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

NCT01227512 | Terminated Phase 3 Results

• 1 other identifier: 156-08-275
• Study Type: interventional
• Target: 124
• Locations: 1 country
• Sites: 56

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.

Conditions

Hyponatremia; Dilutional Hyponatremia; Inappropriate ADH Syndrome

Keywords

Hyponatremia; Dilutional Hyponatremia; Euvolemic Hyponatremia; Hypervolemic Hyponatremia; Fluid Restriction; Tolvaptan

Outcome Measures

Primary Outcomes (1)

• Length of Hospital Stay (LoS)

  LoS was time to clinically ready to be hospital discharged (CRBD) from study treatment initiation, disregarding prolonged hospitalization due solely to social factors.

  45 days

Secondary Outcomes (7)

• 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

Study Arms (2)

Tolvaptan 15-60mg

EXPERIMENTAL

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

Drug: tolvaptan

Fluid Restriction

ACTIVE COMPARATOR

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

Other: Fluid Restriction

Interventions

tolvaptan DRUG

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

Also known as: SAMSCA, OPC-41061, OPC-156

Tolvaptan 15-60mg

Fluid Restriction OTHER

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"

Fluid Restriction

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.: lead

Study Sites (56)

Otsuka Investigational Site

Birmingham, Alabama, 35216, United States

Location

Otsuka Investigational Site

Birmingham, Alabama, 35242, United States

Location

Otsuka Investigational Site

Mobile, Alabama, 36608, United States

Location

Otsuka Investigational Site

Azusa, California, 91702, United States

Location

Otsuka Investigational Site

Banning, California, 92220, United States

Location

Otsuka Investigational Site

Culver City, California, 90232, United States

Location

Otsuka Investigational Site

Fountain Valley, California, 92708, United States

Location

Otsuka Investigational Site

Los Angeles, California, 90025, United States

Location

Otsuka Investigational Site

Los Angeles, California, 90033, United States

Location

Otsuka Investigational Site

Northridge, California, 91324, United States

Location

Otuska Investigational Site

Orange, California, 92868, United States

Location

Otsuka Investigational Site

Yorba Linda, California, 92886, United States

Location

Otsuka Investigational Site

Denver, Colorado, 80210, United States

Location

Otsuka Investigational Site

Washington D.C., District of Columbia, 20010, United States

Location

Otsuka Investigational Site

Jacksonville, Florida, 32207, United States

Location

Otsuka Investigational Site

Jacksonville, Florida, 32209, United States

Location

Otsuka Investigational Site

Jacksonville, Florida, 32216, United States

Location

Otsuka Investigational Site

Orlando, Florida, 32803, United States

Location

Otsuka Investigational Site

Port Charlotte, Florida, 33952, United States

Location

Otsuka Investigational Site

Savannah, Georgia, 31405, United States

Location

Otsuka Investigational Site

Elizabethtown, Kentucky, 42701, United States

Location

Otsuka Investigational Site

Baltimore, Maryland, 21215, United States

Location

Otsuka Investigational Site

Springfield, Massachusetts, 01107, United States

Location

Otsuka Investigational Site

Saginaw, Michigan, 48602, United States

Location

Otsuka Investigational Site

Southfield, Michigan, 48075, United States

Location

Otsuka Investigational Site

Minneapolis, Minnesota, 55455, United States

Location

Otsuka Investigational Site

Rochester, Minnesota, 55905, United States

Location

Otsuka Investigational Site

Jackson, Mississippi, 39216, United States

Location

Otsuka Investigational Site

St Louis, Missouri, 63110, United States

Location

Otsuka Investigational Site

Grand Island, Nebraska, 68803, United States

Location

Otsuka Investigational Site

Omaha, Nebraska, 68131, United States

Location

Otsuka Investigational Site

Haddon Heights, New Jersey, 08035, United States

Location

Otsuka Investigational Site

Newark, New Jersey, 07103, United States

Location

Otsuka Investigational Site

Buffalo, New York, 14203, United States

Location

Otsuka Investigational Site

Buffalo, New York, 14215, United States

Location

Otsuka Investigational Site

Jamaica, New York, 11418, United States

Location

Otsuka Investigational Site

New York, New York, 10032, United States

Location

Otsuka Investigational Site

The Bronx, New York, 10461, United States

Location

Otsuka Investigational Site

Cincinnati, Ohio, 45267, United States

Location

Otsuka Investigational Site

Cleveland, Ohio, 44195, United States

Location

Otsuka Investigational Site

Columbus, Ohio, 43212, United States

Location

Otsuka Investigational Site

Fairfield, Ohio, 45014, United States

Location

Otsuka Investigational Site

Toledo, Ohio, 43560, United States

Location

Otsuka Investigational Site

Oklahoma City, Oklahoma, 73120, United States

Location

Otsuka Investigational Site

Bethleham, Pennsylvania, 18017, United States

Location

Otsuka Investigational Site

Philadelphia, Pennsylvania, 19102, United States

Location

Otsuka Investigational Site

Philadelphia, Pennsylvania, 19140, United States

Location

Otsuka Investigational Site

West Reading, Pennsylvania, 19611, United States

Location

Otsuka Investigational Site

Providence, Rhode Island, 02903, United States

Location

Otsuka Investigational Site

Galveston, Texas, 77555, United States

Location

Otsuka Investigational Site

Houston, Texas, 77030, United States

Location

Otsuka Investigational Site

Mission, Texas, 78572, United States

Location

Otsuka Investigational Site

San Antonio, Texas, 78205, United States

Location

Otsuka Investigational Site

San Antonio, Texas, 78229, United States

Location

Otsuka Investigational Site

Fairfax, Virginia, 22030, United States

Location

Otsuka Investigational Site

Madison, Wisconsin, 53705, United States

Location

MeSH Terms

Conditions

Hyponatremia; Inappropriate ADH Syndrome

Interventions

Tolvaptan

Condition Hierarchy (Ancestors)

Water-Electrolyte Imbalance; Metabolic Diseases; Nutritional and Metabolic Diseases; Pituitary Diseases; Hypothalamic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Global Medical Affairs
• Organization: Otsuka Pharmaceutical Development and Commercialization, Inc.

800 562-3974

Study Officials

• Ann Dandurand, MD

  Otsuka Pharmaceutical Development & Commercialization, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 22, 2010
• First Posted: October 25, 2010
• Study Start: October 1, 2010
• Primary Completion: May 1, 2013
• Study Completion: May 1, 2013
• Last Updated: October 30, 2014
• Results First Posted: October 17, 2014

Record last verified: 2014-10

Locations

US (56)