Multiple Sclerosis Clinical Trials Research Articles

Hypointense and Hyperintense Lesions on Magnetic Resonance Imaging in Secondary-Progressive MS Patients

Cranial magnetic resonance imaging (MRI) is widely used to monitor disease activity in clinical trials in multiple sclerosis (MS). The purpose of this study is to examine lesion burden as determined from hypointense regions on postcontrast T1-weighted scans (or black holes), and lesion burden on conventional T2-weighted scans, from a cohort of secondary progressive MS patients who participated in a placebo-controlled, randomized, double-blind cross-over trial assessing the therapeutic efficacy of cladribine. T2 lesion volumes and black hole volumes are approximately normal distributed when log-transformed, and are highly correlated (adjusted R² = 0.63). Changes in clinical scores could be predicted with a reasonable degree of precision from baseline scores and changes in T2 lesion volumes (adjusted R² values 0.52–0.7). Stratification schemes for clinical trials should include the acute proportion of the disease (enhancing T1 lesions), degree of permanent damage (black holes), and T2 lesion volume.

Statistical power of MRI monitored trials in multiple sclerosis: new data and comparison with previous results

OBJECTIVESTo evaluate the durations of the follow up and the reference population sizes needed to achieve optimal and stable statistical powers for two period cross over and parallel group design...

Oral tolerance in the treatment of inflammatory autoimmune diseases.

Oral tolerance refers to the oral administration of protein antigens, which induces a state of systemic nonresponsiveness specific for the fed antigen. This method of inducing immune non-responsiveness has been applied to the prevention and treatment of experimental animal models of autoimmune disease. Extensive research in this area over the past ten years has led to the conclusion that two mechanisms are operative in the mediation of oral tolerance--active suppression and clonal anergy/deletion. A number of factors have been identified that determine which mechanism of tolerance is operative--antigen dose, antigen form, and the timing of antigen administration. Work from these animal models has recently been extended into human clinical trials of multiple sclerosis, rheumatoid arthritis, diabetes, uveitis, and allergy, with differing degrees of success. In this review, a discussion is provided of the animal model systems where oral tolerance has been applied and the clinical trials where an oral tolerization approach has been attempted. Moreover, recent mechanistic studies are reviewed and a model proposed for the induction of oral tolerance.

The psychometric properties of clinical rating scales used in multiple sclerosis.

OullII;l y Many clinical rating scales have been proposed to assess the impact of multiple sclerosis on patients, but only few have been evaluated formally for reliability, validity and responsiveness. We assessed the psychometric properties of five commonly used scales in multiple sclerosis, the Expanded Disability Status Scale (EDSS), the Scripps Neurological Rating Scale (SNRS), the Functional Independence Measure (FIM), the Ambulation Index (AI) and the Cambridge Multiple Sclerosis Basic Score (CAMBS). The score frequency distributions of all five scales were either bimodal (EDSS and AI) or severely skewed (SNRS, FIM and CAMBS). The reliability of each scale depended on the definition of 'agreement'. Inter-and intra-rater reliabilities were high when 'agreement' was considered to exist despite a difference of up to 1.0 EDSS point (two 0.5 steps), 13 SNRS points, 9 FIM points, 1 AI point and 1 point on the various CAMBS domains. The FIM, AI, and the relapse and progression domains of the CAMBS were sensitive to clinical change, but the EDSS and the SNRS were unresponsive. The validity of these scales as impairment (SNRS and EDSS) and disability (EDSS, FIM, AI and the disability domain of the CAMBS) measures was established. All scales correlated closely with other measures of handicap and quality of life. None of these scales satisfied the psychometric requirements of outcome measures completely, but each had some desirable properties. The SNRS and the EDSS were reliable and valid measures of impairment and disability, but they were unresponsive. The FIM was a reliable, valid and responsive measure of disability, but it is cumbersome to administer and has a limited content validity. The AI was a reliable and valid ambulation-related disability scale, but it was weakly responsive. The CAMBS was a reliable (all four domains) and responsive (relapse and progression domains) outcome measure, but had a limited validity (handicap domain). These psychometric properties should be considered when designing further clinical trials in multiple sclerosis.

Evoked potentials in clinical trials for multiple sclerosis.

Multiple sclerosis produces disruption of conduction in the central nervous system by a variety of mechanisms, relating, in part, to loss of the myelin sheath. Although often not well correlated with the clinical course of the disease in individual patients, the resulting evoked potential (EP) disturbances can serve as measures of an accumulating disease burden, particularly in longitudinal population studies. Accordingly, EPs can serve as useful instruments for assessing the effectiveness of therapeutic agents which may alter the course of the multiple sclerosis. Furthermore, since EPs measure conduction within the central nervous system, they provide a means of directly assessing symptomatic treatments designed to improve central conduction.

