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

Study Overview
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Brief Summary
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The present study is designed to confirm and extend the observation from previous studies that lixivaptan therapy corrects hyponatremia, in euvolemic subject, including subjects with SIADH.

Detailed Description
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Phase I 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, liver cirrhosis with ascites (LCWA) and syndrome of inappropriate antidiuretic hormone (SIADH). Lixivaptan was previously evaluated in disease states characterized by hyponatremia with euvolemia (SIADH)and hyponatremia combined with fluid overload (HF, LCWA). Lixivaptan resulted in correction in hyponatremia together with a marked aquaresis in subject with volume overload. The present study is designed to confirm and extend the observation from previous studies that lixivaptan therapy corrects hyponatremia, in euvolemic subject, including subjects with SIDH.

Official Title
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Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Oral Lixivaptan Capsules in Subject With Euvolemic Hyponatremia

Conditions
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Hyponatremia With Normal Extracellular Fluid Volume

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 (120 ≤ Na+<130 mEq/L) Hospitalized or willing to be admitted to a monitored setting for approximately the first 48 hours of treatment Exclusion Criteria: Pregnant or breast-feeding women, or women planning to become pregnant or to breastfeed Symptomatic hyponatremia (e.g., lethargy, coma, seizures, changes in mental status attributable to hyponatremia) Acute or transient hyponatremia (e.g., associated with head trauma or postoperative state) Hyponatremia in hypovolemic states. Hypovolemic hyponatremia is defined as the presence of clinical evidence of extracellular fluid volume depletion Hyponatremia as a result of any medication that can safely be withdrawn Hyponatremia due to hypothyroidism or adrenal insufficiency Diagnosis of psychogenic polydipsia Receiving within 7 days of enrollment, other medication for treatment of hyponatremia specifically: demeclocycline, lithium carbonate, urea, or conivaptan Use of radiotherapy and chemotherapy within 2 wks of randomization Likely to require, or to receive IV saline for correction of symptomatic or asymptomatic severe hyponatremia during the course of the study Supine systolic arterial blood pressure of ≤ 90 mmHg Serum creatinine >3.0 mg/dL History of uncontrolled type 2 diabetes mellitus Severe pulmonary artery hypertension: patients whose condition is expected to deteriorate with sudden shifts in fluid volumes and cardiac filling pressures Established diagnosis of New York Heart Association (NYHA) class III or IV heart failure History of myocardial infarction, unstable angina or evidence of active ischemia within 30 days prior to screening History of cerebral vascular accident (CVA) within 60 days prior to screening Established diagnosis of nephrotic syndrome Advanced liver disease or documented diagnosis of cirrhosis or alcoholic hepatitis Urinary tract obstruction (benign prostatic hypertrophy [BPH] allowed if non-obstructive) History of alcohol abuse or illicit drug use within the past 6 months 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 (drug or device) within 30 days prior to baseline visit Unable to take oral medications

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: Active Comparator<br>lixivaptan | Drug: lixivaptan<br>* oral capsule<br>|
| Placebo Comparator: Placebo<br>placebo | Drug: placebo<br>* oral capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average daily area under the curve (AUC) of change from baseline in serum sodium concentrations up to 72 hrs in lixivaptan treated subjects compared to placebo |  | 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in serum sodium on Day 30 |  | 60 days | 
| Percentage of subjects achieving normalized serum sodium (Na+ ≥ 135 mEq/L) |  | 60 days | 
| Time to first normalization of serum sodium (Na+≥135 mEq/L) |  | 60 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Euvolemic, Hyponatremia, Serum Sodium, Fluid Overload, Vasopressin Antagonist