scholarly journals Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis

2022 ◽  
Vol 9 (2) ◽  
pp. e1130
Author(s):  
Thomas E. Williams ◽  
Katherine P. Holdsworth ◽  
Jennifer M. Nicholas ◽  
Arman Eshaghi ◽  
Theodora Katsanouli ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Treatment Effect ◽  
Brain Atrophy ◽  
Progressive Multiple Sclerosis ◽  
High Dose ◽  
Lesion Volume ◽  
Phase 2 ◽  
Whole Brain ◽  
Simvastatin Treatment ◽  
Link Type

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.

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 A randomized, placebo-controlled, phase 2 trial of laquinimod in primary progressive multiple sclerosis

Neurology ◽  
2020 ◽  
Vol 95 (8) ◽  
pp. e1027-e1040 ◽  
Author(s):  
Gavin Giovannoni ◽  
Volker Knappertz ◽  
Joshua R. Steinerman ◽  
Aaron P. Tansy ◽  
Thomas Li ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Primary Endpoint ◽  
Treatment Effect ◽  
Brain Volume ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Phase 2 ◽  
Significant Treatment Effect ◽  
Significant Treatment ◽  
Primary Progressive

ObjectiveTo evaluate efficacy, safety, and tolerability of laquinimod in patients with primary progressive multiple sclerosis (PPMS).MethodsIn the randomized, double-blind, placebo-controlled, phase 2 study, ARPEGGIO (A Randomized Placebo-controlled Trial Evaluating Laquinimod in PPMS, Gauging Gradations in MRI and Clinical Outcomes), eligible patients with PPMS were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 mg or 1.5 mg or matching placebo. Percentage brain volume change (PBVC; primary endpoint) from baseline to week 48 was assessed by MRI. Secondary and exploratory endpoints included clinical and MRI measures. Efficacy endpoints were evaluated using a predefined, hierarchical statistical testing procedure. Safety was monitored throughout the study. The laquinimod 1.5 mg dose arm was discontinued on January 1, 2016, due to findings of cardiovascular events.ResultsA total of 374 patients were randomized to laquinimod 0.6 mg (n = 139) or 1.5 mg (n = 95) or placebo (n = 140). ARPEGGIO did not meet the primary endpoint of significant treatment effect with laquinimod 0.6 mg vs placebo on PBVC from baseline to week 48 (adjusted mean difference = 0.016%, p = 0.903). Laquinimod 0.6 mg reduced the number of new T2 brain lesions at week 48 (risk ratio 0.4; 95% confidence interval, 0.26–0.69; p = 0.001). Incidence of adverse events was higher among patients treated with laquinimod 0.6 mg (83%) vs laquinimod 1.5 mg (66%) and placebo (78%).ConclusionsLaquinimod 0.6 mg did not demonstrate a statistically significant effect on brain volume loss in PPMS at week 48.Clinicaltrials.gov identifierNCT02284568.Classification of evidenceThis study provides Class I evidence that, although well tolerated, laquinimod 0.6 mg did not demonstrate a significant treatment effect on PBVC in patients with PPMS.

scholarly journals Effects of ibudilast on MRI measures in the phase 2 SPRINT-MS study

Neurology ◽  
2020 ◽  
pp. 10.1212/WNL.0000000000011314
Author(s):  
Robert T Naismith ◽  
Robert A Bermel ◽  
Christopher S Coffey ◽  
Andrew D Goodman ◽  
Janel Fedler ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Gray Matter ◽  
Brain Atrophy ◽  
Brain Volume ◽  
Secondary Analysis ◽  
Progressive Multiple Sclerosis ◽  
Whole Brain ◽  
T2 Lesions ◽  
Gray Matter Atrophy ◽  
Inflammatory Processes

OBJECTIVE:For progressive forms of multiple sclerosis, determine whether ibudilast has an effect on brain volume and new lesions.METHODS:A randomized, placebo controlled, blinded study evaluated ibudilast at a dose of up to 100 mg over 96 weeks in primary and secondary progressive multiple sclerosis. In this secondary analysis of a previously reported trial, secondary and tertiary endpoints included gray matter atrophy, new or enlarging T2 lesions as measured every 24 weeks, and new T1 hypointensities at 96 weeks. Whole brain atrophy measured by SIENA was a sensitivity analysis.RESULTS:129 participants were assigned to ibudilast and 126 to placebo. New or enlarging T2 lesions were observed in 37.2% on ibudilast and 29.0% on placebo (p=0.82). New T1 hypointense lesions at 96 weeks were observed in 33.3% on ibudilast and 23.5% on placebo (p=0.11). Gray matter atrophy was reduced by 35% for those on ibudilast vs. placebo (p=0.038). Progression of whole brain atrophy by SIENA was slowed by 20% in the ibudilast group compared with placebo (p=0.08).CONCLUSIONS:Ibudilast treatment was associated with a reduction in gray matter atrophy. Ibudilast treatment was not associated with a reduction in new or enlarging T2 lesions, or new T1 lesions. An effect on brain volume contributes to prior data that ibudilast appears to impact markers associated with neurodegenerative processes, but not inflammatory processes.Classification of Evidence:This study provides Class II evidence that for people with MS, ibudilast does not significantly reduce new or enlarging T2 lesions, or new T1 lesions.

