Early Treatment of ALS with Nutrition and NIPPV

描述(申请人提供)：迄今为止的研究表明，尽管肌萎缩侧索硬化症(ALS)较晚才出现，但经皮内窥镜胃造瘘术(PEG术)和无创正压通气(NIPPV)可提高患者的存活率。我们假设，早期干预可能会进一步改善结果。然而，关于早期使用这些治疗的许多问题排除了设计第三阶段临床试验来检验这一假设的可能性。NIPPV和营养学的共同之处是缺乏一个可靠的早期呼吸或营养不足的指标。在营养方面，我们需要可靠和具成本效益的方法来确定病人在疾病不同阶段的能量(即卡路里)需求，并根据能量摄入的充分性来推荐PEG值。对于NIPPV，我们需要确定影响该疗法接受度和耐受性的因素，以及对早期呼吸功能障碍的测量。因此，我们建议进行这项多中心试点研究，以开发最终的第三阶段试验的方法。这项先导性研究的具体目的是：1)开发和验证提高NIPPV耐受性的策略，确定影响接受这种治疗方式的因素，并评估早期呼吸功能障碍的措施；以及2)开发和验证确定ALS能量平衡的方法。在这项初步研究中，所有11个站点都将采用基于FVC(80%-95%比50%-79%)的分层设计招募患者，并在患者下降到FVC水平的下限时提供NIPPV。六个站点将收集更多详细信息，以严格评估NIPPV的可接受性，制定提高耐受性的策略，并验证这一方法，以及收集可能有助于更早识别失败的呼吸测量。其他5个站点将使用纵向设计中的“黄金标准”双标记水方法，根据易于执行的临床测量，推导出可靠地预测个体能量需求的经验公式。这项先导性研究的结果将使我们能够开发和验证方法，以便我们可以设计一项多中心III期试验，以确定早期NIPPV和营养干预的疗效。此外，我们的结果将立即适用于临床医生在实践中使用，并将为重新制定未来ALS药物试验的实验设计提供基础。

DESCRIPTION (provided by applicant): Studies to date indicate that Percutaneous Endoscopic Gastrostomy (PEG) and Non-Invasive Positive Pressure Ventilation (NIPPV) improve survival in Amyotrophic Lateral Sclerosis (ALS), even though introduced late in the disease. We hypothesize that early intervention may improve outcome even further. However, many issues regarding the early use of these treatments preclude the design of a Phase III clinical trial to test this hypothesis. Common to both NIPPV and nutrition is a lack of a reliable indicator of early respiratory or nutritional insufficiency. With respect to nutrition, we need reliable and cost effective methods to determine a patient's energy (i.e. caloric) requirements during different stages of the illness and base the recommendation for PEG on the adequacy of energy intake. For NIPPV, we need to identify factors that influence acceptance and tolerability of this therapy, and measurements of early respiratory dysfunction. Therefore, we propose this multicenter Pilot Study to develop methods for a definitive Phase III trial. The Specific Aims of this Pilot Study are: 1) To develop and validate strategies to improve tolerability of NIPPV, to identify factors that influence acceptance of this treatment modality, and to evaluate measures of early respiratory dysfunction; and 2) To develop and validate methods to determine energy balance in ALS. In this Pilot Study, all 11 sites will enroll patients using a stratified design based on FVC (80-95% vs 50-79%) and offer NIPPV as they decline to the lower limit of this FVC level. Six sites will collect additional detailed information to critically evaluate acceptability of NIPPV, devise strategies to improve tolerance, and validate this approach as well as collect respiratory measurements that may allow earlier identification of failure. The other 5 sites will use the "gold standard" Doubly Labeled Water method in a longitudinal design to derive empiric equations to reliably predict individual energy needs based on easily performed clinical measures. The results of this Pilot Study will allow us to develop and validate methods so that we can design a multicenter Phase III trial to determine the efficacy of early NIPPV and nutritional intervention. In addition, our results will be immediately applicable for use by clinicians in practice and will provide the basis to re-formulate the experimental design of future drug trials in ALS.