Testosterone Plus Finasteride Therapy to Improve Walking Function After SCI

睾酮加非那雄胺治疗可改善 SCI 后的步行功能

• 批准号: 9291884
• 负责人: Dana M Otzel
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9291884
• 关键词: 5 Alpha-Reductase Inhibitor; Adverse effects; Analysis of Covariance; Area; Award; Body Composition; Bone Density; Chibro-Proscar; Chronic; Clinical; Clinical Trials; Data; Data Analyses; Data Collection; Disuse Atrophy; Dose; Double-Blind Method; Elderly man; Eligibility Determination; Evaluation; Exhibits; Expenditure; Extensor; FDA approved; Finasteride; Functional disorder; Funding; Gait; Goals; Health system; Hindlimb; Impairment; Individual; Injury; Intervention; K-Series Research Career Programs; Knee; Lead; Length; Locomotor training; Lower Extremity; Magnetic Resonance Imaging; Measures; Medical; Mentors; Modeling; Motor; Motor Activity; Muscle; Muscle function; Musculoskeletal; Outcome; Outcome Measure; Parents; Participant; Performance; Physical Rehabilitation; Pilot Projects; Placebo Control; Placebos; Population; Prognostic Factor; Protocols documentation; Quality of life; Randomized Clinical Trials; Recruitment Activity; Rehabilitation therapy; Replacement Therapy; Reporting; Research Infrastructure; Risk; Rodent; Role; Safety; Skeletal Muscle; Spinal cord injury; Stanolone; Testing; Testosterone; Testosterone Enanthate; Thigh structure; Thinness; Time; Torque; Training; Veterans; Walking; Width; Work; Yarrow; follow-up; functional improvement; functional outcomes; improved; innovation; instrument; mechanical load; men; meter; muscle form; muscle strength; neuromuscular; neuromuscular function; novel; pre-clinical; prevent; primary outcome; prospective; prostate enlargement; reduced muscle mass; relating to nervous system; secondary outcome; testosterone replacement therapy; walking speed

270,000 individuals have a spinal cord injury (SCI) in the US. Of these, ~42,000 are eligible for treatment in the Veteran Health System, resulting in direct annual medical expenditures exceeding $716 million per year. Walking impairment is a hallmark consequence of motor incomplete (i)SCI. Preventing neuromuscular deficits after iSCI has the potential to improve walking and positively impact functional independence and quality of life (QOL) in Veterans with SCI. The musculoskeletal decline primarily results from reduced neural drive after iSCI and disuse atrophy caused by reduced standing and walking (i.e., low muscle loading). These issues are exacerbated by the dramatic loss of testosterone (T) following iSCI in men. T replacement therapy (TRT) is a viable therapy to improve musculoskeletal function in non-neurologically impaired hypogonadal men. A prospective clinical trial has reported that TRT improves lower extremity lean mass after motor complete SCI, indicating the ability of TRT to produce musculoskeletal benefit independent of physical rehabilitation. Preclinical work by mentors Borst/Yarrow has shown preserved hindlimb musculature and improved locomotor activity in a rodent iSCI model following T administration. However, the ability of TRT to safely improve neuromuscular and locomotor function remains to be determined in men with iSCI, a population that exhibits impaired neuromuscular activation, reduced muscle mass/strength, and functional limitations after injury. Borst/Yarrow have also demonstrated that finasteride (F), an FDA approved 5α-reductase inhibitor that blocks the conversion of T to dihydrotestosterone, completely prevented prostate enlargement resulting from TRT without compromising the associated musculoskeletal benefits in hypogonadal elderly men, indicating that F co-administration improves the TRT risk-to-benefit ratio. This Career Development Award (CDA)-1 will embed itself in a recently funded VA Merit Award which is focused on evaluating the safety/efficacy of TRT plus finasteride (TRT+F) in hypogonadal men with iSCI who exhibit ambulatory dysfunction. The parent Merit Award is a 12-month double-blind placebo-controlled randomized clinical trial assessing: thigh muscle cross-sectional area (CSA), knee extension (KE) neuro-muscular function including strength and voluntary muscle, bone mineral density/body composition, and safety measures. This CDA-1 will expand beyond the above evaluations by adding several unique gait-related measures (functional outcomes that were not originally proposed) that will be performed at baseline, and at follow-up times of 3 and 6 months of treatment, in order to gauge functional improvements following the TRT+F vs. placebo. Twenty-six participants will be recruited and screened from the NF/SG VHS and will be treated according to the parent Merit protocol. Testosterone-enanthate (Delatestryl®) or placebo will be administered once weekly (i.m.) and finasteride (Proscar®) or placebo will be administered daily (p.o.) in FDA approved doses. The primary goal of this CDA-1 is to determine if TRT improves self-selected walking speed in hypogonadal men with iSCI. The primary outcome is 10m preferred walking speed and secondary outcomes will include walking features (i.e. cadence, step length, step width and step variability using the GaitRite® instrumented walking mat). Secondarily, we will evaluate whether walking speed is associated with thigh muscle quality (torque per unit CSA via MRI), KE torque (via dynamometry), and/or KE voluntary activation (via rate of EMG rise) after iSCI and whether TRT+F alters these associations. We hypothesize that walking speed will improve following TRT+F and that positive associations will be found between walking speed and thigh muscle quality, KE torque and/or KE neuromuscular activation. Analysis of covariance will be used where the dependent variable is defined as the average of the 3 and 6 month walking speeds, with baseline walking speed as a covariate. Pearson Correlations will be assessed for prognostic factors for improvement in walking speed at each time point correlated with baseline parameters.

