Phase 3b, Multicenter, Randomized, Single-blind, Parallel Group Trial of the Effects of Titrated Oral SAMSCA(r) (Tolvaptan) 15, 30, or 60 mg QD Compared to Placebo Plus Fluid Restriction on Length of Hospital Stay and Symptoms in Subjects Hospitalized With Dilutional Hyponatremia

Effects of Tolvaptan vs Fluid Restriction in Hospitalized Subjects With Dilutional Hyponatremia

Sponsors

Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Source Otsuka Pharmaceutical Development & Commercialization, Inc.
Brief Summary

The purpose of this study is to determine if hospitalized patients with symptomatic hyponatremia treated with tolvaptan are in the hospital for less time than patients treated with fluid restriction. The study will also test if tolvaptan is better than fluid restriction in treating the symptoms of hyponatremia in hospitalized patients.

Overall Status Terminated
Start Date October 2010
Completion Date May 2013
Primary Completion Date May 2013
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Length of Hospital Stay (LoS) 45 days
Secondary Outcome
Measure Time Frame
Change From Baseline to 48 Hour Post Dose in Clinical Global Impression-Severity (CGI-S) of Hyponatremia Symptoms. Baseline to 48 hours post dose
Change From Baseline to 24 and 72 Hours Post Dose in CGI-S of Hyponatremia Symptoms. Baseline to 24 and 72 hours post dose
Change From Baseline to 48 Hours Post Dose in Clinical Global Impression - Improvement (CGI-I) Score of Hyponatremia Symptoms. Baseline to 48 hours post dose
Change From Baseline in Serum Sodium Concentration (24 Hour Area Under the Curve [AUC]). 0 to 72 hours
Time to First 2-point Improvement in CGI-S Score. Up to 72 hours
Percentage of Participants With Clinical Global Impression-Improvement (CGI-I) Score Improved to a Score of 1 or 2. 48 hours post dose
Percentage of Participants Requiring Rescue Therapy for Hyponatremia 7 days
Enrollment 124
Condition
Intervention

Intervention type: Drug

Intervention name: tolvaptan

Description: 15 mg titrated to 30 mg then 60 mg once daily as oral tablet for up to 7 days based on response.

Arm group label: Tolvaptan 15-60mg

Intervention type: Other

Intervention name: Fluid Restriction

Description: Placebo tablet once daily with prescribed daily fluid intake of 1500 mL, then intensifying to 2 lower volumes of fluid intake for up to 7 days based on response. Since all particpants were blinded to treatment, titration to stricter fluid restriction followed the same algorithm as tolvaptan, increasing both the level of fluid restriction and increasing the placebo "dose"

Arm group label: Fluid Restriction

Eligibility

Criteria:

Inclusion Criteria:

- Hyponatremia in clinically euvolemic or hypervolemic states, defined as serum sodium < 130 mEq/L prior to randomization

- Clinically significant symptoms of hyponatremia, defined as a CGI-S score between 3-6, inclusive

- Female subjects of child bearing potential who agree to remain abstinent or to practice double-barrier forms of birth control from screening through 30 days following first dose on IMP

Exclusion Criteria:

- Women who are pregnant or breast feeding, and females of childbearing potential who are not using acceptable contraceptive methods (such as barrier contraceptives or methods that result in a failure rate of less than 1%)

- Hyponatremia in hypovolemic states, defined as the presence of clinical and historical evidence of extracellular fluid volume depletion, including but not limited to skin turgor, orthostatic changes in blood pressure or heart rate, dry mucous membranes, or a response to IV saline challenge

- Subjects who are likely to require prolonged hospitalization for reasons other than hyponatremia, eg. new femoral fracture, surgeries requiring extended recovery

- Recent prior treatment for hyponatremia: hypertonic saline (including normal saline challenge) (within 8 hours of baseline) or urea, lithium, demeclocycline, conivaptan or tolvaptan (within 4 days of baseline). Includes any treatment, other than fluid restriction for the purpose of increasing serum sodium.

- Hyponatremia symptoms of a severity (eg, CGI = 7) such that they require immediate intervention with hypertonic saline; or are expected to require such therapy within 48 hours

- Causes of neurological symptoms which are attributable to psychological (psychosis), structural (dementia of the Alzheimer's type, stroke, transient ischemic attack, multi-infarct dementia) or other metabolic causes (eg. hyper- or hypo-: oxemia, glycemia, calcemia, ammonemia, etc)

- Acute and transient hyponatremia associated with head trauma or severe neurological injury (eg. stroke, subdural hematoma)or the use of recreational drugs.

