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 sderosis (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 dinical 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.     

Biomarkers and surrogate outcomes in neurodegenerative disease: Lessons from multiple sclerosis

Multiple sclerosis (MS) is a chronic disease of the CNS that most commonly affects young adults. It is usually characterized in the early years by acute relapses followed by partial or complete remission; in later years progressive and irreversible disability develops. Because of the protracted and unpredictable clinical course, biological surrogate markers are much needed to make clinical trials of potential disease-modifying treatments more efficient. Magnetic resonance (MR) outcome measures are now widely used to monitor treatment outcome in MS trials. Areas of multifocal inflammation are detected with a high sensitivity as new areas of gadolinium enhancement and T2 abnormality, and these may be considered as surrogate markers for clinical relapses. However, progressive disability is not clearly related to inflammatory lesions but rather to a progressive and diffuse process with increasing neuroaxonal loss. MR surrogate measures for neuroaxonal loss include atrophy (tissue loss in brain and spinal cord), N-acetyl aspartate, and T1 hypointense lesions. Diffuse abnormality in normal appearing brain tissue may also be monitored using magnetization transfer ratio and other quantitative MR measures. For treatment trials of new agents aimed at preventing disability, measures of neuroaxonal damage should be acquired, especially atrophy, which occurs at all stages of MS and which can be quantified in a sensitive and reproducible manner. Because the MR surrogates for neuroaxonal loss are not yet validated as predicting future disability, definitive trials should continue to monitor an appropriate disability endpoint.     

Magnetic resonance imaging predictors of disability in primary progressive multiple sclerosis: a 5-year study

Magnetic resonance imaging (MRI) has become an accepted tool for monitoring therapeutic trials in relapsing-remitting and secondary progressive multiple sclerosis (MS); it is however unclear whether such MRI markers are equally applicable to primary progressive MS (PPMS). Forty-two patients with PPMS were reviewed five years after commencing a two-year MRI and clinical study. Clinical measures recorded at baseline and five years included both the Expanded Disability Status Scale and the MS functional composite. MRI data collected at baseline and two years included T1 and T2 lesion loads, the number of new brain and cord lesions, and measures of both brain and cord atrophy. The study demonstrated that both the number of new T2 lesions and rate of increase in ventricular volume over two years were modestly predictive of subsequent disease progression and therefore may be useful tools in the testing of new therapeutic agents in PPMS.     

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

OBJECTIVE: To formally validate metrics derived from conventional MRI as surrogate endpoints for relapse rate in MS. BACKGROUND: Although metrics derived from MRI are used widely in clinical trials of MS, a formal statistical validation of MRI metrics as surrogate endpoints for clinical outcome in MS is lacking. METHODS: A validation procedure was applied to clinical and MRI data collected in the context of a randomized, double-blind, placebo-controlled trial of glatiramer acetate in patients with relapsing-remitting MS. The four Prentice operational criteria were applied to assess surrogacy for the number of new enhancing lesions, the percentage change of T2 lesion volume, and a composite MRI score based on these two metrics. RESULTS: The results of this analysis show that all three MRI measures considered by the authors had a behavior compatible with the Prentice criteria for valid surrogates. The composite MRI score correlated with relapses and accounted for much of the treatment effect on relapse rate. CONCLUSIONS: This preliminary study suggests that conventional MRI metrics might serve as valid surrogate endpoints in MS trials with glatiramer acetate or treatments thought to have a similar mode of action.     

Serial gadolinium-enhanced MRI in relapsing/remitting multiple sclerosis of varying disease duration.

In the planning of MRI protocols to monitor disease activity in multiple sclerosis (MS), the clinical subtype needs to be considered. In this serial gadolinium-enhanced MRI study, we demonstrated differences between patients with early relapsing/remitting MS and benign MS in both the production of new lesions and the occurrence of enhancement.     

Conventional magnetic resonance sequences in multiple sclerosis

The role of magnetic resonance imaging (MRI) in multiple sclerosis (MS) has received considerable attention in recent years. MRI has the potential to provide indices of disease activity and progression in clinical trials. Moreover, there is now widespread agreement that conventional MRI sequences are useful not only in diagnosing the disease but also in evaluating the natural course of the disease and the response to therapy. Conventional spin echo (CSE) sequences are widely accepted as sensitive techniques for the evaluation and quantification of brain MS lesions. Fast spin echo (FSE) sequences are now used as an alternative to CSE. They have the advantage of a considerable reduction in imaging time. Fast-fluid attenuation inversion recovery (fast-FLAIR) sequences, in which the signal from cerebrospinal fluid is suppressed, also provide a reliable means to evaluate the total lesion burden in patients with MS. Despite some limitations in the detection of infratentorial lesions, Fast-FLAIR sequences are useful in clinical studies. Compared with lesions load on conventional T2-weighted sequences, an increase in hypointense lesion load on CSE T1-weighted sequences correlates more strongly with increased disability in MS patients. This might be an additional useful MRI parameter to monitor disease progression in long-term studies. Gadolinium-enhanced T1-weighted images provide highly sensitive markers for detecting MRI activity, which represent the primary MRI endpoint for screening promising disease-modifying therapies, especially in phase II trials.     