scholarly journals Longitudinal optical coherence tomography study of optic atrophy in secondary progressive multiple sclerosis: Results from a clinical trial cohort

2017 ◽  
Vol 25 (1) ◽  
pp. 55-62 ◽  
Author(s):  
Kimberly M Winges ◽  
Charles F Murchison ◽  
Dennis N Bourdette ◽  
Rebecca I Spain
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trial ◽  
Optical Coherence Tomography ◽  
Brain Atrophy ◽  
Disease Duration ◽  
Progressive Multiple Sclerosis ◽  
Optical Coherence ◽  
Whole Brain ◽  
Secondary Progressive ◽  
Sd Oct

Background: Limited prospective information exists regarding spectral-domain optical coherence tomography (SD-OCT) in secondary progressive multiple sclerosis (SPMS). Objective: Document cross-sectional and longitudinal retinal nerve fiber layer (RNFL) and macular ganglion cell plus inner plexiform layer (GCIPL) features of an SPMS clinical trial cohort. Methods: Prospective, observational study using a 2-year randomized placebo-controlled SPMS trial cohort with yearly SD-OCT testing. Post hoc analysis determined influences of optic neuritis (ON), disease duration, and baseline SD-OCT on annualized atrophy rates and on correlations between OCT and brain atrophy. Results: Mean RNFL and GCIPL values of patients ( n = 47, mean age = 59 years, mean disease duration = 30 years) were significantly lower among eyes with prior ON than those without (no history of ON (NON)). Annualized RNFL (−0.31 µm/year) and GCIPL (−0.29 µm/year) atrophy rates did not differ between ON and NON eyes. Baseline RNFL thickness >75 µm was associated with greater annualized RNFL atrophy (−0.85 µm/year). Neither RNFL nor GCIPL atrophy correlated with whole-brain atrophy. Conclusion: This study suggests that eyes with and without ON history may be pooled for atrophy analysis in SPMS clinical trials using SD-OCT. Low baseline RNFL, small retinal atrophy rates, and lack of correlation with whole-brain atrophy in this population are important trial design considerations.

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 Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis

2019 ◽  
Vol 116 (22) ◽  
pp. 11020-11027 ◽  
Author(s):  
Arman Eshaghi ◽  
Rogier A. Kievit ◽  
Ferran Prados ◽  
Carole H. Sudre ◽  
Jennifer Nicholas ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Treatment Effect ◽  
Brain Atrophy ◽  
Structural Equation Models ◽  
Block Design ◽  
Progressive Multiple Sclerosis ◽  
Cholesterol Levels ◽  
Total Treatment ◽  
Independent Model

Understanding the mode of action of drugs is a challenge with conventional methods in clinical trials. Here, we aimed to explore whether simvastatin effects on brain atrophy and disability in secondary progressive multiple sclerosis (SPMS) are mediated by reducing cholesterol or are independent of cholesterol. We applied structural equation models to the MS-STAT trial in which 140 patients with SPMS were randomized to receive placebo or simvastatin. At baseline, after 1 and 2 years, patients underwent brain magnetic resonance imaging; their cognitive and physical disability were assessed on the block design test and Expanded Disability Status Scale (EDSS), and serum total cholesterol levels were measured. We calculated the percentage brain volume change (brain atrophy). We compared two models to select the most likely one: a cholesterol-dependent model with a cholesterol-independent model. The cholesterol-independent model was the most likely option. When we deconstructed the total treatment effect into indirect effects, which were mediated by brain atrophy, and direct effects, simvastatin had a direct effect (independent of serum cholesterol) on both the EDSS, which explained 69% of the overall treatment effect on EDSS, and brain atrophy, which, in turn, was responsible for 31% of the total treatment effect on EDSS [β = −0.037; 95% credible interval (CI) = −0.075, −0.010]. This suggests that simvastatin’s beneficial effects in MS are independent of its effect on lowering peripheral cholesterol levels, implicating a role for upstream intermediate metabolites of the cholesterol synthesis pathway. Importantly, it demonstrates that computational models can elucidate the causal architecture underlying treatment effects in clinical trials of progressive MS.

