Randomized controlled trial of atorvastatin in clinically isolated syndrome: the STAyCIS study.

OBJECTIVE: To test efficacy and safety of atorvastatin in subjects with clinically isolated syndrome (CIS). METHODS: Subjects with CIS were enrolled in a phase II, double-blind, placebo-controlled, 14-center randomized trial testing 80 mg atorvastatin on clinical and brain MRI activity. Brain MRIs were performed quarterly. The primary endpoint (PEP) was development of ≥ 3 new T2 lesions, or one clinical relapse within 12 months. Subjects meeting the PEP were offered additional weekly interferon ß-1a (IFNß-1a). RESULTS: Due to slow recruitment, enrollment was discontinued after 81 of 152 planned subjects with CIS were randomized and initiated study drug. Median (interquartile range) numbers of T2 and gadolinium-enhancing (Gd) lesions were 15.0 (22.0) and 0.0 (0.0) at baseline. A total of 53.1% of atorvastatin recipients (n = 26/49) met PEP compared to 56.3% of placebo recipients (n = 18/32) (p = 0.82). Eleven atorvastatin subjects (22.4%) and 7 placebo subjects (21.9%) met the PEP by clinical criteria. Proportion of subjects who did not develop new T2 lesions up to month 12 or to starting IFNß-1a was 55.3% in the atorvastatin and 27.6% in the placebo group (p = 0.03). Likelihood of remaining free of new T2 lesions was significantly greater in the atorvastatin group compared with placebo (odds ratio [OR] = 4.34, p = 0.01). Likelihood of remaining free of Gd lesions tended to be higher in the atorvastatin group (OR = 2.72, p = 0.11). Overall, atorvastatin was well tolerated. No clear antagonistic effect of atorvastatin plus IFNß-1a was observed on MRI measures. CONCLUSION: Atorvastatin treatment significantly decreased development of new brain MRI T2 lesion activity, although it did not achieve the composite clinical and imaging PEP. CLASSIFICATION OF EVIDENCE: This study provided Class II evidence that atorvastatin did not reduce the proportion of patients with CIS meeting imaging and clinical criteria for starting immunomodulating therapy after 12 months, compared to placebo. In an analysis of a secondary endpoint (Class III), atorvastatin was associated with a reduced risk for developing new T2 lesions.

Cost-effectiveness of disease-modifying therapy for multiple sclerosis: a population-based study.

OBJECTIVE: To evaluate the cost-effectiveness of disease-modifying therapies (DMTs) in the United States compared to basic supportive therapy without DMT for patients with relapsing multiple sclerosis (MS). METHODS: Using data from a longitudinal MS survey, we generated 10-year disease progression paths for an MS cohort. We used first-order annual Markov models to estimate transitional probabilities. Costs associated with losses of employment were obtained from the Bureau of Labor Statistics. Medical costs were estimated using the Centers for Medicare and Medicaid Services reimbursement rates and other sources. Outcomes were measured as gains in quality-adjusted life-years (QALY) and relapse-free years. Monte Carlo simulations, resampling methods, and sensitivity analyses were conducted to evaluate model uncertainty. RESULTS: Using DMT for 10 years resulted in modest health gains for all DMTs compared to treatment without DMT (0.082 QALY or <1 quality-adjusted month gain for glatiramer acetate, and 0.126-0.192 QALY gain for interferons). The cost-effectiveness of all DMTs far exceeded $800,000/QALY. Reducing the cost of DMTs had by far the greatest impact on the cost-effectiveness of these treatments (e.g., cost reduction by 67% would improve the probability of Avonex being cost-effective at $164,000/QALY to 50%). Compared to treating patients with all levels of disease, starting DMT earlier was associated with a lower (more favorable) incremental cost-effectiveness ratio compared to initiating treatment at any disease state. CONCLUSION: Use of DMT in MS results in health gains that come at a very high cost.

Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis.