Examination of the role of magnetic resonance imaging in multiple sclerosis: A problem-orientated approach

Magnetic Resonance Imaging (MRI) has brought in several benefits to the study of Multiple Sclerosis (MS). It provides accurate measurement of disease activity, facilitates precise diagnosis, and aid in the assessment of newer therapies. The imaging guidelines for MS are broadly divided in to approaches for imaging patients with suspected MS or clinically isolated syndromes (CIS) or for monitoring patients with established MS. In this review, the technical aspects of MR imaging for MS are briefly discussed. The imaging process need to capture the twin aspects of acute MS viz. the autoimmune acute inflammatory process and the neurodegenerative process. Gadolinium enhanced MRI can identify acute inflammatory lesions precisely. The commonly applied MRI marker of disease progression is brain atrophy. Whole brain magnetization Transfer Ratio (MTR) and Magnetic Resonance Spectroscopy (MRS) are two other techniques use to monitor disease progression. A variety of imaging techniques such as Double Inversion Recovery (DIR), Spoiled Gradient Recalled (SPGR) acquisition, and Fluid Attenuated Inversion Recovery (FLAIR) have been utilized to study the cortical changes in MS. MRI is now extensively used in the Phase I, II and III clinical trials of new therapies. As the technical aspects of MRI advance rapidly, and higher field strengths become available, it is hoped that the impact of MRI on our understanding of MS will be even more profound in the next decade.     

Evaluation of atorvastatin and simvastatin for treatment of multiple sclerosis

Atorvastatin and simvastatin (members of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor family) are widely prescribed as cholesterol-lowering agents. As they have been shown to exhibit potent immunomodulatory effects, they may become a future treatment option for autoimmune disease in general and multiple sclerosis (MS) in particular. Several recent reports have demonstrated that statins prevent and reverse chronic and relapsing experimental autoimmune encephalomyelitis, an animal model of MS. An open-label clinical trial assessing simvastatin in MS revealed a significant decrease in the number and volume of new MRI lesions and a favorable safety profile. The results of a large multicenter, placebo-controlled clinical trial assessing atorvastatin in patients with clinically isolated syndrome (a disease that predisposes to development MS) are expected soon. However, prospective placebo-controlled trials of atorvastatin or simvastatin in definite MS are difficult to perform due to ethical and financial objections. In this review, we discuss the backgrounds, mechanisms of action and future perspectives of atorvastatin and simvastatin as putative future treatment options in MS.     

Magnetic resonance imaging as a surrogate outcome for multiple sclerosis relapses

BACKGROUND: Magnetic resonance imaging (MRI) of lesions in the brain may be the best current candidate for a surrogate biological marker of clinical outcomes in relapsing remitting multiple sclerosis (MS), based on its role as an objective indicator of disease pathology. No biological surrogate marker has yet been validated for MS clinical outcomes. OBJECTIVE: The objective of this study was to use a multi-phased study to determine if a valid surrogate relationship could be demonstrated between counts of contrast enhancing lesions (CELs) and occurrence of relapses in MS. METHODS: We examined correlations for the concurrent and predictive relationship between CELs over 6 months and MS relapses over the same 6 months and an additional 6 months (total: 12 months), using available data on untreated patients from a large clinical trial and natural history database. RESULTS: Concurrent and predictive correlations were inadequate to justify continuation of this study to the planned additional phases required to demonstrate a surrogate relationship between CELs and MS relapses. CONCLUSIONS: Confidence intervals for correlations between CELs and MS relapses exclude the possibility that CELs can be a good surrogate for relapses over the time scales we investigated. Further exploration of surrogacy between MRI measures and MS clinical outcomes may require improved datasets, the development of MRI techniques that couple better to clinical disease, and the ability to test a wide range of imaging- and clinically-based hypotheses for surrogacy.     

