Urea for chronic hyponatremia: a pilot study

尿素治疗慢性低钠血症：一项试点研究

• 批准号: 9978331
• 负责人: Helbert Rondon Berrios
• 金额: $ 23.48万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-11 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978331
• 关键词: Acute; Address; Adherence; Adverse event; American; Brain; Case Series; Chronic; Clinical; Clinical Trials; Data; Development; Disease; Diuretics; Dose; Effectiveness; Electrolyte Disorder; Etiology; Europe; European; Event; Excretory function; Formulation; Fracture; Frequencies; Functional disorder; Gait; Gait abnormality; Hospitalization; Hour; Hyponatremia; Inappropriate ADH Syndrome; Inpatients; Intervention; Liquid substance; Long-Term Effects; Morbidity - disease rate; Musculoskeletal Equilibrium; Neurocognitive; Neurocognitive Deficit; Neurologic Symptoms; Oral; Oral Administration; Osmolalities; Osteoporosis; Outcome; Outpatients; Patient Monitoring; Patient Recruitments; Patient-Focused Outcomes; Patients; Pharmacotherapy; Phase; Pilot Projects; Plasma; Posture; Prevention; Price; Public Health; Publishing; Randomized; Reporting; Retrospective Studies; Retrospective cohort study; Risk; Role; Safety; Serious Adverse Event; Sodium; Sodium Chloride; Symptoms; Tablets; Therapeutic Intervention; United States; Urea; Vasopressin Antagonist; Vasopressin Receptor; Vasopressins; base; clinical center; clinical encounter; compliance behavior; cost; design; effective therapy; efficacy clinical trial; extracellular; fall risk; falls; improved; interest; liver injury; mortality; novel; novel drug class; patient oriented; randomized placebo-controlled clinical trial; recruit; side effect; solute; urinary

PROJECT SUMMARY/ABSTRACT Hyponatremia is the most common electrolyte disorder encountered clinically. While acute and/or severe hyponatremia is commonly associated with significant symptoms, milder and more chronic forms of hyponatremia remain clinically inconspicuous as the brain effectively adapts to the low extracellular osmolality. However, recent evidence suggests that even mild hyponatremia is associated with subtle neurocognitive deficits, gait disturbances, falls, fractures, and osteoporosis, as well as increased mortality. Current therapeutic interventions for hyponatremia, including fluid restriction and loop diuretics lack clinical trial data to support their efficacy and are commonly associated with poor adherence. The discovery of vasopressin antagonists (vaptans) provided a new drug class targeting the most common mechanism of hyponatremia, i.e., elevated vasopressin. Despite the demonstrated efficacy of vaptans in clinical trials, their use has been limited by high cost as well as safety concerns related to risk of liver injury and the potential for rapid correction of hyponatremia. Thus, despite the significant morbidity and mortality associated with chronic non-severe hyponatremia, there is a paucity of definitively effective, safe, well-tolerated, and reasonably priced treatments. Small European case series have suggested that oral urea is safe and effective for the treatment of hyponatremia. However, urea has not been available for the treatment of hyponatremia in the United States until very recently. Our group recently published the first and only study describing the effectiveness and safety of a new American formulation of oral urea among hospitalized patients with hyponatremia. However, ours was a retrospective study limited to hospitalized patients. Data from large clinical trials on the efficacy of urea for the prevention of patient-centered outcomes in those with chronic hyponatremia are lacking. The current proposal is a pilot study that seeks to establish the feasibility of recruiting ambulatory patients with chronic hyponatremia into a study of urea, determine the acceptability of urea to patients, and explore the effect of this agent on plasma sodium level, neurocognitive function, and postural stability. We will recruit 30 ambulatory patients with chronic non-severe hyponatremia and randomize them to oral urea or no drug treatment for a period of 42 days. Following this initial phase, all patients will have a 10-day washout period, followed by a 42 day period in which subjects initially randomized to no drug therapy will receive urea and those initially treated with urea will receive no drug therapy. We will collect data regarding the ease of recruitment, patient adherence to urea, and adverse events related to its use. We will monitor patients’ plasma sodium, neurocognitive function, and postural stability over the course of the study. The feasibility, acceptability, and proof of concept/efficacy data from this pilot study will confirm our group’s capacity to conduct, and will inform the design of a large clinical trial that will assess the efficacy of urea for the prevention of serious clinical outcomes of chronic non-severe hyponatremia.

项目摘要/摘要 低钠血症是临床上最常见的电解质紊乱。在急性和/或严重时 低钠血症通常与明显的症状、较轻微和较慢性的 低钠血症在临床上仍然不明显，因为大脑有效地适应了细胞外的低渗透压。 然而，最近的证据表明，即使是轻微的低钠血症也与细微的神经认知有关。 缺陷、步态障碍、跌倒、骨折和骨质疏松症，以及死亡率增加。目前的治疗方法 对低钠血症的干预措施，包括限液和环状利尿剂，缺乏临床试验数据来支持他们的 有效，通常与依从性差有关。加压素拮抗剂(氯丙沙坦)的发现 提供了一个新的药物类别，针对最常见的低钠血症机制，即升高的加压素。 尽管在临床试验中证明了电子烟的有效性，但它们的使用受到了高昂的成本以及 与肝损伤风险和快速纠正低钠血症的可能性有关的安全问题。因此，尽管 与慢性非严重低钠血症相关的显著发病率和死亡率，缺乏 绝对有效、安全、耐受性好、价格合理的治疗方法。 欧洲的一系列小病例表明口服尿素是安全有效的。 低钠血症。然而，尿素直到在美国才可用于治疗低钠血症 就在最近。我们小组最近发表了第一项也是唯一一项研究，描述了一种 低钠血症住院患者口服尿素的美国新配方。然而，我们的是一个 回顾性研究仅限于住院患者。来自大型临床试验的数据，关于尿素对糖尿病的疗效 缺乏对慢性低钠血症患者以患者为中心的结果的预防。目前的提案 是一项试验性研究，旨在确定招募慢性低钠血症门诊患者的可行性 对尿素进行研究，测定患者对尿素的接受度，探讨尿素对血浆的影响 钠水平、神经认知功能和姿势稳定性。我们将招募30名慢性病门诊患者 对非严重低钠血症患者随机给予口服尿素或不给予药物治疗，疗程42天。 在这一初始阶段之后，所有患者将有10天的冲洗期，然后是42天的冲洗期 最初随机接受药物治疗的受试者将接受尿素治疗，而最初接受尿素治疗的受试者将接受 没有药物治疗。我们将收集有关招募的简便性、患者对尿素的依从性和不良反应的数据 与其使用相关的事件。我们将监测患者的血钠、神经认知功能和姿势稳定性 在研究过程中。这项先导研究的概念/功效数据的可行性、可接受性和证据 将确认我们小组的实施能力，并将公布一项大型临床试验的设计，该试验将评估 尿素预防慢性非严重低钠血症严重临床结局的疗效。