OBJECTIVES: The goal of this study was to determine if memory would be improved by donepezil as compared to placebo in a multicenter, double-blind, randomized clinical trial (RCT). METHODS: Donepezil 10 mg daily was compared to placebo to treat memory impairment. Eligibility criteria included the following: age 18-59 years, clinically definite multiple sclerosis (MS), and performance ≤ ½ SD below published norms on the Rey Auditory Verbal Learning Test (RAVLT). Neuropsychological assessments were performed at baseline and 24 weeks. Primary outcomes were change on the Selective Reminding Test (SRT) of verbal memory and the participant's impression of memory change. Secondary outcomes included changes on other neuropsychological tests and the evaluating clinician's impression of memory change. RESULTS: A total of 120 participants were enrolled and randomized to either donepezil or placebo. No significant treatment effects were found between groups on either primary outcome of memory or any secondary cognitive outcomes. A trend was noted for the clinician's impression of memory change in favor of donepezil (37.7%) vs placebo (23.7%) (p = 0.097). No serious or unanticipated adverse events attributed to study medication developed. CONCLUSIONS: Donepezil did not improve memory as compared to placebo on either of the primary outcomes in this study. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence which does not support the hypothesis that 10 mg of donepezil daily for 24 weeks is superior to placebo in improving cognition as measured by the SRT in people with MS whose baseline RAVLT score was 0.5 SD or more below average.

Assessing disability progression with the Multiple Sclerosis Functional Composite.

BACKGROUND: The initial Multiple Sclerosis Functional Composite (MSFC) proposal was a three-part composite of quantitative measures of ambulation, upper extremity function, and cognitive function expressed as a single composite Z-score. However, the clinical meaning of an MSFC Z-score change is not obvious. This study instead used MSFC component data to define a patient-specific disease progression event. OBJECTIVE: Evaluate a new method for analyzing disability progression using the MSFC. METHODS: MSFC progression was defined as worsening from baseline on scores of at least one MSFC component by 20% (MSFC Progression-20) or 15% (MSFC Progression-15), sustained for >or=3 months. Progression rates were determined using data from natalizumab clinical studies (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] and Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis [SENTINEL]). Correlations between MSFC progression and other clinical measures were determined, as was sensitivity to treatment effects. RESULTS: Substantial numbers of patients met MSFC progression criteria, with MSFC Progression-15 being more sensitive than MSFC Progression-20, at both 1 and 2 years. MSFC Progression-20 and MSFC Progression-15 were related significantly to Expanded Disability Status Scale (EDSS) score change, relapse rate, and the SF-36 Physical Component Summary (PCS) score change. MSFC Progression-20 and MSFC Progression-15 at 1 year were predictive of EDSS progression at 2 years. Both MSFC progression end points demonstrated treatment effects in AFFIRM, and results were replicated in SENTINEL. CONCLUSION: MSFC Progression-20 and MSFC Progression-15 are sensitive measures of disability progression; correlate with EDSS, relapse rates, and SF-36 PCS; and are capable of demonstrating therapeutic effects in randomized, controlled clinical studies.

Proof of concept studies for tissue-protective agents in multiple sclerosis.

BACKGROUND: There is considerable interest in tissue-protective treatments for multiple sclerosis (MS). METHODS AND OBJECTIVES: We convened a group of MS clinical trialists and related researchers to discuss designs for proof of concept studies utilizing currently available data and assessment methods. RESULTS: Our favored design was a randomized, double-blind, parallel-group study of active treatment versus placebo focusing on changes in brain volume from a post-baseline scan (3-6 months after starting treatment) to the final visit 1 year later. Study designs aimed at reducing residual deficits following acute exacerbations are less straightforward, depending greatly on the anticipated rapidity of treatment effect onset. CONCLUSIONS: The next step would be to perform one or more studies of potential tissue-protective agents with these designs in mind, creating the longitudinal data necessary to refine endpoint selection, eligibility criteria, and sample size estimates for future trials.

