University College London
Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences

Author Of 2 Presentations

Clinical Trials Late Breaking Abstracts

LB01.02 - Phase 2 clinical trial evidence that a retinoid-X receptor agonist promotes remyelination in people with relapsing-remitting multiple sclerosis

Abstract

Background

Retinoid acid X receptor [RXR] gamma agonists promote oligodendrocyte progenitor cell differentiation and remyelination following experimental demyelination.

Objectives

To assess the safety and efficacy of bexarotene, a non-specific RXR agonist licensed for cutaneous T-cell lymphoma, as a remyelinating therapy in people with relapsing remitting multiple sclerosis.

Methods

In a double-blind, placebo-controlled, phase 2a trial (Cambridge Centre for Myelin Repair: CCMR-One), participants aged 18-50 years with relapsing remitting multiple sclerosis, stable on dimethyl fumarate for at least 6 months, were randomised to bexarotene 300mg/m2 or placebo for 6 months. The primary efficacy outcome was change in mean lesional magnetisation transfer ratio (MTR) for lesions whose baseline MTR was below the median lesional MTR for that patient. The secondary efficacy outcome was change in full-field visual evoked potential (VEP) latency in eyes with electrophysiological evidence of optic neuropathy (baseline latency >118ms). We analysed by intention to treat.

Results

52 patients were randomised 1:1 to receive six months of bexarotene or placebo. Two placebo patients withdrew before receiving study drug and one bexarotene patient withdrew consent during the trial. All bexarotene patients experienced adverse effects, notably central hypothyroidism (26 [100%]) and hypertriglyceridaemia (24 [92%, mean maximum of 6.79 mmol/L ,SD 4.4]; as well as rash (13 [50%]) and neutropenia (10 [38%]). Two discontinued placebo because of adverse events and five discontinued bexarotene because of rash [2], neutropenia, triglyceridaemia and mood disturbance. The primary efficacy outcome was negative (mean submedian lesion MTR change was 0.25pu in the bexarotene group versus 0.09pu in the placebo group, p=0.54), but in an exploratory, lesion-level analysis, though treatment difference in submedian lesions was too small to achieve significance, it was statistically significantly greater than in supermedian lesions (p=0·007). This suggests that bexarotene has a biological effect on MTR and that this effect is dependent on baseline lesional MTR. This interpretation is supported by the finding that bexarotene treatment reduced full field visual evoked potential latency compared to placebo in the 52 eyes with delayed VEPS at baseline, by 4·66 ms/eye (95% CI -8·38 -0·93; p=0·014) and in all eyes, by a per-protocol analysis, by 4.02ms/eye (P=0.015).

Conclusions

Despite a negative primary efficacy outcome, evidence from both magnetisation transfer ratio imaging and visual evoked potentials suggest that a retinoic X receptor agonist, bexarotene, promotes remyelination in people with multiple sclerosis. We have also a heterogeneous response of MS lesions to a drug promoting remyelination. Although bexarotene’s safety profile precludes its widespread use, these data support efforts to develop a selective RXR-gamma agonist.

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Imaging Oral Presentation

PS07.03 - Predicting disability progression and cognitive worsening in multiple sclerosis with gray matter network measures 

Speakers
Presentation Number
PS07.03
Presentation Topic
Imaging
Lecture Time
13:15 - 13:27

Abstract

Background

In multiple sclerosis (MS), MRI measures at a whole and regional brain level have proven able to predict future disability, albeit to a limited degree. Their modest prognostic ability may reflect how cognitive and neurological functions are served by distributed networks rather than by single brain regions.

Objectives

We aimed to identify data-driven MRI network-based measures of covarying gray matter (GM) volumes that can predict disability progression.

Methods

We used baseline MRI and longitudinal clinical data from 988 patients with secondary progressive MS (SPMS) from a randomized, double-blind, placebo-controlled, multicenter trial (ASCEND). We applied spatial-ICA to baseline structural GM probability maps to identify co-varying GM regions. We computed correlations between the loading of our ICA components and expanded disability status scale (EDSS), 9 hole peg test (9HPT), and symbol digit modalities test (SDMT) scores. We estimated the progression of the EDSS confirmed at 3 months, 6 months, and 1 year, and respectively the 20% and 10% worsening of 9HPT and SDMT. We used Cox proportional hazard models to determine the prognostic value of our ICA-components and conventional MRI measures (whole and deep GM volumes, and white matter lesion load).

Results

We identified 15 networks of co-varying GM patterns that were clinically relevant. At baseline, SDMT and 9HPT scores correlated more strongly with ICA-components than the conventional MRI measures. The highest correlations were with a mainly basal ganglia component (encompassing the thalamus, caudate, putamen, frontal and temporal lobe). EDSS correlated more closely with an ICA-component involving cerebellum, brainstem, temporal and parietal lobes (r= -0.11, p<0.001). Prognostically, the baseline volume of caudate predicted EDSS progression confirmed at 3 months (HR= 0.81, 95%CI [0.68: 0.98], p<0.05), while some GM network-based measures outperformed conventional MRI measures in predicting SDMT and 9HPT worsening. SDMT progression was predicted by 6 ICA-components (component 8 (HR= 1.26, 95% CI [1.08-1.48], p< 0.005, and component 13 (HR= 1.25, 95% CI [1.07:1.46], p<0.005)). Two ICA-components were predictors of 9HPT worsening (HR=1.30, 95% CI [1.06:1.60], p<0.01; and HR= 1.21, 95%CI [1.01:1.45], p<0.05).

Conclusions

Data-driven MRI network-based measures of covarying GM volumes predict disability progression better than volumetric measures of GM and white matter lesion loads. ICA of MRI shows promise as a method that could enrich clinical MS studies with patients more likely to show a treatment response.

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Author Of 2 Presentations

Imaging Poster Presentation

P0549 - Baseline neuroaxonal integrity is associated with upper limb function at 96 weeks in secondary progressive multiple sclerosis (ID 1202)

Abstract

Background

Neurometabolites measured by proton magnetic resonance spectroscopic imaging (MRSI) can be used to examine the relationship between metabolic markers of brain injury and clinical disability in secondary progressive multiple sclerosis (SPMS). Current work has shown an association between normal appearing white matter (NAWM) total N-acetyl aspartate plus N-acetyl aspartyl glutamate (tNAA) and both arm function and measures of processing speed.

Objectives

To determine if baseline tNAA and tNAA/tCr in NAWM are associated with upper limb function (9-hole peg test) and information processing speed (Paced auditory serial addition test) after 96 weeks of follow-up.

Methods

108 participants from the recently reported MS-SMART trial were included.1 All participants had chemical shift imaging in a single slice in the brain (2D-PRESS, TE/TR = 35/2000ms) at 3T and metabolite levels were determined for grey matter and NAWM. Absolute concentrations and ratios to total creatine (tCr) were calculated with LCModel, using an unsuppressed water scan as the internal reference. Along with MRSI, baseline T2 lesion volume (T2LV) and normalised brain volume (NBV) were calculated. Clinical measures were acquired as per MS-SMART protocol at baseline and 96 weeks.2 To determine the association between baseline neurometabolites and 9-hole peg test (9HPT) and Paced auditory serial addition test (PASAT) scores at 96 weeks, multiple regression analysis was used with trial arm, age, sex, disease duration, relapses preceding study entry, T2LV and NBV at baseline as the covariates.

