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: 10251014
• 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/10251014
• 关键词: 18 year old; 3-Dimensional; Address; Aftercare; Area; Blood Pressure; Body Composition; Body fat; Bone Density; Bone Regeneration; 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; randomized placebo-controlled clinical trial; 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.

产品说明： 医学研究所指出，应进行短期、小规模随机临床试验（RCT），以确定睾酮替代疗法（TRT）作为一种增强肌肉力量和减少性腺功能减退男性临床人群残疾的策略的疗效。男性脊髓损伤（SCI）患者的性腺功能减退发生率很高，这会影响损伤后发生的神经、肌肉、骨骼和身体成分缺陷。在这方面，一项回顾性分析报告称，TRT改善了性腺功能减退的不完全SCI男性的运动功能。然而，只有一项小型前瞻性（开放标签）临床试验评价了TRT在SCI男性中的安全性/有效性。该研究报告，低剂量TRT改善了运动性完全性SCI男性的下肢瘦体重，降低了心源性猝死的风险，表明睾酮（T）即使在无自主肌肉活动的情况下也能安全改善瘦体重。然而，在这项研究中，身体成分和骨矿物质密度（BMD）没有改变，因为这些缺陷只对高于替代T的反应。尽管TRT具有潜在的益处，但仍存在关于该疗法安全性的临床问题，荟萃分析证实，红细胞压积增加（很少有害）和前列腺肥大是唯一的健康风险。有趣的是，5 β-还原T为双氢睾酮（DHT）介导前列腺肥大，但这种转化不是TRT获益所必需的。作为证据，药理学5 β-还原酶抑制剂（通过finaldade）消除了接受高于替代T的神经健康性腺功能减退男性的前列腺肥大，而不会抑制这种治疗的实质性肌肉骨骼和脂解益处。然而，这种新的联合治疗的安全性和有效性仍有待确定的男性慢性运动不完全性脊髓损伤。 对于这项双盲安慰剂对照RCT，年龄>18岁的性腺功能减退男性慢性运动不完全性SCI（AIS C/D），表现为行走功能障碍（10米步行试验为0.20 m/s -0.80 m/s），将接受略高于替代T（125 mg/周，i.m.）加非那肽（5 mg/天，p.o.）在FDA批准的剂量或媒介物/安慰剂中持续12个月。我们将评估：通过DXA测定BMD和身体成分，通过MRI测定大腿肌肉横截面积（CSA），通过测力计测定最大膝伸肌（KE）扭矩，通过抽搐插值测定KE肌肉激活，骨转换和代谢健康的循环标志物，以及安全性指标，包括前列腺健康、血细胞比容和其他与TRT相关的推定健康风险。我们的主要假设是，略高于替代T加非那雄胺将安全地1）通过抗吸收作用再生该人群的BMD，2）增强肌肉CSA并改善神经肌肉力的产生，以及3）改善身体组成。为了检验这些假设，将评价以下特定目的：目的1：评价12个月略高于替代的T+非那肽对患有运动不完全性SCI的性腺功能减退男性的骨矿物质特征和骨转换的影响。 目标2：确定略高于替代的T加非那肽对运动不完全性脊髓损伤性腺功能减退男性的肌肉完整性和神经肌肉力量产生的恢复的影响。 探索性目标3：检查略高于替代的T加芬那肽对运动不完全性SCI男性的身体成分和代谢综合征的病理生理学的影响。 该提案将提供有史以来第一个前瞻性临床证据，以评估高于替代T+芬氟拉明是否安全地再生肌肉骨骼完整性，增强神经肌肉功能，并改善性腺功能减退男性运动不完全性脊髓损伤的身体组成和代谢健康。这些发现将使经历肌肉骨骼损伤的SCI退伍军人受益，并可能为VA提供一种新的具有成本效益的治疗方法，能够改善该人群的肌肉骨骼和代谢健康。