在美国，有27万人患有脊髓损伤（SCI）。其中，约42，000人有资格接受治疗， 退伍军人医疗系统，每年直接医疗支出超过7.16亿美元。 行走障碍是运动不完全（i）SCI的标志性后果。预防神经肌肉缺陷 iSCI后有可能改善行走并对功能独立性和生活质量产生积极影响 (QOL)退伍军人SCI肌肉骨骼的衰退主要是由于iSCI后神经驱动的减少 以及由站立和行走减少引起的废用性萎缩（即，低肌肉负荷）。这些问题 男性iSCI后睾酮（T）急剧下降，加剧了这种情况。T替代疗法（TRT）是一种 改善非神经系统受损性腺功能减退男性肌肉骨骼功能的可行疗法。一 前瞻性临床试验已经报道TRT改善了运动完全性SCI后的下肢瘦体重， 表明TRT产生独立于身体康复的肌肉骨骼益处的能力。 导师Borst/Yarrow的临床前工作显示，后肢肌肉组织得到了保护，运动能力得到了改善。 在啮齿动物iSCI模型中，在T施用后的活性。然而，TRT安全改善的能力 iSCI患者的神经肌肉和运动功能仍有待确定， 损伤后神经肌肉激活受损、肌肉质量/强度降低和功能受限。 Borst/Yarrow还证明，FDA批准的5α-还原酶抑制剂芬布地（F） T转化为双氢睾酮，完全阻止了TRT导致的前列腺肥大 而不影响性腺功能减退老年男性的相关肌肉骨骼益处，表明F 联合给药改善了TRT的风险-获益比。此职业发展奖（CDA）-1将嵌入 在最近资助的VA优异奖中，该奖项专注于评估TRT plus的安全性/有效性 在表现出行走功能障碍的iSCI性腺功能减退男性患者中使用芬那肽（TRT+F）。家长优异奖 是一项为期12个月的双盲安慰剂对照随机临床试验，评估：大腿肌肉横截面 区域（CSA），膝关节伸展（KE）神经肌肉功能，包括力量和随意肌，骨 矿物质密度/身体成分和安全措施。这一CDA-1将扩展到上述范围之外 通过增加几个独特的步态相关措施（功能结果，原来不是 建议），将在基线以及治疗3个月和6个月的随访时间进行，以便 评估TRT+F与安慰剂治疗后的功能改善。 将从NF/SG VHS招募和筛选26名受试者，并根据以下标准进行治疗 主Merit协议。庚酸睾酮（Delatestryl®）或安慰剂每周给药一次 （上午）和非那鲁胺（Proscar®）或安慰剂将每天（p.o.）使用FDA批准的剂量。的 CDA-1的主要目的是确定TRT是否能改善性腺功能减退男性的自选步行速度 在SCI。主要结局为10 m首选步行速度，次要结局包括步行 特征（即使用GaitRite®仪器行走的节奏、步长、步宽和步频变化性 垫）。其次，我们将评估步行速度是否与大腿肌肉质量（每分钟的扭矩）相关。 单位CSA（通过MRI）、KE扭矩（通过测力法）和/或KE自主激活（通过EMG上升率） iSCI以及TRT+F是否改变了这些关联。我们假设，步行速度将改善以下 TRT+F，步行速度与大腿肌肉质量、KE扭矩呈正相关 和/或KE神经肌肉激活。当因变量为 定义为3个月和6个月步行速度的平均值，基线步行速度作为协变量。 将评估Pearson相关性，以确定每次步行速度改善的预后因素 点与基线参数相关。