Very late antigen 4 (VLA4) antagonists as anti-inflammatory agents

In recent years antagonists of very late antigen-4 (VLA4, also known as integrin α4β1) have shown great promise in treating inflammatory disorders in a number of animal models. The most advanced in this endeavor is a humanized anti-α4 antibody, Antegren (®), which is in phase II clinical trials for multiple sclerosis. The first reported small-molecule VLA4 antagonist to advance into clinical trials is currently in phase I as an aerosol for treating asthma. A number of peptides, cyclic peptides and peptidomimetics have been disclosed and are in preliminary stages of development.

Statistical methods for evaluating multiple sclerosis therapies.

This article will discuss basic concepts and simple but commonly used methods of statistical analysis which are relevant to the evaluation of the results of randomized controlled clinical trials in multiple sclerosis. The focus throughout will be on an expository discussion to facilitate understanding of the logic, objectives and implementation of these methods. The context for most of the discussion is that of a two-armed clinical trial, involving a placebo and an active treatment arm. Clinical trials are carried out to allow conclusions concerning the efficacy and effectiveness of therapies, so the discussion will focus on aspects of inferential statistics. Simple methods for continuous and count responses, as well some specifically developed for use with categorical and time-to-event data are discussed. A very brief discussion of some of the more sophisticated methods that are often essential for a comprehensive analysis of the data collected in a clinical trial is also provided.

Multiple sclerosis clinical trials: old and new challenges.

The demonstration that several agents with presumed differing mechanisms of action each provide partial effectiveness in the treatment of relapsing-remitting multiple sclerosis (MS) has significantly changed the approach to MS clinical trial research. A number of recently published trials have provided support to these pivotal reports that the short-term course of MS may be favorably influenced by one of a number of treatments. More phase III trials with these and other agents will be completed shortly. Several promising agents have recently been found to be either of no benefit or too toxic for widespread use, whereas several unconfirmed "positive" trials have contributed to a sense of guarded optimism. Important revisions to conventional MS trial methodology are evolving. Additional revisions are needed, however, to expedite the identification of agents that are likely to merit further study and to remove useless or toxic agents from the growing list of potential candidate treatments. These research trends and suggestions for future methodological revisions in the approach to this aspect of MS clinical research are reviewed here.

Tolerance induction to myelin basic protein by intravenous synthetic peptides containing epitope P85VVHFFKNIVTP96 in chronic progressive multiple sclerosis

Peptide-based tolerance induction may be useful for antigen-specific immunotherapy of human autoimmune diseases. Induction of tolerance to myelin basic protein (MBP) was examined in a Phase I clinical trial in multiple sclerosis (MS) patients with chronic progressive disease using a peptide that is immunodominant for MBP specific T cells and B cells. Tolerance induction was monitored by quantification of MBP specific autoantibodies in cerebrospinal fluid (CSF). The route of peptide administration was important since only intravenous but not intrathecal or subcutaneous injection induced tolerance to MBP. Following a single intravenous injection of a peptide containing epitope P85VVHFFKNIVTP96, MBP autoantibodies were undetectable for three to four months. Tolerance was more prolonged following a second injection since autoantibodies were low or undetectable after one year in the majority of patients. Duration of tolerance to MBP depended on MHC class II haplotypes of patients; tolerance was long-lived in all patients with disease associated HLA-DR2. No neurological or systemic side effects were observed, regardless of the route of peptide administration. These data demonstrate that intravenous administration of a soluble peptide can result in long-lasting tolerance to an autoantigen in humans.

Clinical Outcome Measures and Rating Scales in Multiple Sclerosis Trials

In this review, we analyzed clinical outcome measures used in multiple sclerosis (MS) clinical trials in which the primary goal is to slow or arrest progression of disease. In addition, we examined rating scales that quantify symptomatic complications of MS (for example, spasticity) and the current role of magnetic resonance imaging in MS treatment trials. Each proposed scale has advantages and deficiencies, and none meets all the criteria for an ideal outcome measure. The validity of trial design may be improved by using combinations of selected components of current scales as well as new instruments targeted to specific variables (such as motor strength). Symptom-specific rating scales are most appropriately used in trials of symptomatic therapeutic strategies for MS. Until serial magnetic resonance imaging changes are definitely known to predict long-term impairment and disability in patients with MS, clinical outcome measures will remain the primary means of assessing therapeutic efficacy in phase III clinical trials.