Dose comparison trial of sustained-release fampridine in multiple sclerosis.

OBJECTIVE: To examine the efficacy and safety of three different doses of sustained-release fampridine in people with multiple sclerosis (MS). METHOD: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study recruited 206 participants at 24 centers in the United States and Canada. After a single-blind, 2-week placebo run-in, participants were randomly assigned to receive fampridine (10, 15, or 20 mg twice daily) or placebo for 15 weeks. The primary efficacy variable was percent change in walking speed based on the timed 25-foot walk. RESULTS: Trends for increased walking speed were consistent across dose groups vs placebo, but not significant, on the prospective analysis. An increase from baseline in lower extremity strength during the 12-week stable-dose period was seen in the groups receiving 10- and 15-mg doses, compared with placebo (p = 0.018 and 0.003). There were no significant changes in other secondary assessments. Post hoc analysis revealed subsets of participants in each dose group with walking speeds during the treatment period that were consistently faster than during the nontreatment period. There were significantly more "consistent responders" in the drug-treated groups than in the placebo group (36.7% compared with 8.5%). Consistent responders showed significantly greater improvement in self-assessed ambulation on the 12-Item MS Walking Scale than did nonresponders. Fampridine was generally well tolerated. Severe and serious adverse events were more frequent at the highest dose. CONCLUSIONS: This phase 2 study suggests that a subgroup of patients, when treated with fampridine, experiences a clinically relevant improvement in walking ability, which is sustained for at least 14 weeks.

Quantitative risk-benefit analysis of natalizumab.

OBJECTIVE: To model the long-term risks and benefits of natalizumab in individuals with relapsing multiple sclerosis (MS). METHODS: We created a Markov model to evaluate treatment effects on reducing relapses and slowing disease progression using published natural history data and clinical trial results. Health changes, measured in quality-adjusted life-years (QALYs), were based on patient health preferences. Patient cohorts treated with no disease-modifying treatment, natalizumab, subcutaneous interferon beta-1a, and a theoretical "perfect" MS treatment were modeled. Sensitivity analysis was used to explore model uncertainty, including varying risks of developing progressive multifocal leukoencephalopathy (PML). RESULTS: Treatment with natalizumab resulted in 9.50 QALYs over a 20-year time horizon, a gain of 0.80 QALYs over the untreated cohort and 0.38 QALYs over interferon beta-1a. The health loss due to PML was small (-0.06 QALYs). To offset natalizumab's incremental health gain over interferon beta-1a, the risk had to increase from 1 to 7.6 PML per 1,000 patients treated over 17.9 months. The "perfect" MS treatment accumulated 10.59 QALYs over the 20-year time horizon, 1.89 QALYs above the untreated cohort. Interferon beta-1a resulted in greater QALY gains compared with natalizumab if natalizumab's relative relapse reduction was reduced from 68% to 35% or if interferon beta-1a's relative reduction was increased from 32% to 65%. CONCLUSIONS: A more than sevenfold increase in actual risk of progressive multifocal leukoencephalopathy was required to decrease natalizumab's health gain below that of interferon beta-1a, and there remains considerable room for additional gains in health (>50%) beyond those already achieved with current therapies.

Ethics of placebo-controlled clinical trials in multiple sclerosis: a reassessment.

The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.

Quantifying the risks and benefits of natalizumab in relapsing multiple sclerosis.

Using published data, we quantified the risk and benefits of natalizumab in relapsing multiple sclerosis using quality-adjusted life years (QALYs) as a metric. Over the first 2 years of therapy, the negative health effects from progressive multifocal leukoencephalopathy were small (loss of 0.001 QALYs) relative to the positive effects on relapses and disability resulting in 0.033 QALYs (12 quality-adjusted days) gained. For context, we performed an analogous calculation for interferon beta-1a, which also had a net health benefit of 0.033 QALYs (12 quality-adjusted days).

