DAILY VS WEEKLY PREDNISONE THERAPY IN DUCHENNE MUSCULAR DYSTROPHY

杜氏肌营养不良症的每日与每周泼尼松治疗

• 批准号: 7605878
• 负责人: Timothy Edward Lotze
• 金额: $ 0.59万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605878
• 关键词: Adrenal Cortex Hormones; Adverse effects; Age; Animal Model; Animals; Anterior; Area; Azathioprine; Behavior; Behavior Disorders; Behavioral; Binding; Blood Glucose; Blood Pressure; Body mass index; Bone Density; Canis familiaris; Cardiac; Caring; Cataract; Cessation of life; Child; Chromosomes, Human, Pair 1; Clinical; Clinical Research; Clinical Trials; Collaborations; Computer Retrieval of Information on Scientific Projects Database; Cushingoid facies; Cushingoid habitus; Cyclosporine; Cyclosporins; Daily; Data; Defect; Disease; Dose; Duchenne muscular dystrophy; Dystrophin; Educational workshop; Elbow; Ensure; Evaluation; Event; Exhibits; Felis catus; Flexor; Funding; Genes; Genetic Counseling; Gold; Grant; Growth; Hand; Heart failure; Height; Immunosuppressive Agents; Incidence; Individual; Institution; Knee; Life; Lower Extremity; Manuals; Maryland; Measures; Mus; Muscle; Muscle Weakness; Muscular Dystrophies; Mutation; Myoblasts; Obesity; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Physicians; Pilot Projects; Placebos; Prednisone; Process; Prospective Studies; Protocols documentation; Pulmonary function tests; Purpose; Randomized; Rate; Relative (related person); Reporting; Research; Research Personnel; Resources; Respiratory Diaphragm; Respiratory Failure; Respiratory Muscles; Safety; Schedule; Score; Screening procedure; Site; Source; Standards of Weights and Measures; Steroids; Study Section; Teenagers; Testing; Texas; Therapeutic; Time; Training; Treatment Protocols; United States National Institutes of Health; Universities; Upper arm; Washington; Week; Weight; Weight Gain; Wheelchairs; X Chromosome; abstracting; base; boys; clinically significant; day; deflazacort; design; disease natural history; dosage; double-blind placebo controlled trial; experience; falls; grasp; improved; male; news; pilot trial; prospective; research study; size; wasting