Doctors and patients don't agree: cross sectional study of patients' and doctors' perceptions and assessments of disability in multiple sclerosis

Objectives: To compare the judgments of clinicians on which domains of health in the short form questionnaire (SF-36) would be most important to patients with multiple sclerosis with the opinions...

The role of MRI in clinical trials of multiple sclerosis: comparison of image processing techniques.

Magnetic resonance imaging (MRI) has received considerable attention in recent years over its potential for providing indices of multiple sclerosis activity and progression in clinical trials of new pharmaceuticals. The perceived advantages of MRI-derived measurements include greater objectivity, sensitivity, and reproducibility when compared with clinical rating scales. Clinical scales are also somewhat biased toward lesions affecting locomotion. However, the myriad permutations of MRI acquisition parameters, analysis methodologies, and disease indices demand careful consideration when employing MRI. Moreover, the use of MRI in research into the basic mechanisms of a disease may have different requirements than its use in a clinical trial setting. Consequently, a conference was held, sponsored by the US and Canadian multiple sclerosis societies, to review the present status of various MRI processing strategies and their potential role in clinical trials. Thirteen laboratories from North America and Europe as well as regulatory agencies and statistical consultants made formal presentations followed by extended discussion. This report presents the conclusions reached and recommendations for further action that emerged from the meeting.

Longitudinal analyses for magnetic resonance imaging outcomes in multiple sclerosis clinical trials

A basic feature of many clinical trials is the collection of longitudinal data on individual patients. Analysis of such data is often based on summaries over time. This allows use of standard methods to assess treatment effects but sacrifices information on patterns over time as well as potential greater efficiency of analysis. The purpose of this paper is to illustrate the utility of the generalized estimating equations (GEE) approach to the analysis of longitudinal binary count, and continuous responses for the frequent magnetic resonance imaging (MRI) substudy of the 3-year pivotal trial of interferon beta-1b in relapsing-remitting multiple sclerosis.

Clinical outcomes assessment in multiple sclerosis

This article represents initial deliberation of an international task force appointed by the US National Multiple Sclerosis Society to develop recommendations for optimal clinical assessment tools for multiple sclerosis clinical trials. Presented within this article are the key issues identified by the task force during its initial year of deliberation. These include the precise purpose for a clinical assessment tool, the clinical dimensions to be measured in a multidimensional outcome measure, desirable attributes of an optimal clinical outcome measure, the complexities of multidimensional outcome measures, the relative merits of categorical clinical ratings and quantitative functional assessments, and a number of other important design issues that relate to the use of a multidimensional outcome measure. An action plan for analysis of existing data is summarized, as are the plans for more detailed recommendations from the task force.

Outcomes assessment of drug treatment in multiple sclerosis clinical trials.

The purpose of this review is to evaluate the clinical outcomes of drug therapy in the treatment of multiple sclerosis (MS) in those studies which purported to include an assessment of quality of life. Pharmacological management of MS is primarily directed towards control of symptoms and prevention of disease progression or relapse. Although there are many drug and nondrug approaches used in the treatment of MS, this review focuses largely on approaches that incorporate some method of clinical outcome assessment. To aid in the interpretation of the data presented, a short descriptive summary of these assessment methods has been included. Although most studies incorporate at least one clinical outcome measure into the evaluation of efficacy, only one study has examined the economic impact of intervention in MS. The authors of that study demonstrated good correlation between the level of disability assessed using conventional quality-of-life measures and associated healthcare costs. Surprisingly, although many treatment approaches used in MS have significant associated toxicity and only modest benefits in terms of disease control, there is a remarkable paucity of data on the impact of these treatments on patients' quality of life. Studies that incorporate pharmacoeconomic and health-related quality-of-life consequences related to the treatment of MS are required.

Guidelines for the use of magnetic resonance techniques in monitoring the treatment of multiple sclerosis

Because of the major difficulties in measuring clinical end points in multiple sclerosis (MS) treatment trials, there has been much enthusiasm for using magnetic resonance imaging (MRI) findings as an alternative outcome. To provide international consensus guidelines for the use of MRI in MS clinical trials, a task force of the US National MS Society was convened. The recommendations of the task force are presented in this review. Given the high sensitivity for detecting pathological activity in relapsing-remitting and secondary progressive MS, monthly T2-weighted and gadolinium-enhanced brain MRI is an excellent tool for short-term exploratory trials of new agents where it serves as the primary end point; in particular, failure to demonstrate a reduction in lesion activity avoids the time, cost, and risks of a larger clinical end point study. However, conventional MRI findings have a limited correlation with disability in established MS. The primary end point of a definitive trial should therefore be clinical, although serial MRI at 6- to 12-month intervals is a useful secondary end point in providing an index of pathological progression. In trials of patients presenting with clinically isolated syndromes suggestive of MS, MRI findings can be used in the entry criteria, and as a secondary outcome measure, but conversion to clinically definite MS should be the primary outcome. The pathological substrates of irreversible disability are demyelination and axonal loss. Putative magnetic resonance markers for these processes include decreased N-acetylaspartate on proton magnetic resonance spectroscopy, decreased magnetization transfer ratios, hypointensity on T1-weighted images, and loss of short T2 water fractions, some of which relate more closely to disability than conventional MRI findings. Further technical developments should lead to more accurate quantitation, greater pathological specificity, and stronger clinical correlations.