MRI features of pediatric multiple sclerosis.

BACKGROUND: MRI has revolutionized the diagnostic accuracy of multiple sclerosis (MS) in adults, and is now used extensively to evaluate efficacy of immunomodulatory therapies. Although MRI has also been used to aid in the diagnosis and care of children with MS, the MRI features of MS in children are less well understood. METHODS: The present review summarizes the available literature on MRI in pediatric MS, outlines the specific features of other disorders affecting the CNS white matter in children, compares the MRI appearance of MS in children to seminal neuroimaging studies in adult-onset MS, and discusses the potential role of advanced MRI technologies in delineating the underlying pathobiology of acquired demyelinating disease in children. RESULTS: Although the MRI features of MS in children have similarity to adult-onset MS, children tend to have fewer lesions and a lower propensity for lesions to enhance with gadolinium. The MRI findings in children presenting with a clinical phenotype of acute disseminated encephalomyelitis may be indistinguishable from the first attack of MS. CONCLUSIONS: MRI criteria specific for pediatric-onset multiple sclerosis (MS) and criteria predictive of MS outcome in children experiencing a first demyelinating event will be challenged by the overlap in MRI features between acute monophasic demyelinating syndromes and MS, particularly in younger children. Emergence of new clinically silent lesions on MRI scans separated by at least 3 months is characteristic of MS. Newer MRI techniques evaluating white matter biochemistry and integrity in the youngest MS patients may provide new insights into the relative contributions of inflammation and neurodegeneration in MS.

Rasagiline-associated motor improvement in PD occurs without worsening of cognitive and behavioral symptoms.

BACKGROUND: Cognitive and behavioral adverse events (AEs) such as hallucinations, confusion, depression, somnolence and other sleep disorders commonly limit effective management of motor symptoms in PD. Rasagiline (N-propargyl-1(R)-aminoindan) mesylate is a novel, second-generation, selective, irreversible monoamine oxidase type B inhibitor, demonstrated in monotherapy and adjunctive trials to be effective for PD with excellent tolerability. METHODS: The occurrence of cognitive and behavioral AEs and the change from baseline in the Unified Parkinson's Disease Rating Scale (UPDRS) part I mental subscores were reviewed in two multicenter, randomized, placebo-controlled, 26-week trials of rasagiline for early and moderate-to-advanced patients with PD. The UPDRS is a multi-item rating scale specific to PD; part I rates the patient's intellectual impairment, thought disorders, depression and motivation/initiative. RESULTS: The TEMPO study evaluated rasagiline monotherapy in early PD patients (n=404). The PRESTO study evaluated rasagiline as adjunctive therapy in moderate-to-advanced PD patients with motor complications who were receiving optimized levodopa/carbidopa (n=472). In the analysis of adverse event reporting for both studies, no cognitive and behavioral AE in either the rasagiline 1 mg or placebo groups exceeded 10% of the study population and the frequency differences between rasagiline 1 mg and placebo never exceeded 3%. There was no adverse effect on the UPDRS mental subscore relative to placebo in either of the two studies. CONCLUSION: Rasagiline 1 mg once daily improves PD symptoms and motor fluctuations in early and moderate-to-advanced PD patients without causing significant cognitive and behavioral AE or adverse changes in mentation, behavior and mood.

Safety of rasagiline in elderly patients with Parkinson disease.

The authors examined age effects on adverse events from two randomized, controlled trials of rasagiline, comparing younger (younger than 70 years) and older (70 years and older) subjects. Older patients were more prone to serious adverse effects than younger patients, but there was no statistical interaction between age and rasagiline exposure. This absence of an age-rasagiline interaction suggests that rasagiline does not require special safety precautions for elderly subjects with Parkinson disease.

Multiple sclerosis characteristics in African American patients in the New York State Multiple Sclerosis Consortium.