- History of hyponatremia known to be due to severe, untreated hypothyroidism/adrenal insufficiency

- Subjects with psychogenic polydipsia

- Systolic arterial blood pressure < 90 mmHg at screening

- History of hypersensitivity and/or idiosyncratic reaction to benzazepine or benzazepine derivatives (such as benazepril), or tolvaptan

- History of drug or medication abuse within the 3 months prior to screening, or current alcohol abuse

- Uncontrolled diabetes mellitus defined as glucose > 300 mg/dL [16.7 mmol/L]

- Current urinary tract obstruction (eg, obstructive benign prostatic hypertrophy)

- Current condition of anuria

- Serum creatinine > 3.5 mg/dL at screening

- Terminally ill or moribund condition with little chance of short-term (eg, 30 day) survival

- Subjects whose hyponatremia is the result of any medication that can safely be withdrawn (examples of drugs often not withdrawn include: anticonvulsants [eg, carbamazepine] and antipsychotics [eg, haloperidol])

- Patients receiving DDAVP within 2 days of screening

- Patients with history of active variceal bleeding within the past 30 days, without prior approval from sponsor medical monitor

- Participation in another investigational drug trial within the past 30 days

Gender: All

Minimum age: 18 Years

Maximum age: N/A

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
Ann Dandurand, MD Study Director Otsuka Pharmaceutical Development & Commercialization, Inc.
Location
facility
Otsuka Investigational Site | Birmingham, Alabama, 35216, United States
Otsuka Investigational Site | Birmingham, Alabama, 35242, United States
Otsuka Investigational Site | Mobile, Alabama, 36608, United States
Otsuka Investigational Site | Azusa, California, 91702, United States
Otsuka Investigational Site | Banning, California, 92220, United States
Otsuka Investigational Site | Culver City, California, 90232, United States
Otsuka Investigational Site | Fountain Valley, California, 92708, United States
Otsuka Investigational Site | Los Angeles, California, 90025, United States
Otsuka Investigational Site | Los Angeles, California, 90033, United States
Otsuka Investigational Site | Northridge, California, 91324, United States
Otuska Investigational Site | Orange, California, 92868, United States
Otsuka Investigational Site | Yorba Linda, California, 92886, United States
Otsuka Investigational Site | Denver, Colorado, 80210, United States
Otsuka Investigational Site | Washington, District of Columbia, 20010, United States
Otsuka Investigational Site | Jacksonville, Florida, 32207, United States
Otsuka Investigational Site | Jacksonville, Florida, 32209, United States
Otsuka Investigational Site | Jacksonville, Florida, 32216, United States
Otsuka Investigational Site | Orlando, Florida, 32803, United States
Otsuka Investigational Site | Port Charlotte, Florida, 33952, United States
Otsuka Investigational Site | Savannah, Georgia, 31405, United States
Otsuka Investigational Site | Elizabethtown, Kentucky, 42701, United States
Otsuka Investigational Site | Baltimore, Maryland, 21215, United States
Otsuka Investigational Site | Springfield, Massachusetts, 01107, United States
Otsuka Investigational Site | Saginaw, Michigan, 48602, United States
Otsuka Investigational Site | Southfield, Michigan, 48075, United States
Otsuka Investigational Site | Minneapolis, Minnesota, 55455, United States
Otsuka Investigational Site | Rochester, Minnesota, 55905, United States
Otsuka Investigational Site | Jackson, Mississippi, 39216, United States
Otsuka Investigational Site | St. Louis, Missouri, 63110, United States
Otsuka Investigational Site | Grand Island, Nebraska, 68803, United States
Otsuka Investigational Site | Omaha, Nebraska, 68131, United States
Otsuka Investigational Site | Haddon Heights, New Jersey, 08035, United States
Otsuka Investigational Site | Newark, New Jersey, 07103, United States
Otsuka Investigational Site | Bronx, New York, 10461, United States
Otsuka Investigational Site | Buffalo, New York, 14203, United States
Otsuka Investigational Site | Buffalo, New York, 14215, United States
Otsuka Investigational Site | Jamaica, New York, 11418, United States
Otsuka Investigational Site | New York, New York, 10032, United States
Otsuka Investigational Site | Cincinnati, Ohio, 45267, United States
Otsuka Investigational Site | Cleveland, Ohio, 44195, United States
Otsuka Investigational Site | Columbus, Ohio, 43212, United States
Otsuka Investigational Site | Fairfield, Ohio, 45014, United States
Otsuka Investigational Site | Toledo, Ohio, 43560, United States
Otsuka Investigational Site | Oklahoma City, Oklahoma, 73120, United States
Otsuka Investigational Site | Bethleham, Pennsylvania, 18017, United States
Otsuka Investigational Site | Philadelphia, Pennsylvania, 19102, United States
Otsuka Investigational Site | Philadelphia, Pennsylvania, 19140, United States
Otsuka Investigational Site | West Reading, Pennsylvania, 19611, United States
Otsuka Investigational Site | Providence, Rhode Island, 02903, United States
Otsuka Investigational Site | Galveston, Texas, 77555, United States
Otsuka Investigational Site | Houston, Texas, 77030, United States
Otsuka Investigational Site | Mission, Texas, 78572, United States
Otsuka Investigational Site | San Antonio, Texas, 78205, United States
Otsuka Investigational Site | San Antonio, Texas, 78229, United States
Otsuka Investigational Site | Fairfax, Virginia, 22030, United States
Otsuka Investigational Site | Madison, Wisconsin, 53705, United States
Location Countries

United States

Verification Date

October 2014

Responsible Party

Responsible party type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Arm group label: Tolvaptan 15-60mg

Arm group type: Experimental

Description: Oral tablet without fluid restriction. After the initial dose, daily dose may be titrated based on response.

Arm group label: Fluid Restriction

Arm group type: Active Comparator

Description: Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may titrated based response.

Acronym SALACIA
Study Design Info

Allocation: Randomized

Intervention model: Parallel Assignment

Primary purpose: Treatment

Masking: Single (Participant)

Source: ClinicalTrials.gov