A Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Tolerability of Oral Lixivaptan Capsules in Subjects With Euvolemic Hyponatremia

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability of oral lixivaptan capsules in subjects with Euvolemic Hyponatremia.

Detailed Description
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Phase I and Phase II clinical trials have demonstrated that lixivaptan may play an important role in treating hyponatremia and the signs and symptoms of water retention associated with HF, LCWA, and SIADH. Lixivaptan was previously evaluated in disease states characterized by hyponatremia with euvolemia (SIADH) and hyponatremia combined with fluid overload (HF, LCWA). Lixivaptan demonstrated correction in serum sodium concentration together with marked aquaresis in subjects with hyponatremia.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Tolerability of Oral Lixivaptan Capsules in Subjects With Euvolemic Hyponatremia

Conditions
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Euvolemic Hyponatremia

Intervention / Treatment
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* Drug: Lixivaptan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent. Men or women aged 18 or older. Diagnosis of euvolemic hyponatremia (Na+ < 135 mEq/L). Willing to be observed in a monitored setting for approximately the first 8 hours following treatment initiation (first dose). In the Investigator's judgement the patient has adequate visual and auditory acuity to allow participation in the trial. Exclusion Criteria: Pregnant or breast-feeding women, or women planning to become pregnant or to breastfeed. Overt symptoms of hyponatremia requiring immediate medical intervention (e.g., coma, seizures). Acute or transient hyponatremia (e.g., associated with head trauma, postoperative state, or use of radiotherapy and/or chemotherapy). Hyponatremia in hypovolemic states (e.g., due to fluid loss through vomiting, diarrhea, burns, etc.). Hypovolemic hyponatremia is defined as the presence of clinical evidence of extracellular fluid volume depletion. Hyponatremia in hypervolemic states (e.g., congestive heart failure). Hypervolemia is defined as a presence of increased total body water with signs of edema. Pseudohyponatremia (i.e., hyponatremia resulting from a laboratory artifact). Hypertonic hyponatremia (e.g., hyponatremia in the setting of hyperglycemia). Hyponatremia as a result of any medication that can safely be withdrawn. Hyponatremia due to hypothyroidism or adrenal insufficiency. Current diagnosis of psychogenic polydipsia. Receiving within 7 days of enrollment other medication for treatment of hyponatremia, specifically: demeclocycline, lithium carbonate, urea, or any vasopressin antagonist. Supine systolic arterial blood pressure of ≤ 90 millimeters of mercury (mmHg). Serum creatinine > 3.0 mg/dL (> 265.2 mol/L). Hypokalemia based on clinical sign/symptoms or lab findings (e.g., serum potassium < 3.5 mEq/L). Uncontrolled diabetes mellitus as defined by the Investigators (e.g., hemoglobin - glycosylated [HbA1c] > 9%). ST-segment elevation myocardial infarction (STEMI) within 30 days or active myocardial ischemia at the time of enrollment. History of cerebral vascular accident (CVA) within 30 days prior to screening. Severe malnutrition in the Investigator's judgment (e.g., body mass index [BMI] < 17). Advanced liver disease or documented diagnosis of cirrhosis or alcoholic hepatitis. Urinary tract obstruction (benign prostatic hypertrophy [BPH] allowed if non-obstructive). History of chronic drug/medication abuse within the past 6 months or current alcohol abuse. Terminally ill or moribund condition with little chance of short-term survival. Receiving vasopressin or its analogs for treatment of any condition. Known allergy to any vasopressin antagonist. Previous participation in a lixivaptan study. Recipient of any investigational treatment within 30 days prior to baseline visit. Unable to take oral medications. Significant neurological disorders (e.g., permanent neurological deficits, probable Alzheimer's disease, normal pressure hydrocephalus, Parkinsonian dementia complex, multi-infarct dementia, mixed dementia, or Huntington's disease). Conditions limiting access to water or an inability to respond to thirst (e.g., hydrophobia, or non-communicative).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Lixivaptan | Drug: Lixivaptan<br>* Capsules, 25mg lixivaptan or matching placebo once daily. Study medication can be titrated up to 50mg or 100mg once daily. Acceptable dosages are once daily administration of 25mg, 50mg, or 100mg as a single dose.<br>|
| Placebo Comparator: 2<br>Placebo | Drug: Placebo<br>* Capsule. Subjects will be randomized (3:1) on an outpatient basis to 25 mg lixivaptan or matching placebo, once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To demonstrate that lixivaptan is safe and effective in achieving and maintaining increased serum sodium concentration in subjects with SIADH and other conditions of euvolemic hyponatremia. |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| If lixivaptan demonstrates improvement in serum sodium, % of subjects achieving normalized serum sodium, % of subjects requiring fluid restriction, prevention of worsening hyponatremia, and the change from baseline to complete TMT-B. |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Euvolemic Hyponatremia, SIADH, Serum Sodium