Exquisite peptide specificity of oral tolerance in experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE), induced in Lewis rats by injection of myelin basic protein (MBP) and adjuvant, is a T cell-mediated autoimmune disease. Earlier studies from our laboratory have shown that oral administration of guinea pig MBP before encephalitogenic challenge induces T cell anergy and results in the suppression of clinical signs and CNS histopathologic changes of EAE. In contrast, oral administration of rat MBP did not confer a similar degree of protection. This study was undertaken to determine the tolerogenicity of the synthetic peptide 68-88 derived from guinea pig (GP) MBP and rat MBP. These peptides differ by a single amino acid at position 80. Lewis rats fed GP 68-88 were protected from EAE induced with GP 68-88 or rat 68-88. In contrast, feeding rats 68-88 did not protect the animals from challenge with either peptide. Measurement of the frequency of peptide-reactive Th1 cells showed results consistent with the clinical picture. The in vitro proliferative response was significantly suppressed following oral administration of either whole GP MBP, the GP peptide, or the rat peptide, irrespective of clinical status. These results extend our earlier observation at the whole molecule level that GP but not rat MBP confers oral tolerance. These findings suggest that small structural differences at the amino acid level can produce dramatic differences in clinical outcome, with important implications for the design of multiple sclerosis clinical trials.

The treatment of multiple sclerosis

During the past year observations have been published that might lead to further improvement in the design of future clinical trials. At the same time, results of clinical trials have become available that suggest that a number of treatments could be of benefit in the care of patients in the various phases of multiple sclerosis. Future multiple sclerosis clinical trials should involve a blinded investigator restricted to assessing the clinical outcome variables, and because current evidence suggests that magnetic resonance imaging gives an objective and sensitive reflection of the biological evolution of the disease, such scanning should also be included. The use of a composite outcome variable in a trial of chronic progressive multiple sclerosis should also be considered in order to increase the percentage of patients reaching the clinical endpoint. In 1994 recommendations were published for the selection of relapsing-remitting patients for treatment with interferon beta-1b; furthermore, large and well performed clinical trials demonstrated that interferon beta-1a and copolymer-1 are also partially effective, though not curative, for these patients. Two smaller studies suggested that low-dose methotrexate and cladribine might have a beneficial effect on the course of the disease in patients with secondary chronic progressive multiple sclerosis, the former drug probably being less toxic. Unfortunately, therapeutic perspectives for patients with primary progressive multiple sclerosis are less promising at present. Several studies suggest that 4-aminopyridine and tizanidine have therapeutic potential for symptomatic treatment; the former by improving neurological deficits, the latter by relieving troublesome spasticity.(ABSTRACT TRUNCATED AT 250 WORDS)

Outcomes assessment in multiple sclerosis clinical trials: a critical analysis.

The feasibility and precision of clinical trials for the treatment of MS must be improved. Subsequent to the approval by the Food and Drug Administration of the United States of interferon beta-Ib as a safe and effective, though not curative, treatment for relapsing-remitting MS, the testing of other agents in this disease has been undertaken or is anticipated. This report summarises the discussions and recommendations of an international workshop held to review critically the elements of current MS therapeutic trials and to identify the most important aspects of clinical evaluation, study design and data analysis that would allow agents for MS to be tested as accurately, rapidly and economically as possible. While acknowledging the many uncertainties about the pathophysiology and natural history of MS, the workshop participants made recommendations about the preferred components to be used in the design of trials which may be different depending on the treatment goal and agent studied. It was concluded that the formulation of a useful clinical trial design must be based on specific guidelines for clinical scales and imaging for which task forces were recommended and subsequently appointed.

Magnetic resonance imaging in the evaluation of clinical trials in multiple sclerosis.

Magnetic resonance imaging (MRI) provides an objective method of evaluating multiple sclerosis clinical trials and is at least five times more sensitive to disease activity. In a recent clinical trial, MRI was also approximately twice as sensitive as clinical measurements to the treatment effect of a drug.