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Observational study of clinical outcomes for testosterone treatment of pubertal delay in Duchenne muscular dystrophy.

ABSTRACT: BACKGROUND:Adolescents with DMD treated with chronic high dose GC therapy typically have profound pubertal delay. Testosterone, the main circulating androgen in men, promotes virilisation and growth with associated accrual of fat-free muscle mass and bone mineral content. Testosterone therapy is routinely used to mimic the normal stages of pubertal development in patients with hypogonadotrophic hypogonadism, androgen deficiency secondary to testicular disease and in constitutional delay of growth and puberty (CDGP). Improved life expectancy in DMD has meant that more adolescents are eligible for testosterone supplementation but there is little objective data regarding the impact of this treatment on muscle structure and function, bone integrity and overall well-being. METHODS:This is a single centre observational clinical trial (NCT02571205) that aims to follow the progress of 15 adolescents with Duchenne muscular dystrophy and delayed puberty as they are managed with incremental testosterone therapy to induce puberty. Subjects will all be treated with a steadily increasing dose of testosterone administered by injection every 4?weeks and data will be collected to help us determine the effectiveness and tolerability of the described treatment regimen. We will use the data to explore the effects of testosterone on pubertal development, growth, muscle strength and function, bone mineral density, body composition with a detailed record of any adverse events. We will also carry out interviews to explore the boys' views on the tolerability of the regimen. The study will last for 27?months in total for each participant. DISCUSSION:Our experience has indicated that testosterone treatment in adolescents with DMD is liked and well tolerated but we have not collected objective data on a specific treatment regimen and there is no current consensus. Testosterone supplementation is not part of the standard of care of pubertal delay in DMD but inclusion in future protocols may be appropriate depending on the results of this trial. TRIAL REGISTRATION:EudraCT Number: 2015-003195-68. Research Registry & References: Clinical trials.gov- NCT02571205 (registered 8/10/15).

SUBMITTER: Wood CL

PROVIDER: S-EPMC6482579 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Observational study of clinical outcomes for testosterone treatment of pubertal delay in Duchenne muscular dystrophy.

Wood C L CL Cheetham T D TD Hollingsworth K G KG Guglieri M M Ailins-Sahun Y Y Punniyakodi S S Mayhew A A Straub V V

BMC pediatrics 20190425 1

<h4>Background</h4>Adolescents with DMD treated with chronic high dose GC therapy typically have profound pubertal delay. Testosterone, the main circulating androgen in men, promotes virilisation and growth with associated accrual of fat-free muscle mass and bone mineral content. Testosterone therapy is routinely used to mimic the normal stages of pubertal development in patients with hypogonadotrophic hypogonadism, androgen deficiency secondary to testicular disease and in constitutional delay ...[more]

PMID: 31023296

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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

Observational study of clinical outcomes for testosterone treatment of pubertal delay in Duchenne muscular dystrophy.

Publications

Observational study of clinical outcomes for testosterone treatment of pubertal delay in Duchenne muscular dystrophy.

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