Paradoxically aggressive multiple sclerosis in the face of natalizumab therapy

In the pivotal trials of natalizumab in the treatment of relapsing-remitting multiple sclerosis (AFFIRM and SENTINEL), a dramatic reduction in relapse rate, new or enlarging T2-hyperintense lesions, and mean number of gadolinium-enhancing lesions was observed. While both relapses and new MRI lesions were observed in these trials, there has been no comment on the presence of aggressive disease in the face of natalizumab treatment. I report a 31-year-old woman with relapsing remitting MS of 12 years duration who developed aggressive demyelinating disease four months after the initiation of natalizumab. The clinical worsening was accompanied by a significant increase in new large T2-hyperintense signal abnormalities and in both solid and C-shaped contrast-enhancing lesions. Neither the clinical severity nor the striking MRI abnormalities had been noted earlier in her disease course. Neutralizing antibodies to natalizumab were not detected. She subsequently responded to combination therapy of pulsed methylprednisolone and daily glatiramer acetate.     

Neuroimaging in Multiple Sclerosis: Neurotherapeutic Implications

Imaging techniques, in particular magnetic resonance imaging (MRI), play an important role in the diagnosis and management of multiple sclerosis (MS) and related demyelinating diseases. Findings on MRI studies of the brain and spinal cord are critical for MS diagnosis, are used to monitor treatment response and may aid in predicting disease progression in individual patients. In addition, results of imaging studies serve as essential biomarkers in clinical trials of putative MS therapies and have led to important insights into disease pathophysiology. Although they are useful tools and provide in vivo measures of disease-related activity, there are some important limitations of MRI findings in MS, including the non-specific nature of detectable white matter changes, the poor correlation with clinical disability, the limited sensitivity and ability of standard measures of gadolinium enhancing lesions and T2 lesions to predict future clinical course, and the lack of validated biomarkers of long term outcomes. Advancements that hold promise for the future include new techniques that are sensitive to diffuse changes, the increased use of higher field scanners, measures that capture disease related changes in gray matter, and the use of combined structural and functional imaging approaches to assess the complex and evolving disease process that occurs during the course of MS.     

Practical problems in the organisation of clinical trials in multiple sclerosis

The problems of organising clinical trials in MS include the general aspects relating to clinical trials in any discipline but extend also to specific problems arising in the assessment of a relapsing remitting condition. These factors relating to the clinical characteristics of the disease, the diagnosis, the selection of patients and the methods of clinical and laboratory assessment are described and discussed. Suggestions are made for the use of internationally accepted diagnostic criteria for MS and a review is made of the other recognised problems in this field.     

Correlations between monthly enhanced MRI Lesion rate and changes in T2 Lesion volume in multiple sclerosis

Magnetic resonance imaging (MRI) provides a powerful tool for assessing disease activity in multiple sclerosis (MS), and its role as a surrogate marker for monitoring treatment efficacy is now becoming established. The most commonly used MRI parameters in treatment trials are (1) monthly gadolinium-enhanced MRI, with the number of active lesions serving as the outcome measure, and (2) annual lesion load quantification, in which change in MS lesion volume provides the MRI endpoint. We evaluated clinical/MRI correlations and the relationship between these two markers of disease activity in 73 patients with clinically definite MS. Quantification of T2 lesion load was performed at study entry and exit, with a median study duration of 11 months (range, 9 to 14 months). Monthly postgadolinium T1-weighted images were acquired between these time points. Lesion load at study entry was significantly correlated with the baseline Expanded Disability Status Scale (EDSS) score, but no significant longitudinal correlation was demonstrated. The number of enhancing lesions on the entry scan was predictive of subsequent relapse rate over the study duration and also correlated with the subsequent enhancing lesion activity over the study period. A significant correlation was found between change in lesion load and disease activity on the monthly scans. Our results suggest that annual lesion load quantification provides an efficient measure of ongoing disease activity, and this supports its application as a surrogate marker of disease evolution in phase III treatment trials.     

Modelling new enhancing MRI lesion counts in multiple sclerosis.

Magnetic resonance imaging (MRI) has been established as the most relevant paraclinical tool for diagnosing and monitoring multiple sclerosis (MS). In this context, counting the number of new enhancing lesions on monthly MRI scans is widely used as a surrogate marker of MS activity when evaluating the effect of treatments. In this study, we investigated whether parametric models based on mixed Poisson distributions (the Negative Binomial (NB) and the Poisson-Inverse Gaussian (P-IG) distributions) were able to provide adequate fitting of new enhancing lesion counts in MS. We found that the NB model gave good approximations in relapsing-remitting and secondary progressive MS patients not selected for baseline MRI activity, whereas the P-IG distribution modelled better new enhancing lesion counts in relapsing-remitting MS patients selected for baseline activity. This study shows that parametric modelling for MS new enhancing lesion counts is feasible. This approach should provide more targeted tools for the design and the analysis of MRI monitored clinical trials in MS.     

