Dataset Information

Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database.

ABSTRACT: BACKGROUND:Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is required on clinical progression in the older DMD population. OBJECTIVE:To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients. METHODS:In this cross-sectional study we analysed clinical data from 5345 genetically confirmed DMD patients from 31 countries held within the TREAT-NMD global DMD database. For analysis patients were categorised by corticosteroid background and further stratified by age. RESULTS:Loss of ambulation in non-steroid treated patients was 10 years and in corticosteroid treated patients 13 years old (p?=?0.0001). Corticosteroid treated patients were less likely to need scoliosis surgery (p?

SUBMITTER: Koeks Z

PROVIDER: S-EPMC5701764 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database.

Koeks Zaïda Z Bladen Catherine L CL Salgado David D van Zwet Erik E Pogoryelova Oksana O McMacken Grace G Monges Soledad S Foncuberta Maria E ME Kekou Kyriaki K Kosma Konstantina K Dawkins Hugh H Lamont Leanne L Bellgard Matthew I MI Roy Anna J AJ Chamova Teodora T Guergueltcheva Velina V Chan Sophelia S Korngut Lawrence L Campbell Craig C Dai Yi Y Wang Jen J Barišić Nina N Brabec Petr P Lähdetie Jaana J Walter Maggie C MC Schreiber-Katz Olivia O Karcagi Veronika V Garami Marta M Herczegfalvi Agnes A Viswanathan Venkatarman V Bayat Farhad F Buccella Filippo F Ferlini Alessandra A Kimura En E van den Bergen Janneke C JC Rodrigues Miriam M Roxburgh Richard R Lusakowska Anna A Kostera-Pruszczyk Anna A Santos Rosário R Neagu Elena E Artemieva Svetlana S Rasic Vedrana Milic VM Vojinovic Dina D Posada Manuel M Bloetzer Clemens C Klein Andrea A Díaz-Manera Jordi J Gallardo Eduard E Karaduman A Ayşe AA Oznur Tunca T Topaloğlu Haluk H El Sherif Rasha R Stringer Angela A Shatillo Andriy V AV Martin Ann S AS Peay Holly L HL Kirschner Jan J Flanigan Kevin M KM Straub Volker V Bushby Kate K Béroud Christophe C Verschuuren Jan J JJ Lochmüller Hanns H

Journal of neuromuscular diseases 20170101 4

<h4>Background</h4>Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is required on clinical progression in the older DMD population.<h4>Objective</h4>To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients.<h4>Methods</h4>In ...[more]

PMID: 29125504

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Project description:Abstract Delayed puberty is almost universal in patients with Duchenne muscular dystrophy (DMD) treated with pharmacological doses of glucocorticoid. We have demonstrated wide variation in terms of how delayed puberty is managed and set out to evaluate the efficacy of exogenous testosterone on a range of endpoints. This was a single centre clinical trial (NCT02571205) of 15 adolescents with DMD and delayed puberty (12-16 years) treated with an increasing dose of Sustanon 250 starting at 0.2 mls up to a maximum of 1ml every 4 weeks for 2 years. We assessed a range of endpoints including pubertal status, gonadal function, bone turnover markers as well as adverse events (AEs). All 15 patients completed 27 months of follow-up. All were pre-pubertal at baseline with a testicular volume (TV) less than 4mls. Baseline testosterone levels were <2nmol/l. 27 months later (3 months after the last testosterone injection) the mean testicular volume was 3.3 mls (range 1.5-6mls), Tanner stage G4P4 (range G4P4-G5P5) with a mean testosterone of 10.4 nmol/l (1.9-21.8). Mean FSH was 9.1 IU/L (range 1.8-38.3) and mean LH 8.6 IU/L(range <0.5-25.1). By 9-12 months after the last injection there was evidence of endogenous testosterone production with a mean testicular volume of 8mls (4.75-10) and mean testosterone of 11.6nmol/l (5.1-19.1). There were no change in mean P1NP or CTX levels during the study but RANKL decreased from 515.0 pmol/l (227.1) at baseline to 308.2 pmol/l (214.7) after 24 months of testosterone. Qualitative interviews/treatment satisfaction questionnaire responses were encouraging with no significant AEs attributed to testosterone therapy and all patients either ‘satisfied’ or ‘very/extremely satisfied’ with their treatment. 2 patients chose to stop testosterone injections at 18 months because of concerns about potential effects on mobility. They continued to progress through puberty. Testosterone treatment is not part of DMD standard care but this regimen appears to be effective and well-tolerated. By 1 year after cessation of the regimen there is evidence of endogenous testosterone production. Continuing data is required in terms of longer term gonadal function and effects on muscle function and skeletal integrity also require detailed scrutiny.

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

Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database.

Publications

Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database.

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