Higher-Than-Replacement Testosterone Plus Finasteride Treatment After SCI

SCI 后高于替代睾酮加非那雄胺的治疗

• 批准号: 9901435
• 负责人: Joshua F. Yarrow
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901435
• 关键词: 18 year old; 3-Dimensional; Address; Aftercare; Area; Blood Pressure; Body Composition; Body fat; Bone Density; Bone Resorption; Caring; Characteristics; Chronic; Clinical; Clinical Trials; Combined Modality Therapy; Data; Dose; Double-Blind Method; Elderly; Expenditure; Extensor; FDA approved; Finasteride; Functional disorder; Glycosylated hemoglobin A; Health; Health Expenditures; Healthcare Systems; Hematocrit procedure; High Prevalence; Hindlimb; Hypogonadism; Impairment; Individual; Injury; Institute of Medicine (U.S.); Insulin Resistance; Knee; Lead; Lipids; Lower Extremity; Magnetic Resonance Imaging; Measures; Mediating; Medical; Meta-Analysis; Metabolic; Metabolic syndrome; Minerals; Minor; Motor; Muscle; Musculoskeletal; Natural regeneration; Neurologic; Obesity; Osteogenesis; Outcome; Oxidoreductase; Patients; Pharmacology; Physical Function; Physiological; Placebos; Population; Production; Prostate; Randomized Clinical Trials; Recovery; Reporting; Research; Research Support; Risk; Risk Factors; Rodent; Roentgen Rays; Safety; Serum; Serum Markers; Skeletal Muscle; Spinal cord injury; Stanolone; Testing; Testosterone; Testosterone Enanthate; Thigh structure; Thinness; Torque; Translating; Veterans; Visceral; Visceral fat; Walking; bone; bone turnover; circulating biomarkers; cost; cost effective; disability; effective therapy; experience; fasting glucose; hip bone; improved; inhibitor/antagonist; innovation; male; men; motor function improvement; neuromuscular; neuromuscular function; novel; novel strategies; open label; pre-clinical; prevent; primary outcome; prospective; prostate enlargement; public health relevance; rehabilitation strategy; relating to nervous system; secondary outcome; skeletal; sudden cardiac death; testosterone replacement therapy

DESCRIPTION: The Institute of Medicine has indicated that short-term, small scale randomized clinical trials (RCTs) should be conducted to establish the efficacy of testosterone replacement therapy (TRT) as a strategy to enhance muscular strength and reduce disability in clinical populations of hypogonadal men. Men with spinal cord injury (SCI) experience a high prevalence of hypogonadism which influences the neural, muscular, skeletal, and body composition deficits that occur after injury. In this regard, a single retrospective analysis has reported that TRT improved motor function in hypogonadal men with incomplete SCI. However, only one small prospective (open label) clinical trial has evaluated the safety/efficacy of TRT in men with SCI. This study reported that low- dose TRT improved lower extremity lean mass and reduced risk of sudden cardiac death in men with motor complete SCI, demonstrating that testosterone (T) safely improves lean mass even in the absence of voluntary muscle activity. However, body composition and bone mineral density (BMD) were unaltered in this study because these deficits respond only to higher-than-replacement T. Despite the potential benefits of TRT, clinical concern exists regarding the safety of this therapy, with increased hematocrit (which is rarely detrimental) and prostate enlargement being the only health risks proven by meta-analysis. Interestingly, the 5�-reduction of T to dihydrotestosterone (DHT) mediates prostate enlargement, but this conversion is not required for the benefits of TRT. As evidence pharmacologic 5�-reductase inhibition (via finasteride) ablates prostate enlargement in neurologically healthy hypogonadal men receiving higher-than-replacement T, without inhibiting the substantial musculoskeletal and lipolytic benefits of this treatment. However, the safety and efficacy of this novel combination therapy remains to be determined in men with chronic motor incomplete SCI. For this double-blind placebo-controlled RCT, hypogonadal men >18 years of age with chronic motor incomplete SCI (AIS C/D) who present with ambulatory dysfunction (0.20m/s - 0.80m/s on 10m walk test) will receive slightly higher-than-replacement T (125mg/week, i.m.) plus finasteride (5mg/day, p.o.) in FDA approved doses or vehicle/placebo for 12 months. We will assess: BMD and body composition via DXA, thigh muscle cross-sectional area (CSA) via MRI, maximal knee extensor (KE) torque via dynamometry, KE muscle activation via twitch interpolation, circulating markers of bone turnover and metabolic health, and safety measures including prostate health, hematocrit, and other putative health risks associated with TRT. Our primary hypotheses are that slightly higher-than-replacement T plus finasteride will safely 1) regenerate BMD in this population via antiresorptive actions, 2) enhance muscle CSA and improve neuromuscular force production, and 3) improve body composition. In order to test these hypotheses, the following Specific Aims will be evaluated: AIM 1: Evaluate the effects of 12 months of slightly higher-than-replacement T plus finasteride on bone mineral characteristics and bone turnover in hypogonadal men with motor incomplete SCI. AIM 2: Determine the effects of slightly higher-than-replacement T plus finasteride on the recovery of muscle integrity and neuromuscular force production in hypogonadal men with motor incomplete SCI. Exploratory AIM 3: Examine the effects of slightly higher-than-replacement T plus finasteride on body composition and the pathophysiology underlying metabolic syndrome in men with motor incomplete SCI. This proposal will provide the first-ever prospective clinical evidence evaluating whether higher-than- replacement T plus finasteride safely regenerates musculoskeletal integrity, enhances neuromuscular function, and improves body composition and metabolic health in hypogonadal men with motor incomplete SCI. These findings will benefit Veterans with SCI who experience musculoskeletal impairments and may provide the VA with a novel cost-effective therapy able to improve musculoskeletal and metabolic health in this population.