The objective of this study was to determine the clinical characteristics of multiple sclerosis (MS) in African American (AA) patients in the New York State Multiple Sclerosis Consortium (NYSMSC) patient registry. The NYSMSC is a group of 18 MS centers throughout New York State organized to prospectively assess clinical characteristics of MS patients. AAs comprise 6% (329) of the total NYSMSC registrants (5602). Demographics, disease course, therapy, and socioeconomic status were compared in AA registrants versus nonAfrican Americans (NAA). There was an increased female preponderance and a significantly younger age at diagnosis in the AA group. AA patients were more likely to have greater disability with increased disease duration. No differences were seen in types of MS and use of disease modifying therapies. Our findings suggest a racial influence in MS. Further genetic studies that consider race differences are warranted to elucidate mechanisms of disease susceptibility.

Quantitative functional measures in MS: what is a reliable change?

As a first step toward understanding which changes should be considered as meaningful, the authors assessed the reliability of quantitative functional tests on 5 consecutive days in 63 patients with MS, determining the range of measurement variability present when patients are clinically stable. Time to walk 25 feet (T25FW) and the 9-hole peg test (9HPT) varied by <20% of individual mean scores on repeated testing. Therefore, a 20% change on these tests can be considered to be the threshold that reliably indicates a true change in function for an individual.

Interferon beta-1a in children with multiple sclerosis is well tolerated.

BACKGROUND: Multiple sclerosis is a chronic demyelinating disease rare in children. Currently marketed disease modifying therapies are limited to adults. OBJECTIVE: To determine the tolerability of interferon beta-1a (IFNB-1 a) 30 mcg injected intramuscularly once a week in children with clinically definite relapsing-remitting multiple sclerosis (RRMS). DESIGN/METHODS: A standardized questionnaire was sent to neurologists in the United States to determine the tolerability of IFNB-1 a in patients younger than 16 years. RESULTS: Tolerability data were available for 9 of 33 children who were reported to initiate IFNB-1 a. Mean age on initiating treatment was 12.7 years (range 8 - 15) and mean duration of therapy was 17 months (range 5 - 36). No patient discontinued therapy due to an adverse event. CONCLUSIONS: Preliminary data indicate that weekly intramuscular injections of IFNB-1 a are well tolerated.

A randomized, controlled trial of remacemide for motor fluctuations in Parkinson's disease.

BACKGROUND: Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. RESULTS: Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. CONCLUSION: Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

A 12-week, open trial of donepezil hydrochloride in patients with multiple sclerosis and associated cognitive impairments.

Cognitive dysfunction occurs in up to 65% of patients with multiple sclerosis (MS), but there is no effective treatment for the symptoms. The authors conducted a 12-week, open-pilot study to assess the efficacy and tolerability of donepezil HCl administered in patients with MS and cognitive impairment. Seventeen patients at a long-term care facility with Mini-Mental State Examination scores of < or = 25 received 5 mg of donepezil HCl for a 4-week period, followed by 8 weeks of 10 mg of donepezil HCl. Cognitive, neurologic, functional, and behavioral assessments were conducted at baseline and at 4 and 12 weeks. Statistically significant improvement was observed in several cognitive domains including attention, memory, and executive functioning, as well as different aspects of behavior. These data suggest that donepezil HCl merits further study as a potentially viable treatment option for patients with cognitive impairment associated with MS.

Are quantitative functional measures more sensitive to worsening MS than traditional measures?

The authors used data collected prospectively during a multicenter trial in 133 patients with secondary progressive MS to assess the relative sensitivity of quantitative functional tests and traditional measures, including the Expanded Disability Status Scale (EDSS) and Ambulation Index. Quantitative functional measures worsened in 69% of patients during an average of 6 months of observation, whereas the Clinical Global Impression of Change worsened in 33% and the EDSS worsened in 25% of patients. These changes should be interpreted in the context of the test-retest reliability for each measure.