MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials

doi:10.1016/S1474-4422(13)70103-0

The Lancet Neurology

Volume 12, Issue 7, July 2013, Pages 669-676

https://doi.org/10.1016/S1474-4422(13)70103-0 Get rights and content

Summary

Background

A meta-analysis of randomised trials in relapsing-remitting multiple sclerosis published in 2009 showed a quantitative relation between the treatment effects detected on MRI lesions and clinical relapses. We aimed to validate that relation using data from a large and independent set of clinical trials in multiple sclerosis.

Methods

We searched Medline for clinical trials that assessed disease-modifying drugs for relapsing-remitting multiple sclerosis published from Sept 1, 2008, to Oct 31, 2012. We extracted data for the treatment effects on MRI lesions and on relapses from each trial, and the correlation of log transformed relative measures of these treatment effects was assessed with a weighted linear regression analysis. The R² value was estimated to quantify the strength of the correlation, and we used an interaction test to test for a difference in slope from the previously estimated equation. We also ran several sensitivity analyses.

Findings

We identified 31 eligible trials, which provided data for 18 901 patients with relapsing-remitting multiple sclerosis. The regression equation derived using data from these studies showed a relation between the concurrent treatment effects on MRI lesions and relapses (slope=0·52; R²=0·71), much the same as was previously estimated (p_interaction=0·45). Analysis of trials that tested the same drugs in phase 2 and phase 3 studies showed that the effects on MRI lesions over short follow-up periods (6–9 months) can also predict the effects on relapses over longer follow-up periods (12–24 months), with reported effects on relapses that were within the 95% prediction intervals in eight of nine trials.

Interpretation

Our findings indicate that the effect of a treatment on relapses can be accurately predicted by the effect of that therapy on MRI lesions, implying that the use of MRI markers as primary endpoints in future clinical trials of treatments for multiple sclerosis can be considered, in specific situations, such as in trials testing generics or biosimilars of drugs with a well known mechanism of action or in paediatric trials testing drugs already approved for adults.

Funding

None.

Introduction

MRI markers have not been formally accepted by drug regulatory agencies as surrogate endpoints for assessing the effect of new drugs and for monitoring individual patients' response to treatments for multiple sclerosis.¹ Findings from a meta-analysis of randomised trials assessing different drugs for multiple sclerosis showed a strong relation between the effect of treatment on conventional MRI markers and relapses²—ie, that MRI markers can be good surrogate markers for assessing the effect of treatments on relapses in clinical trials.³ Further support for a role of MRI endpoints as reliable surrogates for clinical relapses—at least in patients with relapsing-remitting disease treated with immunomodulatory drugs—comes from findings from validation studies based on individual patient data from trials of interferon beta4, 5 and glatiramer acetate.⁶ With the present analysis, we had the following aims: to confirm the previously estimated association² between the effect of drugs on MRI lesions and the effect on relapses using the results of an independent set of trials; to develop a robust algorithm to enable prediction of the effect of treatments on relapses on the basis of the effect on MRI lesions; to explore the validity of MRI as a surrogate in trials of generic or biosimilar versions of immunomodulatory drugs (using data from trials of interferon beta and glatiramer acetate); and to estimate the sample sizes needed in the design of phase 3 trials with MRI lesions as the primary endpoint.

The issues surrounding trials of generics or biosimilars of immunomodulatory drugs are becoming increasingly important as the patents for both subcutaneous interferon beta-1a (Rebif; Merck Serono International, Geneva, Switzerland) and intramuscular interferon beta-1a (Avonex; Biogen Idec, Cambridge, USA) are expiring on Dec 31, 2013, and the patent of glatiramer acetate (Copaxone; Teva Pharmaceutical Industries, Kansas City, MO, USA) is expiring on Dec 31, 2014, in the USA and on Dec 31, 2015, in Europe. The use of MRI metrics for the assessment of biosimilar and generic drugs would be the only way to make such clinical trials feasible, because non-inferiority studies with relapses as the primary outcome would need thousands of patients and would be difficult to recruit for.

