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Importance of SPP1 genotype as a covariate in clinical trials in Duchenne muscular dystrophy.

ABSTRACT: To test the effect of the single nucleotide polymorphism -66 T>G (rs28357094) in the osteopontin gene (SPP1) on functional measures over 12 months in Duchenne muscular dystrophy (DMD).This study was conducted on a cohort of ambulatory patients with DMD from a network of Italian neuromuscular centers, evaluated longitudinally with the north star ambulatory assessment (NSAA) and the 6-minute walk test (6MWT) at study entry and after 12 months. Genotype at rs28357094 was determined after completion of the clinical evaluations. Patients were stratified in 2 groups according to a dominant model (TT homozygotes vs TG heterozygotes and GG homozygotes) and clinical data were retrospectively compared between groups.Eighty patients were selected (age 4.1-19.3 years; mean 8.3 ± 2.7 SD). There were no differences in age or steroid treatment between the 2 subgroups. Paired t test showed a significant difference in both NSAA (p = 0.013) and 6MWT (p = 0.03) between baseline and follow-up after 12 months in patients with DMD carrying the G allele. The difference was not significant in the T subgroup. The analysis of covariance using age and baseline values as covariate and SPP1 genotype as fixed effect showed that these parameters are significantly correlated with the 12-month values.These data provide evidence of the role of SPP1 genotype as a disease modifier in DMD and support its relevance in the selection of homogeneous groups of patients for future clinical trials.

SUBMITTER: Bello L

PROVIDER: S-EPMC3390537 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Importance of SPP1 genotype as a covariate in clinical trials in Duchenne muscular dystrophy.

Bello Luca L Piva Luisa L Barp Andrea A Taglia Antonella A Picillo Esther E Vasco Gessica G Pane Marika M Previtali Stefano C SC Torrente Yvan Y Gazzerro Elisabetta E Motta Maria Chiara MC Grieco Gaetano S GS Napolitano Sara S Magri Francesca F D'Amico Adele A Astrea Guja G Messina Sonia S Sframeli Maria M Vita Gian Luca GL Boffi Patrizia P Mongini Tiziana T Ferlini Alessandra A Gualandi Francesca F Soraru' Gianni G Ermani Mario M Vita Giuseppe G Battini Roberta R Bertini Enrico E Comi Giacomo P GP Berardinelli Angela A Minetti Carlo C Bruno Claudio C Mercuri Eugenio E Politano Luisa L Angelini Corrado C Hoffman Eric P EP Pegoraro Elena E

Neurology 20120627 2

<h4>Objective</h4>To test the effect of the single nucleotide polymorphism -66 T>G (rs28357094) in the osteopontin gene (SPP1) on functional measures over 12 months in Duchenne muscular dystrophy (DMD).<h4>Methods</h4>This study was conducted on a cohort of ambulatory patients with DMD from a network of Italian neuromuscular centers, evaluated longitudinally with the north star ambulatory assessment (NSAA) and the 6-minute walk test (6MWT) at study entry and after 12 months. Genotype at rs283570 ...[more]

PMID: 22744661

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Project description:BackgroundCurrently, the most promising therapies for Duchenne muscular dystrophy (DMD) are exon skipping and stop codon read-through, two strategies aimed at restoring the expression of dystrophin. A phase 3 clinical trial with drisapersen, a drug designed to induce exon 51-skipping, has failed to show significant improvement of the primary outcome measure, the six-minute walk test.DiscussionHere, we review some key points that should be considered when designing clinical trials for these new therapies. First, younger patients have more functional abilities and more muscle fibers to preserve than older patients and therefore are better subjects for trials designed to demonstrate the success of new treatments. Second, the inclusion of patients on corticosteroids both in the treatment and placebo groups is of concern because the positive effect of corticosteroids might mask the effect of the treatment being tested. Additionally, the reasonable expectation from these therapies is the slowing of disease progression rather than improvement. Therefore, the appropriate clinical endpoints are the prolongation of the ability to stand from the floor, climb stairs, and walk, not an increase in muscle strength or function. Hence, the time frames for the detection of new dystrophin, which occurs within months, and the ability to demonstrate a slowing of disease progression, which requires years, are strikingly different. Finally, placebo-controlled trials are difficult to manage if years of blindness are required to demonstrate a slowing of disease progression. Thus, accelerated/conditional approval for new therapies should be based on surrogate biochemical outcomes: the demonstration of de novo dystrophin production and of its beneficial effect on the functional recovery of muscle fiber. These data suggest that clinical trials for DMD patients must be adapted to the particular characteristics of the disease in order to demonstrate the expected positive effect of new treatments.

Dataset Information

Importance of SPP1 genotype as a covariate in clinical trials in Duchenne muscular dystrophy.

Publications

Importance of SPP1 genotype as a covariate in clinical trials in Duchenne muscular dystrophy.

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