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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 Overview Duchenne 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 Approach Daily 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 (http://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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 抽象的 假设 1）间歇性地给予的高剂量泼尼松（每天2倍）将与每日剂量一样有效，以减慢Duchenne肌肉营养不良症（DMD）的肌肉无力进度。 2）间歇性的高剂量泼尼松（每天2次）的毒性较小，因此比DMD中的每日剂量治疗更少。 具体目标 客观的： 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). 具体目的： 1）比较每日泼尼松剂量为.75mg/kg的疗效，并且每周连续两天剂量为10 mg/kg。主要疗效措施将是上肢和下肢的定量肌肉测试（QMT）评分，由配对的屈肌/伸肌组组成。次级功效措施将包括肘部和膝盖屈肌的单个QMT分数以及手动肌肉测试，定时功能测试，肺功能测试和功能评估。 2）比较两个方案之间的副作用曲线，包括身高，体重，体重/身高比，体重指数，骨密度，白内障形成，血糖，血压和行为变化。 CINRG临床评估者可靠性培训的目标和目标： 正在进行此培训，以确保多中心CINRG组的临床评估人员进行手动肌肉测试（MMT），QMT和功能测试的评估者间可靠性。 临床评估者的可靠性培训将回答以下问题：德克萨斯州儿童医院CINRG站点（相对于该多中心研究小组的“金标准”临床评估者）的评价者间可靠性是什么，QMT，QMT和功能性测试是什么？ 背景和意义 概述 Duchenne肌肉营养不良（DMD）是最常见和毁灭性的肌肉营养不良类型（全球3500名活出生的男性中有1个）。 DMD的特征是肌营养不良蛋白的完全丧失，导致进行性肌肉无力和浪费。 DMD患者通常在10-12岁时就会坐轮椅，并且由于隔膜和其他呼吸道肌肉的参与而屈服于青少年二十多岁的呼吸衰竭。尽管心脏受累是频繁的，但是直到十几岁的时候，当一些男孩表现出症状性心力衰竭而导致其过早死亡时，它才变得临床意义。该疾病的主要缺陷是肌营养不良蛋白基因的突变，该基因是迄今为止已知的最大基因，该基因位于X染色体的短臂上[1，2]。由于基因的大小，因此自发性突变率很高，因此通过遗传咨询和筛查不可能消除该疾病。存在同源狗，小鼠和猫动物模型，可用于DMD动物研究。 与疾病的自然病史相比，以0.75mg/kg/d剂量的泼尼松已被证明可有效治疗Duchenne肌肉营养不良（DMD），延长了长达三年的移动。由于泼尼松的副作用，通常包括线性生长停滞，肥胖症，骨密度损失，库什类动物特征和行为障碍，医生试图通过改变药物剂量和时间表来减少不良反应。但是，比较每日剂量与替代剂量泼尼松的疗效和安全性的唯一前瞻性研究表明，尽管副作用显着降低，但后者不有效。由于泼尼松是该疾病可用的唯一治疗方法，因此非常希望找到一种对每日剂量方案同样有效的剂量方案，具有较少的不良反应。一项对20个男孩的试点研究，他们在我们的一个机构（圣路易斯的华盛顿大学）进行了一年以上的跟踪，这表明每周连续两天分裂10毫克/千克的剂量与日常治疗方案一样有效，副作用较少。这构成了拟议的前瞻性，随机研究的基础。 当前方法的理由 每日泼尼松稳定或改善了DMD男孩的力量，这是该疾病的唯一可靠治疗方法。 Drachman等人在2 mg/kg/day的开放试验中首次报道了这一点[3]。这一发现在开放设计试验[4] [5]中复制了，随后通过在双盲安慰剂对照试验中对Duchenne营养不良（CIDD）研究人员进行临床研究的合作[6-8]。有效剂量包括1.5 mg/kg/day和0.75 mg/kg/day。在10天的时间内看到对强度的影响，在3个月时达到峰值，然后稳定期[9]。在那些维持0.5和0.6 mg/kg/天的儿童中，改善的持续时间长达3年[6]。每日除法表现出类似的强度益处，副作用较少[10，11] [12，13]。然而，与安慰剂相比，体重增加和cushingoid的特征，泼尼松的两个常见副作用也发生在接受Deflazacort的男孩中。较低的剂量方案，包括替代日皮质类固醇和一个月的前10天的治疗，尚未表现出持续的疗效[6，14]。其他免疫抑制药物的结果不同。虽然硫唑嘌呤没有任何益处[7]，这是一项小型试验试验，使用环孢素作为肌细胞转移实验的免疫抑制剂药物，表明这种药物改善了患有DMD男孩的胫骨前肌的最大自愿收缩[15,16]。 尽管每天的泼尼松受益于80％的DMD男孩，但这种治疗方法并未成为Duchenne患者的护理标准，即使在使用类固醇的那些中心，也经常延迟治疗，直到男孩开始下降。延迟治疗的主要原因是已知的类固醇副作用。副作用包括体重增加，cushingoid相和行为改变，在60-100％的治疗男孩中发生。根据我们的经验，超过50％的接受每日皮质类固醇治疗的男孩开始在疾病过程中开始产生足够的副作用，以至于药物被降低或中断。当类固醇治疗开始较早时，大约在4岁时，尽管看不到体重增加或行为障碍，但生长迟缓成为一个重大问题。 试图确定泼尼松的剂量方案，该方案对日常治疗同样有效，并且副作用较低的概况将是非常可取的，如果发现，将成为DMD的护理标准。关于泼尼松作用剂量和作用机理的进一步临床研究被确定为在NIH研讨会上需要在2000年5月15日至16日在美国国家卫生研究院（National Institutes of National Institutes of National Institutes of National Institutes of Duchenne Muscular Dyromhophy）的NIH研讨会上探索的研究领域之一。 （http://www.ninds.nih.gov/news_and_events/dmdsessionsummary.htm）。这项研究的PI（Connoly博士）在研讨会上提出了一项针对高剂量的高剂量（每日总剂量两倍）泼尼松的试点研究，每周连续两天（2天休假2天）在20名DMD的男孩中使用AS Control 18未经治疗的男孩和每天的perdnisone中的4个男孩。随访患者至少一年。这项研究的结果表明，新的给药时间表可能与每日泼尼松治疗一样有益，与未经治疗的男孩相比，体重增加没有变化，并保存线性生长。该试验数据（在初步研究部分中介绍）是当前随机研究的基础。