Brain atrophy in multiple sclerosis: impact of lesions and of damage of whole brain tissue

2002 ◽  
Vol 8 (5) ◽  
pp. 410-414 ◽  
Author(s):  
N F Kalkers ◽  
H Vrenken ◽  
B MJ Uitdehaag ◽  
C H Polman ◽  
F Barkhof
Keyword(s):  
Multiple Sclerosis ◽  
Brain Tissue ◽  
Brain Atrophy ◽  
Brain Volume ◽  
Peak Height ◽  
Tissue Loss ◽  
Magnetization Transfer Ratio ◽  
Lesion Volume ◽  
Intracranial Volume ◽  
Whole Brain

Introduction: In multiple sclerosis (MS), brain atrophy measurement on magnetic resonance imaging (MRI) reflects overall tissue loss, especially demyelination and axonal loss. We studied which factor contributes most to the development of brain atrophy: extent and severity of lesions or damage of whole brain tissue (WBT). Methods: Eighty-six patients with MS [32 primary progressive (PP), 32 secondary progressive (SP)] and 22 relapsing-remitting (RR) were studied. MRI included T1- and T2-weighted imaging to obtain hypointense T1 lesion volume (T1LV) and two brain volume measurements: 1) the parenchymal fraction (PF; whole brain parenchymal volume/intracranial volume) as a marker of overall brain volume, and 2) the ventricular fraction (VF; ventricular volume/intracranial volume) as a marker of central atrophy. From magnetization transfer ratio (MTR) histograms, the relative peak height (rHp) was derived as an index of damage of WBT (a lower peak height reflects damage of WBT). Results: Multiple linear regression analysis revealed that damage of WBT explains most of the variance of PF (standardized coefficient b=0.59, p <0.001 for WBT and b= −0.19, p <0.05 for T1LV). These findings are independent of disease phase; even in RR patients, damage of WBT plays a dominant role in explaining the variance in overall brain volume. By contrast, the variance in VF is explained by both T1LV and damage of WBT (standardized coefficient b =0.43, p<0.001 for T1LV and b = −0.38, p <0.001 for WBT). Conclusion: This study shows that overall brain volume (PF) is best explained by damage of WBT, supporting the significance of nonfocal pathology in MS in producing tissue loss. Central atrophy (VF) is determined by both lesion volume and damage of WBT. Our results underline the importance of nonfocal pathology even in the early (RR) phase of the disease.

scholarly journals LesionQuant for Assessment of MRI in Multiple Sclerosis—A Promising Supplement to the Visual Scan Inspection

2020 ◽  
Vol 11 ◽  
Author(s):  
Synne Brune ◽  
Einar A. Høgestøl ◽  
Vanja Cengija ◽  
Pål Berg-Hansen ◽  
Piotr Sowa ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Brain Atrophy ◽  
Significant Positive Correlation ◽  
Brain Mri ◽  
Lesion Volume ◽  
Radiological Evaluation ◽  
Lesion Count ◽  
Whole Brain ◽  
Positive Correlation ◽  
Time Points

Background and Goals: Multiple sclerosis (MS) is a central nervous system inflammatory disease where magnetic resonance imaging (MRI) is an important tool for diagnosis and disease monitoring. Quantitative measurements of lesion volume, lesion count, distribution of lesions, and brain atrophy have a potentially significant value for evaluating disease progression. We hypothesize that utilizing software designed for evaluating MRI data in MS will provide more accurate and detailed analyses compared to the visual neuro-radiological evaluation.Methods: A group of 56 MS patients (mean age 35 years, 70% females and 96% relapsing-remitting MS) was examined with brain MRI one and 5 years after diagnosis. The T1 and FLAIR brain MRI sequences for all patients were analyzed using the LesionQuant (LQ) software. These data were compared with data from structured visual evaluations of the MRI scans performed by neuro-radiologists, including assessments of atrophy, and lesion count. The data from LQ were also compared with data from other validated research methods for brain segmentation, including assessments of whole brain volume and lesion volume. Correlations with clinical tests like the timed 25-foot walk test (T25FT) were performed to explore additional value of LQ analyses.Results: Lesion count assessments by LQ and by the neuro-radiologist were significantly correlated one year (cor = 0.92, p = 2.2 × 10−16) and 5 years (cor = 0.84, p = 2.7 × 10−16) after diagnosis. Analyzes of the intra- and interrater variability also correlated significantly (cor = 0.96, p &lt; 0.001, cor = 0.97, p &lt; 0.001). Significant positive correlation was found between lesion volume measured by LQ and by the software Cascade (cor = 0.7, p &lt; 0.001. LQ detected a reduction in whole brain percentile &gt;10 in 10 patients across the time-points, whereas the neuro-radiologist assessment identified six of these. The neuro-radiologist additionally identified five patients with increased atrophy in the follow-up period, all of them displayed decreasing low whole brain percentiles (median 11, range 8–28) in the LQ analysis. Significant positive correlation was identified between lesion volume measured by LQ and test performance on the T25FT both at 1 and 5 years after diagnosis.Conclusion: For the number of MS lesions at both time-points, we demonstrated strong correlations between the assessments done by LQ and the neuro-radiologist. Lesion volume evaluated with LQ correlated with T25FT performance. LQ-analyses classified more patients to have brain atrophy than the visual neuro-radiological evaluation. In conclusion, LQ seems like a promising supplement to the evaluation performed by neuro-radiologists, providing an automated tool for evaluating lesions in MS patients and also detecting early signs of atrophy in both a longitudinal and cross-sectional setting.

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