially for cord atrophy. Advanced magnetic resonance imaging (MRI) techniques (e.g. magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), spectroscopy) have been included in few trials so far and hold promise for the future, as they can reflect specific pathological changes targeted by neuroprotective treatments. Position emission tomography (PET) and optical coherence tomography have yet to be included. Applications, limitations and future perspectives of these techniques in clinical trials in progressive MS are discussed, with emphasis on measurement sensitivity, reliability and sample size calculation.

Monthly oral methylprednisolone pulse treatment in progressive multiple sclerosis

2015 ◽  
Vol 22 (7) ◽  
pp. 926-934 ◽  
Author(s):  
Rikke Ratzer ◽  
Pernille Iversen ◽  
Lars Börnsen ◽  
Tim B Dyrby ◽  
Jeppe Romme Christensen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Outcome Measures ◽  
Primary Outcome ◽  
Diffusion Tensor ◽  
Unmet Need ◽  
Progressive Multiple Sclerosis ◽  
Magnetization Transfer Ratio ◽  
Pulse Treatment ◽  
Methylprednisolone Pulse ◽  
Clinical Scores

Background: There is a large unmet need for treatments for patients with progressive multiple sclerosis (MS). Phase 2 studies with cerebrospinal fluid (CSF) biomarker outcomes may be well suited for the initial evaluation of efficacious treatments. Objective: To evaluate the effect of monthly oral methylprednisolone pulse treatment on intrathecal inflammation in progressive MS. Methods: In this open-label phase 2A study, 15 primary progressive and 15 secondary progressive MS patients received oral methylprednisolone pulse treatment for 60 weeks. Primary outcome was changes in CSF concentrations of osteopontin. Secondary outcomes were other CSF biomarkers of inflammation, axonal damage and demyelination; clinical scores; magnetic resonance imaging measures of disease activity, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI); motor evoked potentials; and bone density scans. Results: We found no change in the CSF concentration of osteopontin, but we observed significant improvement in clinical scores, MTR, DTI and some secondary CSF outcome measures. Adverse events were well-known side effects to methylprednisolone. Conclusion: Monthly methylprednisolone pulse treatment was safe, but had no effect on the primary outcome. However, improvements in secondary clinical and MRI outcome measures suggest that this treatment regimen may have a beneficial effect in progressive MS.

scholarly journals Multiple Sclerosis Atlas: A Molecular Map of Brain Lesion Stages in Progressive Multiple Sclerosis

2020 ◽  
Vol 3 (1) ◽  
pp. 122-129
Author(s):  
Tobias Frisch ◽  
Maria L. Elkjaer ◽  
Richard Reynolds ◽  
Tanja Maria Michel ◽  
Tim Kacprowski ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Brain Lesion ◽  
Progressive Multiple Sclerosis ◽  
Molecular Map

scholarly journals Suggestions for improving the design of clinical trials in multiple sclerosis—results of a systematic analysis of completed phase III trials

2019 ◽  
Vol 10 (4) ◽  
pp. 425-436 ◽  
Author(s):  
Sinje Gehr ◽  
Thomas Kaiser ◽  
Reinhold Kreutz ◽  
Wolf-Dieter Ludwig ◽  
Friedemann Paul
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Patient Reported Outcomes ◽  
Progressive Multiple Sclerosis ◽  
Phase Iii ◽  
Primary Progressive Multiple Sclerosis ◽  
Systematic Overview ◽  
Patient Reported ◽  
Phase Iii Trials ◽  
Secondary Endpoints