描述： 医学研究所表明，应进行短期，小规模的随机临床试验（RCT），以确定睾丸激素替代疗法（TRT）的有效性，以增强肌肉力量并减少降低肌次度男性临床群体的残疾。患有脊髓损伤（SCI）的男性经历了高度的高度患病率，这会影响神经，肌肉，骨骼和身体成分定义在损伤后发生的。在这方面，单个回顾性分析报告说，TRT改善了SCI不完整的性不完整男性的运动功能。但是，只有一个小的前瞻性（开放标签）临床试验评估了SCI男性TRT的安全性/功效。这项研究报告说，低剂量TRT改善了运动完全SCI的男性心脏死亡的风险降低，表明即使没有自愿肌肉活动，睾丸激素（T）也可以安全地改善瘦质量。 However, body composition and bone mineral density (BMD) were unaltered in this study because these definitions respond only to higher-than-replacement T. Despite the potential benefits of TRT, clinical concern exists regarding the safety of this therapy, with increased hematocrit (which is rarely detrimental) and prostate enhancement being the only health risks proven by meta-analysis. 5.将T减少到二氢睾丸激素（DHT）介导了前列腺增强，但是TRT的益处并不需要这种转换。作为药理学的证据5.减少抑制（通过芬太赛）在神经系统健康的性下可抑制t的抑制作用，而抑制了比替代t较高的神经性性肌张力，而不会抑制这种治疗方法的实质性肌肉骨骼和脂解益处。但是，这种新型组合疗法的安全性和效率在患有慢性运动不完全SCI的男性中仍有待确定。对于这款双盲安慰剂控制的RCT，慢性运动不完整的SCI（AIS C/D），患有卧床功能障碍（0.20m/s-0.80m/s的步行测试），慢性运动不完整的SCI（AIS C/D）年龄> 18岁，将获得稍高的T（I.M.M.M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M.） doses or vehicle/placebo We will assess: BMD and body composition via DXA, thigh muscle cross-sectional area (CSA) via MRI, maximal knee extension (KE) torque via dynamometry, KE muscle activation via twitch interpolation, circulating markers of bone turnover and metabolic health, and safety measures including prostate health, hematocrit, and other putative health risks associated with TRT.我们的主要假设是，稍高的替换t P​​lus finastalide将安全地1）通过抗疾病动作在该人群中再生BMD，2）增强肌肉CSA并改善神经肌肉力量的产生，3）改善身体组成。为了检验这些假设，将评估以下特定目的：目标1：评估12个月稍高的t替代t加非那雄胺对骨矿物质特征和骨转换的影响，患有运动不完整的SCI。 AIM 2：确定稍高的替换t和非那雄胺对肌肉完整性和神经肌肉力量产生的恢复的影响，具有运动不完整的SCI。探索目的3：检查略高的替补t和非雄胺对运动不完整SCI男性的身体成分和病理生理的代谢综合征的影响。该提案将提供有史以来的第一个前瞻性临床证据，以评估高于较高的t和fienesteride是否可以安全再生肌肉骨骼完整性，增强神经肌肉功能，并改善具有运动不完整SCI的性超大型男性的身体组成和代谢健康。这些发现将使经历肌肉骨骼障碍的SCI的退伍军人受益，并可能为VA提供一种新型的具有成本效益的疗法，能够改善该人群中的肌肉骨骼和代谢健康。