Progression rates and sample size estimates for PPMS based on the CLIMB study population

2014 ◽  
Vol 21 (2) ◽  
pp. 180-188 ◽  
Author(s):  
Kesav Raghavan ◽  
Brian C Healy ◽  
Robert L Carruthers ◽  
Tanuja Chitnis
Keyword(s):  
Median Time ◽  
Trial Design ◽  
Age Of Onset ◽  
Clinical Trial Design ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Disability Progression ◽  
Interval Censored ◽  
Study Population ◽  
Size Estimates

Background: The clinical trial design for primary progressive multiple sclerosis (PPMS) requires understanding of disability progression in modern patient cohorts. Objective: The objective of this paper is to characterize demographic and clinical characteristics of PPMS and assess rate of disability progression. Methods: We studied PPMS ( n = 73) and relapsing-onset MS (ROMS) patients ( n = 1541) enrolled in CLIMB, a longitudinal study of MS patients at the Brigham and Women’s Hospital (Boston, MA). Disability progression for each group was compared using interval-censored survival analysis and time to six-month sustained progression. Results: The PP group had a 1.09:1 male:female ratio compared to 1:2.89 for the RO group and greater mean age of onset (PP: 44.4±9.6; RO: 32.7±9.9; p < 0.0001). Motor symptoms at onset and first symptoms localized to spinal cord were each strongly associated with PPMS ( p < 0.001). Median time from onset to EDSS 6.0 was faster in PPMS ( p < 0.001). PPMS patients progressed faster to EDSS 3 ( p < 0.001) and from EDSS 3 to 6 ( p < 0.001). Median time to sustained progression in the PP group was 4.85 years (95% CI 2.83–8.35), significantly faster than the RO group ( p < 0.001). Conclusions: Our modern PPMS cohort is demographically similar to previously studied cohorts. PPMS is associated with faster disability accrual than ROMS. Current real-world observations of time to sustained progression will inform design of new clinical trials for PPMS.

EDSS variability before randomization may limit treatment discovery in primary progressive MS

2012 ◽  
Vol 19 (6) ◽  
pp. 775-781 ◽  
Author(s):  
Jiameng Zhang ◽  
Emmanuelle Waubant ◽  
Gary Cutter ◽  
Jerry S Wolinsky ◽  
Robert Glanzman
Keyword(s):  
Therapeutic Effect ◽  
Controlled Trial ◽  
Simulated Data ◽  
Real Data ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Disability Progression ◽  
Mixed Effect ◽  
Primary Progressive ◽  
Pre Treatment

Background: Baseline Expanded Disability Status Scale (EDSS) is usually based on a single measurement. Here we evaluated whether using a baseline EDSS derived from two pre-treatment measurements improves the detection of progression events and the ability to demonstrate a therapeutic effect in delaying MS disability progression. Methods: Real data from OLYMPUS, a phase II/III randomized, placebo-controlled trial of rituximab in patients with primary progressive multiple sclerosis (PPMS), as well as simulated data were analyzed. Several definitions of baseline EDSS were used to capture sustained disability progression (SDP) events. Variations in the EDSS were estimated by linear mixed-effect models. Results: Selecting the higher of two baseline EDSS scores lowered the number of SDP events in both treatment groups, so decreasing sensitivity, and reduced the number of false SDP events, so increasing specificity. Conversely, selecting the lower of two baseline scores increased sensitivity but decreased specificity. Increased power (~7% based on the simulation study) was observed when the average of screening and Week 0 EDSS scores was used for baseline. Conclusion: Baseline EDSS derived from two pre-treatment EDSS measurements may enhance the ability of detecting a therapeutic effect in slowing disability progression in PPMS. This strategy could be implemented in future clinical trials of patients with MS.

scholarly journals Ongoing microstructural changes in the cervical cord underpin disability progression in early primary progressive multiple sclerosis

2020 ◽  
Vol 27 (1) ◽  
pp. 28-38 ◽  
Author(s):  
Rosa Cortese ◽  
Carmen Tur ◽  
Ferran Prados ◽  
Torben Schneider ◽  
Baris Kanber ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Brain Mri ◽  
Progressive Multiple Sclerosis ◽  
Cervical Cord ◽  
Primary Progressive Multiple Sclerosis ◽  
Disability Progression ◽  
Mixed Effect ◽  
Primary Progressive ◽  
Over Time

