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MR outcome measures in MS trials

PART OF MS Alumni FEATURE
MR outcome measures in MS trials
  • Neurology

Maria A. Rocca, MD.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Introduction

In MS, MRI is much more sensitive to disease activity than clinical assessment of relapses. This is why MRI measures are used for monitoring response to treatment. At present, in MS clinical trials, MRI is used as a primary outcome measure in phase II studies, in which serial scans are acquired to detect disease activity (new/enlarged T2 lesions and enhancing lesions).1 In phase III trials, MRI measures (absolute or percentage increase in total T2 lesion load) are used as secondary outcomes.2 These measures provide a good surrogacy of treatment effect on relapse rate and disability progression in patients with relapsing remitting (RR) MS, whereas their value in patients with a progressive disease course remains elusive.

Given that conventional MRI measures are sensitive only to inflammatory demyelination, they should not be applied in isolation in MS clinical trials, but would rather need to be combined with quantities providing estimates of irreversible tissue loss, which have already been used in some clinical trials (e.g., evolution of active lesions into permanent black holes - PBH - and brain atrophy). Novel measures which have demonstrated a great value in explaining patients’ clinical outcome but which still need to be fully validated, include the quantification of gray matter (GM) and spinal cord atrophy. Finally, other MRI quantities which have been implemented in research settings, such as the evaluation of cortical lesions, assessment of microscopic tissue damage and functional cortical reorganization might show a value for clinical trial monitoring in the future.  

MRI measures currently applied in MS clinical trials

a) Measures of inflammation (T2-hyperintense lesions and Gd-enhancing lesions). MRI measures of inflammation (active lesions) include the count of new or enlarged T2 lesions and gadolinium (Gd) enhancing lesions. Two meta-analysis studies of randomized, placebo-controlled clinical trials of disease modifying drugs (DMD) in RRMS3, 4 have shown that around 80% of the variance in treatment effect on relapses is explained by the variance of the effect on active MRI lesions. Analysis of trials that tested the same drugs in phase II and III studies showed that the effect on MRI lesions over short follow-up (6-9 months) can also predict that on relapses over longer follow-up (12-24 months), with the exception of fingolimod (the effect of this drug on relapses was 67% higher than that predicted on MRI).4 MRI surrogacy in predicting treatment effect on disability progression has also been validated both at trial5 and individual patient6-8 levels in RRMS5-7 and secondary progressive (SP) MS patients.8 A recent analysis of RRMS patients treated with IFN beta-1a subcutaneously6 found that a combined measure of 1-year change of MRI lesions and relapses during therapy fully estimates the effect on 2-year Expanded Disability Status Scale worsening.

b) Measures of neurodegeneration (PBH evolution and brain atrophy). Halting inflammation in MS does not necessarily modify favourably the disease course, since neurodegeneration, which is not only a mere reflection of inflammatory mediated abnormalities, is also known to occur from the earliest stages of the disease.

MRI markers sensitive to irreversible tissue damage include monitoring the evolution of active lesions into PBH and quantification of brain atrophy. Significant effect in modifying the fate of active lesions evolving into PBH in RRMS patients have been described for GA,9 natalizumab10 and laquinimod,11 but not for BHT-3009, a DNA plasmid-encoding myelin basic protein (MBP).12 Two comparative studies, BECOME and BEYOND, suggested that RRMS patients treated with IFN beta-1b might have a lower proportion of new lesions evolving into PBH than those treated with GA.13, 14

Studies of atrophy progression in clinically stable and untreated MS patients have shown that brain volume loss occurs at a rate of about 0.5-1% per year compared to 0.1-0.3% of healthy controls.15 Only a subset of available MS clinical trials has assessed treatment effect on brain atrophy progression. IFNs,11, 16, 17 GA,18 natalizumab,19 fingolimod,20 laquinimod21 and haemapoietic stem cell transplantation22-24 were shown to slow significantly the progression of brain atrophy. A recent meta-analysis of randomized clinical trials in RRMS lasting at least 2 years demonstrated that treatment effect on brain atrophy is correlated with the effect on disability progression (R2=0.48) and is independent of the effect on active MRI lesions. However, these two MRI measures predicted treatment effect on disability more closely when used in combination (R2=0.75).25

A paradoxical loss of brain volume has been observed in the early phase of treatment following administration of steroids,26 intramuscular (im) IFN beta-1a16 and natalizumab,19 whilst such an effect has not been detected with fingolimod.20 Such an acute reduction of brain volume is likely to reflect the resolution of inflammation-associated edema, a phenomenon described as “pseudoatrophy”.

