TITRATED ORAL TOLVAPTAN TABLET ADMINISTRATION IN PATIENTS W/CHRONIC HYPONATREMIA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 低钠血症或低钠血症是住院患者最常见的电解质异常，报告发病率约为1%(1，2)。大多数低钠血症都是轻微的，通常是无症状的。然而，当血钠降至临界水平以下时，出现重大神经问题的可能性就会增加。这些神经问题包括注意力难以集中、迷失方向、神志不清、嗜睡和精神错乱，如果血清钠水平低于115-120mEq/L(正常钠为140-145mEq/L)，就会出现癫痫、昏迷，最终呼吸停止。(3，4)低钠血症的原因很多，包括：利尿剂(水丸)引起的盐分和水分丧失，充血性心力衰竭，肝功能衰竭，肾脏疾病，以及一种名为抗利尿激素分泌不当综合征(SIADH)的疾病，这种疾病可能与癌症、肺部疾病、肺炎、脑功能障碍和某些药物的摄入有关。有趣的是，所有这些低钠血症原因背后的共同主题是一种名为加压素或AVP的激素的分泌。加压素使肾脏重新吸收水分，从而导致液体滞留和血液钠的稀释。 治疗低钠血症的方法是根据症状的严重程度和低钠血症的根本原因。急性症状性低钠血症患者出现癫痫和/或惊厥时，应迅速纠正低钠血症。唯一有效的治疗方法是高渗盐水(一种浓缩的静脉钠溶液)。在症状较轻的患者中，例如，失代偿性充血性心力衰竭(CHF)、肝功能衰竭和SIADH患者，低钠血症的治疗可能具有挑战性，因为许多传统的利尿剂治疗进一步增强了加压素的释放，导致低钠血症加重。此外，在失代偿性肝功能衰竭和SIADH的情况下，传统的利尿剂治疗要么效果甚微，要么完全禁忌。无症状性低钠血症的治疗方法是限制液体。然而，虽然液体限制有效地抵消了过度分泌加压素(AVP)的影响，但它并不直接抑制它的作用。 拮抗AVP的药物可以为低钠血症患者提供一个重要的治疗选择。托伐普坦是一种口服加压素拮抗剂，已被证明可以诱导利尿，其自由水比钠流失的比例更多。这项研究是为了评估口服AVP抑制剂托伐普坦在纠正轻到中度低钠血症方面是否有效，而不伴随水分限制。 研究目标/假设： 这项研究将评估在以前参加过短期3期研究的患者中长期使用托伐普坦的安全性，并收集关于托伐普坦治疗和潜在疾病状态下低钠血症自然病史的信息。 研究设计： 参与这项研究的时间最长为26个月，约为763天。多达400名参与低钠血症第三阶段研究(156-02-235或156-03-238)的成年男性和女性患者可能有资格参加这项研究。患者必须有持续性或复发性低钠血症(血钠135mEq/L)，并在筛查时处于正常或高容量状态。符合条件的患者将在潜在登记前两天进行同意和筛查。入选的患者将开始使用托伐普坦(15毫克片剂，每天一次)治疗。15毫克、30毫克或60毫克研究药物的目标剂量之间的滴定将基于患者血钠浓度的变化和研究药物的临床耐受性。患者将继续服用托伐普坦长达108周。滴定的主要目标是使患者的血钠发生缓慢的变化。调查人员可自行决定在几天至几周内进行此类更正。一旦患者的血钠维持在135mEq/L以上，则不会进一步升高滴定；但是，如果患者出现无法忍受的口渴、多尿、脱水或其他可归因于研究药物的症状，或如果血钠升高至正常或高钠范围，则可能发生向下滴定。研究访问将在以下时间点进行：第1、14、31天，然后是第10、18、26、34、42、50、58、70、82、94、106周，以及研究药物停药后1周的随访。至少必须遵守这一时间表；然而，研究人员可以根据患者的临床情况安排更频繁的实验室评估和临床访问，特别是在滴定阶段。访问内容包括不良事件评估(S)、体格检查、心电图(第1天、第14天、第58、106周、第7天随访)、问卷调查、研究药物及伴随用药回顾(S)和实验室安全评估(S)。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hyponatremia, or low blood sodium, is the most frequently encountered electrolyte abnormality in hospitalized patients, with a reported incidence of approximately 1% (1,2). Most cases of hyponatremia are mild, and generally speaking, asymptomatic. However, as blood sodium falls below a critical level, the possibility of significant neurological problems increase. These neurological problems range from difficulty in concentration, disorientation, confusion, lethargy, and psychosis, to seizures, coma and ultimately respiratory arrest if serum sodium levels fall below 115 - 120 mEq/L (normal sodium is 140 - 145 mEq/L) (3,4) Hyponatremia has many causes including: diuretic (water-pill) induced salt and water loss, congestive heart failure, liver failure, kidney disorders, and a condition called syndrome of inappropriate antidiuretic hormone secretion (SIADH), which may be associated with cancer, lung diseases, pneumonia, brain disorders, and ingestion of certain medications. Interestingly, the common theme underlying all of these causes of hyponatremia is the secretion of a hormone called vasopressin or AVP. Vasopressin causes the kidney to reabsorb water, which leads to fluid retention and dilution of blood sodium. The approach to the treatment of hyponatremia is based on the symptom severity and the underlying cause of the low sodium. In the acute symptomatic hyponatremic patient, presenting with seizures and/or convulsions, rapid correction of the low sodium is indicated. The only effective treatment is hypertonic saline (a concentrated intravenous sodium solution). In the less severely symptomatic patient, for example, patients with