Background: Pathology in the spinal cord of patients with primary progressive multiple sclerosis (PPMS) contributes to disability progression. We previously reported abnormal Q-space imaging (QSI)-derived indices in the spinal cord at baseline in patients with early PPMS, suggesting early neurodegeneration. Objective: The aim was to investigate whether changes in spinal cord QSI over 3 years in the same cohort are associated with disability progression and if baseline QSI metrics predict clinical outcome. Methods: Twenty-three PPMS patients and 23 healthy controls recruited at baseline were invited for follow-up cervical cord 3T magnetic resonance imaging (MRI) and clinical assessment after 1 year and 3 years. Cord cross-sectional area (CSA) and QSI measures were obtained, together with standard brain MRI measures. Mixed-effect models assessed MRI changes over time and their association with clinical changes. Linear regression identified baseline MRI indices associated with disability at 3 years. Results: Over time, patients deteriorated clinically and showed an increase in cord QSI indices of perpendicular diffusivity that was associated with disability worsening, independently of the decrease in CSA. Higher perpendicular diffusivity and lower CSA at baseline predicted worse disability at 3 years. Conclusion: Increasing spinal cord perpendicular diffusivity may indicate ongoing neurodegeneration, which underpins disability progression in PPMS, independently of the development of spinal cord atrophy.

028 Treating progressive multiple sclerosis

2018 ◽  
Vol 89 (6) ◽  
pp. A12.1-A12
Author(s):  
Jordana Hughes ◽  
Vilija Jokubaitis ◽  
Mark Slee ◽  
Jeannette Lechner-Scott ◽  
Anneke Van der Walt ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Progressive Disease ◽  
Progressive Multiple Sclerosis ◽  
Hazard Ratio ◽  
Primary Progressive Multiple Sclerosis ◽  
Disability Progression ◽  
Primary Progressive ◽  
Effect Of Therapy ◽  
Multivariable Regression ◽  
Multivariable Regression Models

IntroductionWe showed that the available immunotherapies do not modify disability outcomes when used in secondary progressive multiple sclerosis. However, these therapies are effective in advanced active multiple sclerosis. Primary progressive multiple sclerosis may present with or without superimposed relapses. Significance of these relapses for disability accumulation and treatment remains contested. We aimed to examine the effect of the available immunotherapies in primary progressive multiple sclerosis.Methods1427 eligible patients with primary progressive multiple sclerosis from MSBase were studied. Confirmed disability progression of disability was compared between treated and untreated propensity score-matched cohorts. Multivariable regression models were used to compare disability accrual between primary progressive multiple sclerosis with and without superimposed relapses. Finally, the effect of therapy on disability accrual in cohorts with and without superimposed relapses was analysed.Results173 treated and 373 untreated patients were matched. No differences in the risk of disability progression (p=0.79) and improvement (p=0.98) were observed over the median 3 year follow-up.The likelihood of disability progression was relatively lower in patients with superimposed relapses (hazard ratio=0.83, p<0.01). We observed an association between the proportion of time on immunotherapy and the hazard of disability progression in active (hazard ratio=0.96, p=0.01) but not in the inactive primary progressive disease (p=0.21).ConclusionSuperimposed relapses in primary progressive multiple sclerosis represent a favourable prognostic marker, associated with slower disability accrual. This is most likely attributed to the effectiveness of immunotherapy in active primary progressive disease. Relapse activity, therefore, is a treatable modifier of disability accrual in primary progressive disease.

Diagnostic brain MRI findings in primary progressive multiple sclerosis

2000 ◽  
Vol 6 (2) ◽  
pp. 81-85 ◽  
Author(s):  
M Kremenchutzky ◽  
D Lee ◽  
G P A Rice ◽  
G C Ebers
Keyword(s):  
Multiple Sclerosis ◽  
Age Of Onset ◽  
Brain Mri ◽  
Diagnostic Value ◽  
Progressive Multiple Sclerosis ◽  
Normal Brain ◽  
Primary Progressive Multiple Sclerosis ◽  
Mri Findings ◽  
Primary Progressive ◽  
Mri Scans

The clinical course of multiple sclerosis can be classified as relapsing from onset (relapsing-remitting), or progressive from onset (primary progressive -PPMS). These clinical phenotypes have been based on historical and clinical observations. It has been reported that PPMS patients tend to have quantitatively less MRI activity and disease burden. We evaluated the sensitivity and diagnostic value of conventional brain MRI scan in 143 PPMS patients. Brain MRIs were blindly evaluated to determine if they satisfied Paty and/or Fazekas diagnostic criteria. Patient were divided into those with typical atypical or normal scans. They satisfied brain MRI criteria in 92% cases. Findings included: 131 typical four atypical, and eight normal scans. All 12 non-typical scans' subject had spinal onset; spinal MRI scans were positive in four of seven cases. Sex, age of onset, site and number of symptoms involved at onset among those groups were not significantly different but accumulation of disability had a tendency to be slower in these few individuals with normal or atypical head MRI's. Although there may be quantitative differences in lesion activity/burden, MRI scanning in PPMS unexpectedly has diagnostic sensitivity very similar to that seen in RRMS. A normal brain MRI is unusual in PPMS patients.