Early intervention with immunomodulatory agents in the treatment of multiple sclerosis

Multiple sclerosis (MS) is a lifelong neurologic disease leading to moderate or severe disability in the majority of affected patients. Studies of the natural history of MS suggest that 90% of patients with relapsing-remitting MS eventually develop secondary progressive (SP) disease. Magnetic resonance imaging (MRI) studies have consistently shown a high frequency of new T2 lesions and new gadolinium enhancing lesions even in the absence of clinical relapse. Lesion burden on T2 MRI increases by 5% to 10% per year and both axonal transection and cerebral atrophy are present at the earliest stages of RR MS. A wealth of evidence suggests that MS is a disease process that is continuously active, and that irreversible damage occurs early in the disease. Despite knowledge of the natural history and the availability of treatments that reduce relapse rates, decrease the accumulation of disability, and decrease surrogate measures of disease activity, only 60% of eligible patients have been treated with immunomodulating agents. This paper reviews the available evidence suggesting that immunomodulatory therapy modifies the natural history of MS and presents an argument for early intervention in the treatment of MS.     

Magnetic resonance imaging metrics and their correlation with clinical outcomes in multiple sclerosis: a review of the literature and future perspectives

Magnetic resonance imaging (MRI) has revolutionized the diagnosis and management of patients with multiple sclerosis (MS). Conventional MRI metrics are employed as primary endpoints in proof-of-concept clinical trials evaluating new drugs for MS and as secondary endpoints in definitive phase III trials. Metrics derived from non-conventional MRI techniques are now emerging and hold significant promise since they appear to be more correlated with the most disabling features of MS. However, none of these has been approved for use as a surrogate endpoint for accumulation of physical disability, which is the most important clinical endpoint of this disease. Taking into account the large numbers of patients needed, the extensive exposure to placebo, and the relatively long duration required for phase III clinical trials to show a meaningful effect on progression of disability, the need for a valid, reliable, and objective paraclinical marker of disease evolution cannot be overemphasized. This paper reviews the most up-to-date data regarding MRI techniques, their relationship with central nervous system pathology, as well as with clinical endpoints, and proposes future insights into the use of MRI metrics as surrogate endpoints in clinical trials of MS.     

Magnetic resonance imaging as surrogate for clinical endpoints in multiple sclerosis: data on novel oral drugs

Recent studies have provided evidence for using magnetic resonance imaging (MRI) active lesions as surrogate for relapses and disability progression in multiple sclerosis (MS). However, the validity of MRI metrics as surrogate endpoints in MS is controversial. Furthermore, the extrapolation of previous results to novel therapies is not warranted. We tested here the validity of MRI surrogacy in MS studies on recently published trials of oral drugs. The 92% of observed effects of oral drugs on clinical outcomes resulted close to those predicted by MRI active lesions. This further validates MRI surrogacy in MS, with important implications for future trials planning.     

Assessing treatment effects on axonal loss--evidence from MRI monitored clinical trials

Magnetic resonance imaging (MRI) is a collection of very sensitive and versatile techniques for detecting multiple sclerosis (MS) related damage in the central nervous system. Each technique is characterised by a particular combination of sensitivity, tissue and pathological specificity, and technical requirements that enable diverse aspects of MS to be explored.MRI techniques also offer the possibility of quantitatively assessing the effects of therapeutic interventions, and to correlate these effects to clinical outcomes. Of special interest are newer MR techniques that correlate more strongly with disability than gadolinium-enhancement and T2 lesion load, and this review focuses on T1 hypointense lesions, MR spectroscopy, and brain atrophy as surrogate markers of axonal loss, and their application in randomised clinical trials. Several disease-modifying therapies appear to have differential effects on inflammation, demyelination and axonal loss as judged by MRI, illustrating the unique capability of MRI to interrogate the pathophysiology of MS. At the same time it illustrates the difficulties in understanding the mechanisms leading to axonal loss and persistent clinical deficit.     

MRI techniques to monitor MS evolution: the present and the future

Conventional MRI (cMRI) is limited in its ability to provide specific information about pathology in MS. Measures commonly derived from cMRI include T2 lesions, T1-enhanced lesions, atrophy, and possibly T1-hypointense lesions, which have been extensively investigated in many clinical trials. Better MRI measures are needed to advance our understanding of MS and design ideal clinical trials. This article reviews the strengths and weaknesses of the major MRI-based methods used to monitor MS evolution and submits that 1) metrics derived from magnetization transfer MRI, diffusion-weighted MRI, and proton MRS should be implemented to achieve reliable specific in vivo quantification of MS pathology; 2) targeted multiparametric MRI protocols rather than generic application of cMRI should be used in all possible clinical circumstances and trials; and 3) reproducible quantitative MR measures should ideally be used for the assessment of patients but are essential for clinical trials.