The role of MRI as a surrogate outcome measure in multiple sclerosis

The need for more specific and more sensitive outcome measures for use in testing new therapies in multiple sclerosis (MS) is generally accepted. This need has been accentuated by the realization that the ability to conduct large placebo-controlled trials will be limited in the future. From the first use of magnetic resonance imaging (MRI) to study MS, the ability of this imaging technique to identify areas of the central nervous system damage by the disease process in MS has been impressive. Thus, the possibility that MRI could serve as a surrogate outcome measure in clinical trials in MS has been attractive. The use of MRI as a surrogate outcome measure has been examined by an international group of investigators with expertise in clinical aspects of MS, the use of MRI in MS, and in experimental therapeutics. The group agreed that MRI does not represent a validated surrogate in any clinical form of MS. It was also agreed, however, that MRI does provide a reflection of the underlying pathology in the disease, but no single MRI measurement in isolation was seen as sufficient to monitor disease. The use for multiple imaging techniques, especially new, emerging techniques that may better reflect the underlying pathology, was seen as particularly important in monitoring studies of patients with either secondary or primary progressive MS. The choice of MRI techniques used to monitor new therapies needs to be consistent with the proposed mechanisms of the new therapy and phase of the disease. It was also noted, however, that additional validation is required for nonconventional imaging techniques. Finally, the participants noted that clinical trials using MRI as a primary outcome measure may fail to fully identify the effects of the therapy on clinical measures and that the risk and cost-benefit ratio of the treatment might be unresolved. Thus, before MRI is used as a primary outcome measure, new approaches to trial design must be given careful consideration. Multiple Sclerosis (2002)8, 40-51

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Lesional magnetization transfer ratio: a feasible outcome for remyelinating treatment trials in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458510364630 ◽

2010 ◽

Vol 16 (6) ◽

pp. 660-669 ◽

Cited By ~ 30

Author(s):

IJ van den Elskamp ◽

DL Knol ◽

H. Vrenken ◽

G. Karas ◽

A. Meijerman ◽

...

Keyword(s):

Multiple Sclerosis ◽

Clinical Trials ◽

Primary Outcome ◽

Outcome Measure ◽

Magnetization Transfer ◽

Primary Outcome Measure ◽

Magnetization Transfer Ratio ◽

Power Calculations ◽

Transfer Ratio ◽

Feasible Outcome

Magnetization transfer ratio (MTR) is a sensitive parameter to quantify the integrity of myelinated white matter in patients with multiple sclerosis. Lesional MTR decreases in the acute phase due to demyelination, and subsequently shows recovery depending on the degree of remyelination in the absence of axonal loss. Recovery of average lesion MTR therefore might prove a viable outcome measure to assess the effect of remyelinating agents. Our objective was to determine the required sample size for phase II multicentre clinical trials using the recovery of average lesion MTR as primary outcome measure. With 7-monthly MRI scans, the MTR evolution of 349 new enhancing lesions before and after enhancement was assessed in 32 MS patients from 5 centres. Multilevel models were fitted to the data yielding estimates for the variance components, which were applied in power calculations. Sample sizes were determined for placebo-controlled, multicentre trials using lesional MTR recovery post-enhancement as primary outcome measure. Average lesion MTR decreased slightly in the build-up to enhancement, decreased dramatically during enhancement and showed recovery in the period after cessation. The power calculations showed that for a power of 80%, approximately 136 patients per trial (mean number of 6 lesions per patient) are required to detect a 30% increase in lesional MTR post-enhancement compared with placebo, whereas 48 subjects are required to detect a 50% increase in lesional MTR compared with placebo. Recovery of lesion MTR is a feasible outcome measure for future multicentre clinical trials measuring the effect of remyelinating agents.

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Statistical analysis, trial design and duration in Alzheimer's disease clinical trials: a review

International Psychogeriatrics ◽

10.1017/s1041610211001116 ◽

2011 ◽

Vol 24 (5) ◽

pp. 689-697 ◽

Cited By ~ 17

Author(s):

P. A. Thompson ◽

D. E. Wright ◽

C. E. Counsell ◽

J. Zajicek

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Statistical Analysis ◽

Statistical Methods ◽

Outcome Measures ◽

Primary Outcome ◽

Outcome Measure ◽

Primary Outcome Measure ◽

Primary Analysis

ABSTRACTBackground: The social and economic burden of Alzheimer's disease (AD) and its increasing prevalence has led to much work on new treatment strategies and clinical trials. The search for surrogate markers of disease progression continues but traditional parallel group trial designs that use well-established, but often insensitive, clinical outcome measures predominate.Methods: We performed a systematic search across the Cochrane Library and PubMed abstracts published between January 2004 and August 2009. Information regarding the clinical trial methodology, outcome measures, intervention type and primary statistical analysis techniques was extracted and categorized, according to a standard protocol.Results: We identified 149 papers describing results from clinical trials in AD containing sufficient detail for our purposes. The largest proportion (38%) presented results of trials based on tests of cognition as the primary outcome measure. The primary analysis in most papers (85%) was a univariate significance test of a single primary outcome measure.Conclusions: The majority of trials reported a comparison of baseline and end-point assessment over relatively short patient follow-up periods, using univariate statistical methods to compare differences between intervention and control groups in the primary analysis. There is considerable scope to introduce newer statistical methods and trial designs in treatment evaluations in AD.