Section snippets

Search strategy and selection criteria

We prospectively collected all reports of randomised clinical trials that assessed disease modifying drugs for relapsing-remitting multiple sclerosis published from Sept 1, 2008, to Oct 31, 2012, by searching PubMed. We used search terms for the disease name (“multiple sclerosis”, “demyelinating disease”) and disease phenotype (“relapsing”, “relapsing-remitting”), and MeSH terms for indexing articles for PubMed (“multiple sclerosis [Mesh] AND (“2008/09/01”[PDat]:” 2012/10/31”[PDat]) AND

Results

We identified 347 studies published between Sept 1, 2008, and Oct 31, 2012 (figure 1). We excluded trials studying symptomatic and reparative treatments, trials studying a disease phase other than relapsing-remitting, uncontrolled trials, trials that did not report data for relapses or for MRI lesions, open-label extensions of previous randomised studies. A final set of 31 randomised controlled trials for the treatment of relapsing-remitting multiple sclerosis was identified—26 published after

Discussion

This analysis, which is based on an independent set of randomised clinical trials in relapsing-remitting multiple sclerosis, reproduces the results of our previous meta-analysis, which was based on earlier placebo-controlled studies, validating the role of MRI parameters as surrogate endpoints for relapses in efficacy trials in multiple sclerosis. First, our findings substantiate the strong association between the effect of a treatment on MRI lesions and its effect on relapse rate. Second, our

References (39)

M Filippi et al.
Effects of oral glatiramer acetate on clinical and MRI-monitored disease activity in patients with relapsing multiple sclerosis: a multicentre, double-blind, randomised, placebo-controlled study
Lancet Neurol
(2006)
N De Stefano et al.
Efficacy and safety of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis: further outcomes from the IMPROVE study
J Neurol Sci
(2012)
L Kappos et al.
Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial
Lancet
(2011)
G Comi et al.
Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study
Lancet
(2008)
L Kappos et al.
Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study
Lancet
(2008)
Guideline on clinical investigation of medicinal products for the treatment of Multiple Sclerosis
MP Sormani et al.
Magnetic resonance imaging as a potential surrogate for relapses in multiple sclerosis: a meta-analytic approach
Ann Neurol
(2009)
M Buyse et al.
The validation of surrogate endpoints in meta-analyses of randomized experiments
Biostatistics
(2000)
MP Sormani et al.
MRI metrics as surrogate endpoints for EDSS progression in SPMS patients treated with IFN beta-1b
Neurology
(2003)
MP Sormani et al.
Magnetic resonance active lesions as individual-level surrogate for relapses in multiple sclerosis
Mult Scler
(2011)

MP Sormani et al.

MRI metrics as surrogate markers for clinical relapse rate in relapsing-remitting MS patients

Neurology

(2002)

MP Sormani et al.

Clinical trials of multiple sclerosis monitored with enhanced MRI: new sample size calculations based on large data sets

J Neurol Neurosurg Psychiatry

(2001)

MP Sormani et al.

Time to first relapse as an endpoint in multiple sclerosis clinical trials

Mult Scler

(2013)

DW Paty et al.

Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group

Neurology

(1993)

Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial

Neurology

(1993)

LD Jacobs et al.

Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis

Ann Neurol

(1996)

JH Simon et al.

Magnetic resonance studies of intramuscular interferon beta-1a for relapsing multiple sclerosis

Ann Neurol

(1998)

Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis

Lancet

(1998)

DK Li et al.

Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-controlled study of interferon-beta1a in relapsing-remitting multiple sclerosis. Prevention of relapses and disability by interferon-beta1a subcutaneously in multiple sclerosis

Ann Neurol

(1999)

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ArticlesMRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Search strategy and selection criteria

Results

Discussion

Lancet Neurol

J Neurol Sci

Lancet

Lancet

Lancet

Guideline on clinical investigation of medicinal products for the treatment of Multiple Sclerosis

Magnetic resonance imaging as a potential surrogate for relapses in multiple sclerosis: a meta-analytic approach

Ann Neurol

The validation of surrogate endpoints in meta-analyses of randomized experiments

Biostatistics

MRI metrics as surrogate endpoints for EDSS progression in SPMS patients treated with IFN beta-1b

Neurology

Magnetic resonance active lesions as individual-level surrogate for relapses in multiple sclerosis

Mult Scler

MRI metrics as surrogate markers for clinical relapse rate in relapsing-remitting MS patients

Neurology

Clinical trials of multiple sclerosis monitored with enhanced MRI: new sample size calculations based on large data sets

J Neurol Neurosurg Psychiatry

Time to first relapse as an endpoint in multiple sclerosis clinical trials

Mult Scler

Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group

Neurology

Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial

Neurology

Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis

Ann Neurol

Magnetic resonance studies of intramuscular interferon beta-1a for relapsing multiple sclerosis

Ann Neurol

Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis

Lancet

Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-controlled study of interferon-beta1a in relapsing-remitting multiple sclerosis. Prevention of relapses and disability by interferon-beta1a subcutaneously in multiple sclerosis

Ann Neurol

Articles
MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials