Statistical methods for the analysis of relapse data in MS clinical trials

Wang, Y.C.; Meyerson, Laura J.; Tang, Yongqiang; Qian, N.

doi:10.1016/j.jns.2009.07.017

Cited by 49 publications

(72 citation statements)

References 30 publications

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“…18 We assessed relapse rate using an Andersen-Gill model 19 for recurrent events and assessed time to confirmed EDSS score progression using Cox regression analysis.…”

Section: Genotype Assessmentmentioning

confidence: 99%

Association of Vitamin D Levels With Multiple Sclerosis Activity and Progression in Patients Receiving Interferon Beta-1b

et al. 2015

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IMPORTANCE Low serum 25-hydroxyvitamin D (25[OH]D) levels are associated with an increased risk of multiple sclerosis (MS) as well as with increased disease activity and rate of progression in clinically isolated syndromes and early MS. OBJECTIVE To assess the association between 25(OH)D and disease course and prognosis in patients with relapsing-remitting MS treated with interferon beta-1b. DESIGN, SETTING, AND PARTICIPANTS We conducted a prospective cohort study assessing 25(OH)D levels and subsequent MS disease course and progression characterized by magnetic resonance imaging (MRI) and clinical end points. The study took place between November 2003 and June 2005; data analysis was performed between June 2013 and December 2014. The study was conducted among participants in the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) study, a large, phase 3, prospective, multicenter, blinded, randomized clinical trial. Patients were monitored for at least 2 years. Clinic visits were scheduled every 3 months, and MRI was performed at baseline and annually thereafter. Eligible patients included 1482 participants randomized to receive 250 μg or 500 μg of interferon-1b with at least 2 measurements of 25(OH)D obtained 6 months apart. EXPOSURES Serum 25(OH)D measurements were performed at baseline, 6 months, and 12 months. MAIN OUTCOMES AND MEASURESMain outcomes included cumulative number of new active lesions (T2 lesions and gadolinium acetate-enhancing lesions), change in normalized brain volume, relapse rate, and progression determined by the Expanded Disability Status Scale (EDSS). Statistical analyses were adjusted for age, sex, randomized treatment, region, disease duration, and baseline EDSS score. RESULTS Overall, average 25(OH)D levels in 1482 patients were significantly inversely correlated with the cumulative number of new active lesions between baseline and the last MRI, with a 50.0-nmol/L increase in serum 25(OH)D levels associated with a 31% lower rate of new lesions (relative rate [RR], 0.69; 95% CI, 0.55-0.86; P = .001). The lowest rate of new lesions was observed among patients with 25(OH)D levels greater than 100.0 nmol/L (RR, 0.53; 95% CI, 0.37-0.78; P = .002). No significant associations were found between 25(OH)D levels and change in brain volume, relapse rates, or EDSS scores. Results were consistent following adjustment for HLA-DRB1*15 or vitamin D-binding protein status.CONCLUSIONS AND RELEVANCE Among patients with MS treated with interferon beta-1b, higher 25(OH)D levels were associated with lower rates of MS activity observed on MRI. Results for brain atrophy and clinical progression were more equivocal.

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“…18 We assessed relapse rate using an Andersen-Gill model 19 for recurrent events and assessed time to confirmed EDSS score progression using Cox regression analysis.…”

Section: Genotype Assessmentmentioning

confidence: 99%

Association of Vitamin D Levels With Multiple Sclerosis Activity and Progression in Patients Receiving Interferon Beta-1b

et al. 2015

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“…A subsequent publication recommended negative binomial regression as the best technique for the analysis of the overdispersed Poisson distributed variable, relapse rate. 15 Therefore, the negative binomial method, without adjustment for strata, is presented for all such analyses in this paper. The treatment effect and a dispersion parameter were used to model the number of relapses with an offset variable reflecting the log of the duration over which the subject was followed.…”

Section: Methodsmentioning

confidence: 99%

A randomized clinical trial of autologous T-cell therapy in multiple sclerosis: subset analysis and implications for trial design

et al. 2011

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Background: Tovaxin is an autologous T-cell immunotherapy under investigation for the treatment of MS. The product consists of in vitro expanded myelin-reactive T-cells manufactured against up to six immunodominant peptides derived from three myelin antigens. Methods: A Phase 2b placebo controlled study (TERMS) was conducted in 150 subjects to gather safety and efficacy data in relapsing-remitting MS and clinically isolated syndrome subjects. Results: Tovaxin had a favorable safety profile. Although no statistically significant clinical or radiological benefit of Tovaxin immunotherapy was identified in the modified intent-to-treat population, a prospective analysis of subjects with more active disease favored Tovaxin in terms of annualized relapse rate (ARR) and disability progression. An analysis also found a possible legacy effect of prior disease-modifying treatment (DMT) which may have contributed to a lowered ARR in the placebo group. DMT-naïve subjects treated with Tovaxin had a lower ARR compared to the placebo group, particularly in those with active baseline disease (ARR≥1, ARR>1). However, clinical benefit was not was accompanied by a treatment-dependent improvement in MRI measures. Conclusions: Previous DMT exposure may reduce effect size and study power. Limiting subject selection to DMTtreatment-naïve individuals may be a reasonable approach to phase 2 or proof-of-concept studies of limited duration.

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“…The most durable efficacy measures are annualised relapse rate (ARR) [19], probability of or time to sustained disability progression (increase in Expanded Disability Status Scale [EDSS] sustained for 3 or 6 months) [20] and MRI measures of gadolinium (Gad)-enhancing or T2-weighted lesions [21]. More recently measures of whole brain atrophy (believed to be a surrogate marker of long term disability) have emerged [22].…”

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confidence: 99%

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 1 Historical and established therapies

Broadley

Barnett

Boggild

et al. 2014

Journal of Clinical Neuroscience

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Statistical methods for the analysis of relapse data in MS clinical trials

Cited by 49 publications

References 30 publications

Association of Vitamin D Levels With Multiple Sclerosis Activity and Progression in Patients Receiving Interferon Beta-1b

Association of Vitamin D Levels With Multiple Sclerosis Activity and Progression in Patients Receiving Interferon Beta-1b

A randomized clinical trial of autologous T-cell therapy in multiple sclerosis: subset analysis and implications for trial design

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 1 Historical and established therapies

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