AbstractThis manuscript reviews the primary and secondary endpoints of pivotal phase III trials with immunomodulatory drugs in multiple sclerosis (MS). Considering the limitations of previous trial designs, we propose new standards for the planning of clinical trials, taking into account latest insights into MS pathophysiology and patient-relevant aspects. Using a systematic overview of published phase III (pivotal) trials performed as part of application for drug market approval, we evaluate the following characteristics: trial duration, number of trial participants, comparators, and endpoints (primary, secondary, magnetic resonance imaging outcome, and patient-reported outcomes). From a patient perspective, the primary and secondary endpoints of clinical trials are only partially relevant. High-quality trial data pertaining to efficacy and safety that stretch beyond the time frame of pivotal trials are almost non-existent. Understanding of long-term benefits and risks of disease-modifying MS therapy is largely lacking. Concrete proposals for the trial designs of relapsing (remitting) multiple sclerosis/clinically isolated syndrome, primary progressive multiple sclerosis, and secondary progressive multiple sclerosis (e.g., study duration, mechanism of action, and choice of endpoints) are presented based on the results of the systematic overview. Given the increasing number of available immunotherapies, the therapeutic strategy in MS has shifted from a mere “relapse-prevention” approach to a personalized provision of medical care as to the choice of the appropriate drugs and their sequential application over the course of the disease. This personalized provision takes patient preferences as well as disease-related factors into consideration such as objective clinical and radiographic findings but also very burdensome symptoms such as fatigue, depression, and cognitive impairment. Future trial designs in MS will have to assign higher relevance to these patient-reported outcomes and will also have to implement surrogate measures that can serve as predictive markers for individual treatment response to new and investigational immunotherapies. This is an indispensable prerequisite to maximize the benefit of individual patients when participating in clinical trials. Moreover, such appropriate trial designs and suitable enrolment criteria that correspond to the mode of action of the study drug will facilitate targeted prevention of adverse events, thus mitigating risks for individual study participants.

scholarly journals Disease-modifying treatments for progressive multiple sclerosis

2013 ◽  
Vol 19 (11) ◽  
pp. 1428-1436 ◽  
Author(s):  
Giancarlo Comi
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Progressive Disease ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Laboratory Science ◽  
New Concepts ◽  
Relapsing Remitting ◽  
Relapsing Remitting Multiple Sclerosis ◽  
Major Progress

The last 20 years have seen major progress in the treatment of relapsing–remitting multiple sclerosis (RRMS) using a variety of drugs targeting immune dysfunction. In contrast, all clinical trials of such agents in primary progressive multiple sclerosis (PPMS) have failed and there is limited evidence of their efficacy in secondary progressive disease. Evolving concepts of the complex interplay between inflammatory and neurodegenerative processes across the course of multiple sclerosis (MS) may explain this discrepancy. This paper will provide an up-to-date overview of the rationale and results of the published clinical trials that have sought to alter the trajectory of both primary and secondary MS, considering studies involving drugs with a primary immune target and also those aiming for neuroprotection. Future areas of study will be discussed, building on these results combined with the experience of treating RRMS and new concepts emerging from laboratory science and animal models.

scholarly journals Advancing trial design in progressive multiple sclerosis

2017 ◽  
Vol 23 (12) ◽  
pp. 1573-1578 ◽  
Author(s):  
Robert J Fox ◽  
Jeremy Chataway
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Progressive Multiple Sclerosis ◽  
Participant Selection ◽  
Funding Agencies ◽  
Disability Status ◽  
New Treatments ◽  
Clinical Measures ◽  
Development And Validation ◽  
Further Development

The failure of a majority of clinical trials in progressive multiple sclerosis (MS) has highlighted the need to reconsider how these trials are designed and conducted, and many areas deserve focus. Basic scientists are reconceptualising the pathophysiology of progressive MS into three broad areas: systemic inflammation, compartmentalized inflammation and non-inflammatory neurodegeneration, with the latter two becoming predominant as the disease progresses. This framework will guide the choice of experimental therapies. Previous clinical trials have highlighted how participant selection can have a significant impact on study outcome. Phase 2 biomarkers which are biologically stable, dynamically changing over time, and easy to assess in multi-centre studies are greatly needed. Shortcomings inherent in the Expanded Disability Status Scale are prompting the development and validation of better clinical measures. The standard two-arm, fixed-duration trial paradigm has been challenged with new, innovative approaches that can test more therapies efficiently. International collaboratives such as the Progressive MS Alliance will support increased dialogue with regulators, industry and other funding agencies. Better engagement with people living with progressive MS will transform them from simply being the recipient of MS therapies to partners in the search for new treatments. Focused, targeted action will drive further development of effective therapies for progressive MS.

scholarly journals Alterations in sensorimotor and mesiotemporal cortices and diffuse white matter changes in primary progressive multiple sclerosis detected by adiabatic relaxometry

2020 ◽  
Author(s):  
Pavel Filip ◽  
Michal Dufek ◽  
Silvia Mangia ◽  
Shalom Michaeli ◽  
Martin Bares ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Large Scale ◽  
Diffusion Tensor ◽  
Neuronal Loss ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Primary Progressive ◽  
T1 And T2

Abstract Background: The research of primary progressive multiple sclerosis (PPMS) has not been able to capitalize on recent progresses in advanced MRI protocols searching for disease-specific microstructural changes. Methods: Conventional free precession T1 and T2, and rotating frame adiabatic T1ρ and T2ρ maps in combination with diffusion weighted parameters were acquired in 13 PPMS patients and 13 age and sex-matched controls.Results: T1ρ, a marker of crucial relevance for PPMS due to its sensitivity to neuronal loss, revealed large-scale changes in mesiotemporal structures, sensorimotor cortex and cingulate, in combination with diffuse alterations in the white matter and cerebellum. T2ρ, particularly sensitive to local tissue background gradients and thus indicator of iron accumulation, concurred with similar topography of damage, but of lower extent. Moreover, these adiabatic protocols completely dwarfed the outcomes of both conventional T1 and T2 maps and diffusion tensor/kurtosis approaches –methods previously implicated in the MRI research of PPMS.Conclusion: This study introduces adiabatic T1ρ and T2ρ as elegant markers confirming large-scale cortical grey matter, cerebellar and white matter alterations in PPMS invisible to other in vivo biomarkers.

scholarly journals MRI of the corpus callosum in multiple sclerosis: association with disability

2010 ◽  
Vol 16 (2) ◽  
pp. 166-177 ◽  
Author(s):  
A. Ozturk ◽  
SA Smith ◽  
EM Gordon-Lipkin ◽  
DM Harrison ◽  
N. Shiee ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Corpus Callosum ◽  
Diffusion Tensor ◽  
Magnetization Transfer ◽  
Quantitative Mri ◽  
Magnetization Transfer Ratio ◽  
Lesion Volume ◽  
Impaired Performance ◽  
Disability Status ◽  
Axon Damage

Inflammatory demyelination and axon damage in the corpus callosum are prominent features of multiple sclerosis (MS) and may partially account for impaired performance on complex tasks. The objective of this article was to characterize quantitative callosal MRI abnormalities and their association with disability. In 69 participants with MS and 29 healthy volunteers, lesional and extralesional callosal MRI indices were estimated via diffusion tensor tractography. expanded disability status scale (EDSS) and MS functional composite (MSFC) scores were recorded in 53 of the participants with MS. All tested callosal MRI indices were diffusely abnormal in MS. EDSS score was correlated only with age (r = 0.51). Scores on the overall MSFC and its paced serial auditory addition test (PASAT) and 9-hole peg test components were correlated with callosal fractional anisotropy (r = 0.27, 0.35, and 0.31, respectively) and perpendicular diffusivity (r = —0.29, —0.30, and —0.31) but not with overall callosal volume or callosal lesion volume; the PASAT score was more weakly correlated with callosal magnetization-transfer ratio (r = 0.21). Anterior callosal abnormalities were associated with impaired PASAT performance and posterior abnormalities with slow performance on the 9-hole peg test. In conclusion, abnormalities in the corpus callosum can be assessed with quantitative MRI and are associated with cognitive and complex upper-extremity dysfunction in MS.

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