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： 英国医学研究所表示，应进行短期、小规模随机临床试验（RCT）来确定睾酮替代疗法（TRT）作为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有效性。患有脊髓损伤 (SCI) 的男性性腺功能减退症的患病率很高，这会影响损伤后出现的神经、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症的运动功能。然而，只有一项小型前瞻性（开放标签）临床试验评估了 TRT 对 SCI 男性的安全性/有效性。该研究报告称，低剂量 TRT 可改善下肢肌肉质量并降低心源性猝死的风险。在患有运动性完全性 SCI 的男性中，证明即使在没有随意肌肉活动的情况下，睾酮 (T) 也能安全地改善瘦体重。然而，在这项研究中，身体成分和骨矿物质密度 (BMD) 没有改变，因为这些缺陷仅对尽管 TRT 具有潜在益处，但临床仍对该疗法的安全性存在担忧，荟萃分析证明血细胞比容增加（很少不健康）和前列腺肥大是唯一的健康风险 5�-。 T 还原为二氢睾酮 (DHT) 会介导前列腺增大，但这种转化并不是 TRT 获益所必需的，证据表明药理学 5°-还原酶抑制（通过非那雄胺）可消融前列腺。神经健康性腺功能减退男性接受高于替代 T 的治疗，但不会抑制这种治疗对肌肉骨骼和脂肪分解的显着益处。然而，这种新型联合疗法在患有慢性运动不完全性 SCI 的男性中的安全性和有效性仍有待确定。这项双盲安慰剂对照随机对照试验，对象是患有慢性运动不完全性 SCI (AIS C/D) 且表现为行走功能障碍的 18 岁以上性腺功能减退男性（10m 步行测试中为 0.20m/s - 0.80m/s）将接受略高于替代 T（125 毫克/周，肌肉注射）加非那雄胺（5 毫克/天，口服）的 FDA 批准剂量或载体/安慰剂 12 次我们将评估：通过 DXA 评估 BMD 和身体成分、通过 MRI 评估大腿肌肉横截面积 (CSA)、最大膝伸肌 (KE) 扭矩。通过测力法、通过抽搐插值进行 KE 肌肉激活、骨转换和代谢健康的循环标记以及包括前列腺健康、血细胞比容和与 TRT 相关的其他假定健康风险的安全措施，我们的主要假设是略高于替代 T plus。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 并改善神经肌肉力量的产生，以及 3) 改善身体成分。为了测试这些假设，将评估以下具体目标： 目标 1：评估 12 个月略高于替代 T 加非那雄胺对患有运动不完全 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。高于替代 T 加非那雄胺对性腺功能减退男性运动不完全性 SCI 的肌肉完整性恢复和神经肌肉力量产生的影响探索性 AIM。 3：检查略高于替代的 T 加非那雄胺对运动不完全性 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评估高于替代 T 的前瞻性临床证据。加用非那雄胺可以安全地再生患有运动不完全性脊髓损伤的性腺功能减退男性的肌肉骨骼完整性，增强神经肌肉功能，并改善身体成分和代谢健康。这些发现将使经历过脊髓损伤的退伍军人受益。肌肉骨骼损伤，并可能为 VA 提供一种新的具有成本效益的疗法，能够改善该人群的肌肉骨骼和代谢健康。