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Rationale for use of the Clinical Dementia Rating Sum of Boxes as a primary outcome measure for Alzheimer's disease clinical trials

Alzheimer s & Dementia ◽

10.1016/j.jalz.2011.11.002 ◽

2012 ◽

Vol 9 (1S) ◽

pp. S45-S55 ◽

Cited By ~ 41

Author(s):

Jesse M. Cedarbaum ◽

Mark Jaros ◽

Chito Hernandez ◽

Nicola Coley ◽

Sandrine Andrieu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Primary Outcome ◽

Outcome Measure ◽

Primary Outcome Measure ◽

Clinical Dementia Rating

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THE SELECTION OF HARD CLINICAL ENDPOINTS VERSUS SURROGATE ENDPOINTS AS THE PRIMARY OUTCOME MEASURE IN MAJOR CARDIOVASCULAR CLINICAL TRIALS IS NOT INFLUENCED BY THE SOURCE OF FUNDING

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(10)61237-5 ◽

2010 ◽

Vol 55 (10) ◽

pp. A132.E1236

Author(s):

Ashish Aneja ◽

Ricardo Esquitin ◽

Kshitij Shah ◽

Louai Razzouk ◽

Rupa Iyengar ◽

...

Keyword(s):

Clinical Trials ◽

Primary Outcome ◽

Outcome Measure ◽

Primary Outcome Measure ◽

Surrogate Endpoints ◽

Clinical Endpoints ◽

Selection Of

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Change in quality of life in patients with relapsing–remitting multiple sclerosis over 2 years in relation to other clinical parameters: results from a trial of intramuscular interferon β-1a

Multiple Sclerosis Journal ◽

10.1177/1352458510397221 ◽

2011 ◽

Vol 17 (6) ◽

pp. 734-742 ◽

Cited By ~ 13

Author(s):

DM Miller ◽

B Weinstock-Guttman ◽

D Bourdette ◽

X You ◽

P Foulds ◽

...

Keyword(s):

Quality Of Life ◽

Multiple Sclerosis ◽

Primary Outcome ◽

Outcome Measure ◽

Primary Outcome Measure ◽

Disability Progression ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

Background: A randomized, placebo-controlled, multicenter study of weekly intramuscular injections of interferon beta-1a (IFNβ-1a) in relapsing–remitting multiple sclerosis included the Sickness Impact Profile (SIP), a validated measure of patient-reported quality of life (QoL). Objective: To demonstrate the impact of moderate to severe SIP disability at baseline and change in QoL as measured by SIP over 2 years in relation to other study parameters. Methods: In 158 patients, SIP scores were determined at baseline and 2 years. Scores were correlated with disease progression and treatment. Results: Patients who experienced disability progression, as defined by Expanded Disability Status Scale (EDSS) and annualized relapse rate, during the study demonstrated significant worsening in Physical SIP scores compared with patients who did not progress ( p = 0.031). In patients with low SIP scores, indicating moderate or severe disability at baseline, treatment with IFNβ-1a significantly improved Physical SIP subscores. Conclusions: Patients with disability progression defined using EDSS, the physician-derived primary outcome measure, had Physical SIP scores indicating worsening disability, validating the physician-derived primary outcome measure using patient self-report. Treatment with IFNβ-1a had beneficial effects on QoL in patients with worse SIP scores at baseline.

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Persistent T1 hypointensity as an MRI marker for treatment efficacy in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458507087842 ◽

2008 ◽

Vol 14 (6) ◽

pp. 764-769 ◽

Cited By ~ 23

Author(s):

IJ van den Elskamp ◽

J Lembcke ◽

V Dattola ◽

K Beckmann ◽

C Pohl ◽

...

Keyword(s):

Multiple Sclerosis ◽

Black Hole ◽

Phase Ii ◽

Primary Outcome ◽

Negative Binomial ◽

Outcome Measure ◽

Primary Outcome Measure ◽

Cumulative Number ◽

Sample Sizes ◽

Simulation Procedure

Background MRI is often used as primary outcome measure in phase II clinical trials in multiple sclerosis (MS). Since persistent T1 hypointense lesions are a surrogate parameter for axonal damage and demyelination, they may serve as a marker for monitoring the efficacy of neuroprotective drugs. At present, a power analysis using black hole (BH) evolution as primary outcome measure has not been performed. Objective To assess the feasibility of using BH evolution on serial brain MR images as primary outcome measure in proof of concept studies in MS. Methods MRI-data obtained from 169 active RRMS patients were analysed for BH evolution by determining the cumulative number of contrast enhancing lesions (CEL) evolving into a persistent black hole (PBH) after 3 months. With a parametric simulation procedure, based on a statistical distribution fitting the data, sample sizes were calculated. Results 21.2% of the total number of CELs observed during the study period evolved into a PBH. Ring enhancing lesions evolved most frequently into a PBH (59.4%), followed by lesions larger than 10 mm (57.4%) and periventricular CELs (30.6%). The simulation procedure, based on the statistical negative binomial (NB) model resulted in a sample sizes between 200 subjects and 30 subjects per arm, for treatment effects ranging from 50% to 90% reduction of the number of CELs evolving into a PBH, respectively. Conclusion To perform a MRI monitored phase II clinical trial with a feasible sample size, using the evolution of CELs into PBHs as primary outcome parameter, a potent drug is required to obtain sufficient power.

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