Measures ready to be moved to MS clinical trials

a) GM atrophy. Recent trials have included GM atrophy quantification as an outcome measure. In RRMS patients, laquinimod was shown to slow the rate of progression of GM and thalamic atrophy over a two-year period, and such an effect was more pronounced during the first year of treatment.11 In SPMS patients, GM atrophy progression was reduced following treatment with pioglitazione used as add-on therapy to im IFN beta-1a.27

b) Spinal cord atrophy. Improvements of spinal cord imaging technologies and analysis methods have made feasible estimating cord atrophy in large-scale and multi-centre studies.28, 29 By using a new semi-automatic method,30 which allows segmentation of relatively long portions of the cord based on an active surface (AS) modelling of the cord surface, it has been demonstrated that cord cross-sectional area (CSA) differs significantly among the main MS clinical phenotypes and is correlated with disability.28 The AS method has been recently applied in a 6 month longitudinal study.31 

A few single-centre trials have used cord atrophy as an exploratory endpoint.32-35 Reduction of cord CSA over a four year period did not differ between RRMS patients treated with various formulations of INF beta-1a vs those initially on placebo.33 In PPMS patients, riluzole slowed the rate of progression of cord atrophy.32

More distant MRI measures

a) Cortical lesions. Cross-sectional and longitudinal studies have shown the clinical relevance of cortical lesion detection for the diagnosis36 and prognosis37 of MS. Despite several strategies have been applied to improve imaging of such lesions,37 double inversion recovery (DIR) sequences compared to post mortem assessment detect only less than 20% of all cortical lesions.38 In addition, sequence acquisition for the detection of such lesions has not been standardized yet across centres. Consensus recommendations for scoring cortical lesions using DIR sequences have been nonetheless formulated and tested.39 However, only two single-centre trials40, 41 have included cortical lesion quantification. In RRMS patients, over a two-year period, natalizumab slowed significantly new cortical lesion formation compared to other DMD,40 and sc IFN beta-1a was shown to have a faster and more pronounced effect on this measure than im IFN beta-1a or GA.41

b) Miscroscopic tissue abnormalities. In research settings, several quantitative MR techniques, such as magnetization transfer (MT) MRI, diffusion tensor (DT) MRI, and proton MR spectroscopy (1H-MRS), have been extensively used to assess the severity and clinical relevance of structural damage within lesions, normal-appearing white matter (NAWM) and GM. Effort has also been spent to set-up and standardize the acquisition of these sequences in multi-centre studies.42-44 Recovery of MT ratio (MTR) in focal T2 lesions has been proposed as an outcome measure to assess the effect of remyelinating agents.45, 46 A technique to quantify longitudinal changes in MTR has been developed and applied to patients treated with autologous stem cell transplant.46 A single-centre MT MRI study has suggested that alemtuzumab protects against GM damage.47 A combined MT MRI and 1H-MRS study11 showed that compared to placebo, patients treated with laquinimod tend to accumulate less microscopic WM and GM damage.47

c) Functional reorganization. The potential of fMRI in a multicentre setting has been explored by a few studies of the motor system.48, 49 At present, only a limited number of single-centre studies have applied fMRI to monitor drug or rehabilitation effects in MS. Despite having no effect on cognitive performance, chronic administration of rivastigmine modified the patterns of activations and functional connectivity of frontal lobe areas in MS patients.50 Modifications of the pattern of brain functional recruitment and resting activity have been associated to a better clinical outcome following motor51 and cognitive52 rehabilitation.

Conclusions

At present, reliable MRI measures to monitor disease activity and treatment response in MS clinical trials are available. However, these metrics are unable to define the potential of the various interventions to impact on MS-related neurodegenerative processes. Other MR metrics are therefore needed, some of which have already shown to have a role in the monitoring of the most destructive aspects of MS. Several considerations should guide the choice of novel MR-based trial outcomes, including the mechanism of action of the drug under investigation, and clinical phenotype and disease stage of the patients enrolled. For instance, trials in RRMS might benefit from the assessment of the effect of treatment on demyelination/remyelination (e.g., the rate of PBH from active lesions and recovery of MTR values) and trials in progressive MS from the quantification of brain and cord atrophy, and GM damage.

 

References

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Preceptorship
Milan, Italy
Oct 30 - 31, 2014
Target audience
Clinicians and scientists currently involved in MS and/or NMO management., Radiologists
EACCME®
by Excemed
Neurology

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