scholarly journals CSF chitinase 3-like-1 association with disability of primary progressive MS

2020 ◽  
Vol 7 (5) ◽  
pp. e815 ◽  
Author(s):  
Francisco Pérez-Miralles ◽  
Daniel Prefasi ◽  
Antonio García-Merino ◽  
Francisco Gascón-Giménez ◽  
Nicolás Medrano ◽  
...  
Keyword(s):  
Disease Diagnosis ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Disability Progression ◽  
Neuropsychological Battery ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Primary Progressive ◽  
Disease Modifying Therapy ◽  
Neurologic Disability

ObjectiveTo assess the role of CSF chitinase 3-like-1 (CHI3L1), chitinase 3-like-2 (CHI3L2), and neurofilament light chain (NfL) in predicting the course of primary progressive MS (PPMS).MethodsWe analyzed CSF CHI3L1, CHI3L2, and NfL levels in 25 patients with PPMS with disease duration ≤10 years and no disease-modifying therapy for ≥6 months from the prospective Understanding Primary Progressive Multiple Sclerosis cohort study. CSF samples taken at disease diagnosis were analyzed using commercial ELISAs and following the manufacturer's instructions. Data on Expanded Disability Status Scale (EDSS) scores, disability progression, and cognitive function according to the Brief Repeatable Neuropsychological Battery were also assessed throughout the 1-year study follow-up.ResultsIncreasing CHI3L1 levels correlated with higher EDSS scores at baseline (ρ = 0.490, 95% CI 0.118–0.742, p = 0.013) and month 12 (ρ = 0.455, 95% CI 0.063–0.725, p = 0.026) and tended to be associated with a higher risk of disability progression according to EDSS scores (OR = 1.008, 95% CI 0.999–1.017, p = 0.089). Increasing CHI3L2 levels also tended to correlate with lower baseline EDSS scores (ρ = −0.366, 95% CI -0.676–0.054, p = 0.086). There was no correlation with regard to NfL levels.ConclusionsThis analysis supports the association between CSF CHI3L1 levels and neurologic disability according to EDSS scores in patients with PPMS. Other chitinase-like proteins such as CHI3L2 may also be involved.Classification of evidenceThis study provides Class II evidence that CSF CHI3L1 is associated with neurologic disability in patients with PPMS.

scholarly journals Severe Delayed-Onset Neutropenia Induced by Ocrelizumab

2020 ◽  
Vol 11 (1) ◽  
pp. 59-61
Author(s):  
Jonatha Baird-Gunning ◽  
James Yun ◽  
William Stevenson ◽  
Karl Ng
Keyword(s):  
Late Onset ◽  
Case Reports ◽  
Rare Complication ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Granulocyte Colony Stimulating Factor ◽  
Disability Progression ◽  
Primary Progressive ◽  
Anti Cd20 ◽  
Stimulating Factor

Background: Ocrelizumab is an anti-CD20 monoclonal antibody that has been shown to reduce disability progression in primary progressive multiple sclerosis (MS). The adverse event profile is still being determined through postmarketing surveillance and case reports. Objective: To report a case of severe late-onset neutropenia associated with ocrelizumab in a patient with primary progressive MS. Methods: Case report. Result: A 34-year-old male with primary progressive MS developed severe late-onset neutropenia 42 days after infusion of ocrelizumab, which necessitated hospital admission and administration of broad-spectrum antibiotics and granulocyte colony-stimulating factor. Conclusion: Late-onset neutropenia is a rare complication of ocrelizumab. Patients should be counseled to present for urgent evaluation if they develop fever.

Definitions of primary-progressive multiple sclerosis trajectories by rate of clinical disability progression

2021 ◽  
Vol 50 ◽  
pp. 102814
Author(s):  
Anat Achiron ◽  
Sapir Dreyer-Alster ◽  
Michael Gurevich ◽  
Shay Menascu ◽  
David Magalashvili ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Disability Progression ◽  
Primary Progressive

scholarly journals Clinical trial design for progressive MS trials

2017 ◽  
Vol 23 (12) ◽  
pp. 1642-1648 ◽  
Author(s):  
Matteo Pardini ◽  
Gary Cutter ◽  
Maria Pia Sormani
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Progressive Multiple Sclerosis ◽  
Phase 2 ◽  
The Right ◽  
Selection Of Patients ◽  
Selection Of

The design of clinical trials is a key aspect to maximizing the possibility to detect a treatment effect. This fact is particularly challenging in progressive multiple sclerosis (PMS) studies due to the uncertainty about the right target and/or outcome in phase-2 studies. The aim of this review is to evaluate the current challenges facing the design of clinical trials for PMS. The selection of patients, the instrumental and clinical outcomes that can be used in PMS trials, and issues in their design will be covered in this report.

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