Results

At baseline, mean age of the cohort was 55 years (sd 7.1) and 67% female, mean disease duration was 22 years (sd 9.6), median EDSS 6.0 (IQR 1.0), mean PASAT score 42.8, 95% CI [40.4-45.2], mean 9HPT (sec-1) 0.036, 95% CI [0.034-0.037] and median T2LV 9.0mL (IQR 13.6). At 96 weeks, mean 9HPT (sec-1) was 0.034, 95% CI [0.032-0.036] and mean PASAT3 score was 43.6, 95% CI [40.8-46.3]. Baseline tNAA (β = 0.22, 95% CI [0.02-0.41], p = 0.03) and tNAA/tCr (β = 0.23, 95% CI [0.5-0.42], p = 0.02) in NAWM were associated with 9HPT at 96 weeks. Baseline NAWM tNAA and tNAA/tCr were not significantly associated with 96-week PASAT scores.

Conclusions

Baseline neuroaxonal integrity in NAWM as measured by tNAA and tNAA/tCr are associated with upper limb function at 96-weeks. Baseline neuroaxonal integrity in NAWM was not associated with a measure of processing speed at 96 weeks.

1. Chataway J et al. Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial. Lancet Neurol 2020

2. Connick P et al. 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

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Imaging Poster Presentation

P0651 - The effects of amiloride, fluoxetine and riluzole over 96 weeks on metabolic markers of brain injury in secondary progressive multiple sclerosis. (ID 1206)

Abstract

Background

MS-SMART is a recently reported phase 2b randomised placebo controlled multi-arm study of the neuroprotective potential of amiloride, fluoxetine and riluzole in secondary progressive multiple sclerosis [NCT01910259]. No change in atrophy rate was observed in any arm compared to placebo. We obtained brain metabolic data using proton magnetic resonance spectroscopic imaging (MRSI) at baseline and 96 weeks to explore postulated candidate drug mechanisms of action for the three interventions. Fluoxetine has previously shown an increase in total N-acetyl aspartate plus N-acetyl aspartyl glutamate [tNAA]; myoinositol was also examined as a marker of astrogliosis. Amiloride blocks the acid sensing ion channel-1 receptor that mediates sodium and calcium and therefore could increase neuroaxonal integrity (tNAA). It is known that riluzole decreases glutaminergic transmission.

Objectives

MRSI data at baseline and then 96 weeks was used to interrogate drug specific effects of fluoxetine on tNAA and myoinositol (mIns); riluzole on Glx (glutamate + glutamine); and amiloride on tNAA levels, all compared to placebo.

Methods

108 participants from the MS-SMART trial were included and had chemical shift imaging in a single slice in the brain (2D-PRESS, TE/TR =35/2000ms) at 3T. Metabolite levels and ratios to creatine (tCr) were determined for normal appearing white matter (NAWM) and grey matter (GM) with LCModel using an unsuppressed water scan as the internal reference. Multiple regression models adjusting for age, sex and baseline Expanded Disability Status Scale (EDSS) were used.

Results

Mean age of the entire cohort was 55 (sd 7.1) years, 67% female, mean disease duration was 22 years (sd 9.6), median EDSS 6.0 (range 4.0-6.5) and median T2 lesion volume 9.0mL (IQR 6.0).

In the fluoxetine arm, there was no significant change in tNAA (or tNAA/Cr) in NAWM or GM; mIns/tCr (but not mIns) was lower at 96 weeks (β = -0.21, 95% CI [-0.40 to -0.02], p = 0.03) in NAWM (but not GM).

In the riluzole arm, there was a reduction in GM Glx (β = -0.25, 95% CI [-0.47 to -0.04], p = 0.02) and Glx/tCr (β = -0.29, 95% CI [-0.50 to -0.08], p = 0.007), but no change was seen in NAWM.

In the amiloride arm, there was no change in tNAA (or tNAA/tCr) in NAWM or GM.

Conclusions

Neither fluoxetine nor amiloride had any effect on proposed measures of neuroaxonal integrity in NAWM or GM as reflected in tNAA levels. There was a fluoxetine reduction in NAWM mIns/tCr perhaps reflecting some decrease in astrogliosis. Riluzole decreased GM Glx levels as anticipated. However, despite these target effects for these drugs, ultimately they did not translate into a reduction in atrophy rate in the trial.

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