This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.ABSTRACT HYPOTHESIS 1) High dose prednisone (2X daily dose) given intermittently will be as effective as daily dose in slowing down the progress of muscle weakness in Duchenne muscular dystrophy (DMD). 2) High dose prednisone (2X daily dose) given intermittently will be less toxic and hence cause fewer side effects than daily dose therapy in DMD.
SPECIFIC AIMS Objective:The purpose of this protocol is to conduct a prospective, randomized study to compare efficacy and safety of two dose schedules of prednisone (0.75 mg/kg/day given daily and 10 mg/kg/week given in equal doses over two days) in boys with Duchenne muscular dystrophy (DMD).
Specific Aims :1) To compare efficacy of a daily prednisone dose of .75mg/kg with a weekly dose of 10 mg/kg split over two consecutive days. The primary efficacy measures will be quantitative muscle testing (QMT) scores of the upper and lower extremities, consisting of paired flexor/extensor groups. Secondary efficacy measures will include individual QMT scores of elbow and knee flexors and extensors and hand grip, manual muscle testing, timed function tests, pulmonary function tests and functional evaluation. 2) To compare side effect profiles between the two regimens, to include height, weight, weight/ height ratio, body mass index, bone density, cataract formation, blood glucose, blood pressure and behavioral changes. Objective and Aims of the CINRG Clinical Evaluator Reliability Training:This training is being conducted to ensure inter-rater reliability of clinical evaluators performing manual muscle testing (MMT), QMT, and functional tests for the multicenter CINRG group. The Clinical Evaluator Reliability Training will answer the following question: What is the inter-rater reliability of clinical evaluators at the Texas Children's Hospital CINRG site (relative to the 'gold standard' clinical evaluators of this multicenter research group) for MMT, QMT, and functional testing of DMD subjects?BACKGROUND AND SIGNIFICANCE OverviewDuchenne muscular dystrophy (DMD) is the most common and devastating type of muscular dystrophy (incidence 1 in 3500 live born males worldwide). DMD is characterized by a complete loss of dystrophin, leading to progressive muscle weakness and wasting. DMD patients typically become wheelchair-bound at the age of 10-12, and succumb to respiratory failure in their late teens-early twenties due to involvement of the diaphragm and other respiratory muscles. Although cardiac involvement is frequent, it does not become clinically significant until the late teens, when some boys exhibit symptomatic heart failure that causes their premature death. The primary defect in this disease is a mutation in the dystrophin gene, the largest gene known to date, which is located on the short arm of the X chromosome [1, 2]. Because of the size of the gene, there is a very high spontaneous mutation rate, which makes eradication of the disease by genetic counseling and screening impossible. Homologous dog, mouse, and cat animal models exist, which can be used for animal studies of DMD.Prednisone at a dose of .75mg/kg/d has been proven effective for the treatment of Duchenne muscular dystrophy (DMD), prolonging ambulation for up to three years as compared to the natural history of the disease. Because of the side effects of prednisone, which commonly include linear growth arrest, obesity, loss of bone density, cushingoid features and behavior disturbances, physicians have tried to reduce adverse effects by varying drug doses and schedules. However, the only prospective study comparing efficacy and safety of daily vs. alternate dose prednisone showed the latter not to be effective, although side effects were significantly reduced. Because prednisone is the only treatment available for this disease, it is highly desirable to find a dosing regimen that is equally effective to the daily dose regimen with fewer adverse effects. A pilot study of 20 boys who were followed for more than a year at one of our institutions (Washington University at St. Louis) has suggested that a dose of 10mg/kg split over two consecutive days once per week can be just as effective as the daily regimen, with fewer side effects. This constitutes the basis for the proposed prospective, randomized study.Justification of Current ApproachDaily prednisone stabilizes or improves the strength of boys with DMD and it is the only proven treatment for this disease. Drachman et al first reported this in an open trial of 2 mg/kg/day [3] . This finding was duplicated in open design trials [4] [5] and subsequently, through the collaboration of the Clinical Investigation of Duchenne Dystrophy (CIDD) investigators, in double blinded placebo controlled trials [6-8]. Effective doses include both 1.5 mg/kg/day and 0.75 mg/kg/day. Effects on strength are seen as soon as 10 days, with a peak at 3 months and then a stabilization period [9]. The duration of the improvement extends as long as 3 years in those children who maintained doses of 0.5 and 0.6 mg/kg/day [6]. Daily deflazacort shows a similar benefit in strength with fewer side effects [10, 11] [12, 13]. However, weight gain and cushingoid features, two common side effects of prednisone, also occur in boys treated with deflazacort compared to placebo. Lower dose regimens including alternate day corticosteroids and treatment for the first 10 days of the month have not demonstrated sustained efficacy [6, 14]. Other immunosuppressive medications have mixed results. While azathioprine shows no benefit [7], a small pilot trial using cyclosporine as the immunosuppressant drug for myoblast transfer experiments, showed that this drug improved maximal voluntary contraction on the tibialis anterior muscle in boys with DMD [15,16].Despite the fact that daily prednisone benefits 80% of boys with DMD, this treatment has not become the standard of care for Duchenne patients and even in those centers where steroids are used, therapy is often delayed until the boys are beginning to fall. The main reason for the delay in treatment is the known steroid side effects. Side effects including weight gain, cushingoid facies, and behavioral changes occur in 60-100% of treated boys. In our experience, more than 50% of boys treated with daily corticosteroids and started later in the disease process develop significant enough side effects that medication is decreased or discontinued. When steroid treatment begins early, at about age 4, although significant weight gain or behavioral disorders are not seen, growth retardation becomes a significant concern.Trying to identify a dosing regimen of prednisone that will be equally effective to daily therapy and have a much lower side effect profile would be highly desirable and, if found, would become a standard of care for DMD. Further clinical research on the dosage and mechanism of action of prednisone was identified as one of the research areas that need to be explored at the NIH Workshop on Therapeutic Approaches for Duchenne Muscular Dystrophy, conducted on May 15-16, 2000 at the National Institutes of Health, Bethesda, Maryland (www.ninds.nih.gov/news_and_events/dmdsessionsummary.htm). One of the PIs of this study (Dr. Connoly) presented at the workshop a pilot study of a high dose (double of total daily dose) prednisone divided on two consecutive days every week (2 days on- 5 days off) in 20 boys with DMD, using as control 18 untreated boys and 4 boys on daily prednisone. The patients were followed for at least one year. Results of this study suggest that the new dosing schedule could be as beneficial as the daily prednisone treatment, with no change in weight gain compared to untreated boys and conservation of linear growth. This pilot data (presented in the preliminary study section) is the base for the current randomized study.
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