decompensated congestive heart failure (CHF), liver failure and SIADH, treatment of hyponatremia can be challenging, since many of the conventional diuretic treatments further potentiate vasopressin release, resulting in aggravation of hyponatremia. Also, in the case of decompensated liver failure and SIADH, conventional diuretic treatments are either minimally effective or completely contraindicated. The treatment for asympomatic hyponatremia is fluid restriction. However, while fluid restriction effectively counteracts the effect of excess vasopressin (AVP) secretion, it does not directly inhibit it's actions. Agents that antagonize AVP could offer a significant treatment option for patients with hyponatremia. Tolvaptan is an oral vasopressin antagonist which has been shown to induce a diuresis with proportionally more free-water then sodium loss. This study is being undertaken to evaluate whether tolvaptan, an oral AVP inhibitor, will be effective in correcting mild to moderate hyponatremia without associated water restricition. Study Objective/Hypothesis: This study will assess the safety of long-term tolvaptan use in patients previously enrolled in shorter-term Phase 3 studies and gather information on the natural history of hyponatremia in the context of tolvaptan therapy and underlying disease states. Study Design: Participation in this study will be up to 26 months or approximately 763 days. Up to 400 adult male and female patients who participated in the Phase 3 studies for hyponatremia (156-02-235 or 156-03-238) may be eligible to participate in this study. Patients must have persistent or recurrent hyponatremia (serum sodium < 135 mEq/L) and in a euvolemic or hypervolemic state at screening. Eligible patients will be consented and screened up to two days prior to potential enrollment. Patients who are enrolled will begin treatment with tolvaptan (15mg tablet once a day). A titration between target doses of 15 mg, 30 mg or 60 mg of study drug will be based on the patient's change in serum sodium concentration and clinical tolerance of the study drug. Patients will remain on tolvaptan for up to 108 weeks. The primary goal of titration will be to effect a slow change in the patient's serum sodium. Such corrections may be made over a few days to a few weeks at the discretion of the investigator. Once the patient's serum sodium is maintained above 135 mEq/L further up-titration will not occur; however down titration may occur if the patient experiences intolerable thirst, polyuria, dehydration or other symptoms attributable to the study drug or if serum sodium increases to a high normal or hypernatremic range. Study visits will fall at the following time points: Days 1, 14, 31, then Weeks 10, 18, 26, 34, 42, 50, 58, 70, 82, 94, 106 and 1 week follow-up visit after the study drug is stopped. This schedule must be adhered to as a minimum; however the investigator may arrange for more frequent laboratory assessments and clinic visits based on the individual patient's clinical situation, particularly during the titration phase. Visits will consist of assessment of adverse event (s) , a physical exam, electrocardiogram (Day 1, Day 14, Week 58,106, 7 day follow-up), questionnaires, review of study drug and concomitant medication(s), and safety laboratory assessment(s).