Growth hormone secretagogue MK-677 therapy in CKD and ESRD

描述(申请人提供)：随着慢性肾脏疾病(CKD)的发展和进展到终末期肾脏疾病(ESRD)，营养不良成为一个日益严重的问题。这被认为是通过两种机制发生的：继发于尿毒症的食欲下降和分解代谢炎症环境的发展。患者的肌肉质量和功能活动减少，发病率和死亡率增加。许多疗法都被使用过，但收效甚微。生长激素(GH)和胰岛素样生长激素(IGF-I)可改善肌肉质量、生活质量、营养参数、免疫和身体功能，但必须由父母服用，并受到费用和患者依从性的限制。最近，内源性生长激素受体促分泌剂(GHRS)Ghrelin被证明可以提高内源性GH和改善食物摄入量，但必须由父母给药，目前还没有。合成的生长激素释放激素，类似于Ghrelin的MK-677口服，最近被证明可以增加老年人的IGF-I和肌肉质量。其在慢性肾脏病和终末期肾病中的作用尚不清楚。我们推测MK-677在CKD和ESRD中会增加IGF-I，并与外源性GH和IGF-I具有相似的作用。首先，必须证明它在CKD/ESRD人群中是有效的。我们提出了一项初步研究来解决这一假设。如果成功，则可以启动大规模研究，以检查潜在的更广泛的长期影响。我们提出了三个具体目标。所有这些在本质上都是双重盲目的。目标1将在CKD第4/5期的短期交叉研究中确定MK-677是否引起IGF-I的增加。目标2将以与目标1相同的研究形式评估MK-677是否会增加终末期肾病患者的IGF-I。如果目标1和2如预期的那样证明IGF-I的增加，那么将进行一项为期一年的研究，以评估MK-677对CKD/ESRD患者肌肉质量的影响。具体目标1和2的主要结果将是IGF-I水平。对于目标3，主要结果将是肌肉质量。次要结果将是对细胞因子水平、营养参数、生活质量、身体功能和经济参数的影响。这是一项由调查人员发起的提案，默克公司将只提供有效的MK-677药丸和匹配的安慰剂以及来自未公布数据和试验的建议。W.Kline 7项目叙述：相关性：慢性肾病(CKD)和需要透析的终末期肾病(ESRD)是美国的主要公共卫生问题。CKD和ESRD的发病率和死亡率与营养状况有关，营养状况最差的患者死亡、住院和疾病并发症的风险更高。CKD和ESRD的营养不良目前还没有很好的治疗方法。如果这一问题能够得到缓解或消除，这将对CKD和ESRD患者产生重大的经济和社会影响。本研究旨在确定MK-677是否能在CKD和ESRD患者中引起类似的变化。MK-677在正常受试者中诱导生长激素，并随后在临床上产生有益效果。如果这样做，这将减少这一群体患者的营养不良，显著提高他们死亡和肾脏疾病并发症的风险，并降低住院和医疗保健成本。

DESCRIPTION (provided by applicant): With development and progression of chronic kidney disease (CKD) to end stage renal disease (ESRD), malnutrition becomes an increasingly severe problem. This is thought to occur from two mechanisms: decreased appetite secondary to uremia and development of a catabolic inflammatory milieu. Patients experience decreased muscle mass and functional activity associated with increased morbidity and mortality. Many therapies have been used with little success. Growth hormone (GH) and insulin like growth hormone (IGF-I) improve muscle mass, quality of life, nutritional parameters, immune and physical functions but must be given parentally and are limited by expense and patient compliance. Recently, the endogenous GH receptor secretagogue (GHRS) ghrelin has been shown to raise endogenous GH and improve food intake but must be given parentally and is not available. The synthetic GHRS, ghrelin mimetic MK-677 given orally, has recently been shown to increase IGF-I and muscle mass in the elderly. Its effects in CKD and ESRD are unknown. We hypothesize that MK-677 will effect an increase of IGF-I and have similar effects to exogenous GH and IGF-I in CKD and ESRD. First it must be shown to be effective in the CKD/ESRD population. We propose a pilot study to address this hypothesis. If successful, then large scale studies can be initiated to examine a potential broader effect long term. We propose three specific aims. All would be double blind in nature. Aim 1 will determine if MK-677 elicits an increase in IGF-I in short term cross-over studies in CKD stage 4/5. Aim 2 will assess if MK-677 increases IGF-I in ESRD in the same study format as Aim 1. If Aims 1 and 2 demonstrate an increase in IGF-I, as anticipated, then a one year study to assess the effect of MK-677 on muscle mass in patients with CKD / ESRD will be performed. The primary outcome in Specific Aim 1 and 2 will be IGF-I levels. For Aim 3, the primary outcome will be muscle mass. Secondary outcomes will be the effects on cytokine levels, nutritional parameters, quality of life, physical function and economic parameters. This is an investigator initiated proposal for which Merck will only supply active MK-677 pills with matching placebo and advice from unpublished data and trials. Bolton, W. Kline 7 Project narrative: Relevance: Chronic kidney disease (CKD) and the need for dialysis, end stage renal disease (ESRD) are major public health issues in the United States. Morbidity and mortality in CKD and ESRD are related to nutritional status with patients having worst nutritional status and having a higher risk for death, hospitalization, and complication of their diseases. There is currently no good treatment of the malnutrition of CKD and ESRD. If this problem could be alleviated or eliminated, this would have a significant financial and societal impact on patients with CKD and ESRD. The present proposal seeks to determine if MK-677, which induces growth hormone in normal subjects with subsequent beneficial effects clinically, can induce similar changes in patients with CKD and ESRD. If it does so, this would decrease the malnutrition in this group of patients and significantly improve their risk for death and complications of kidney disease, and decrease the cost for hospitalization and medical care.