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Clinical Trial Details — Status: Terminated

Administrative data

NCT number NCT01227512
Other study ID # 156-08-275
Secondary ID
Status Terminated
Phase Phase 3
First received October 22, 2010
Last updated October 21, 2014
Start date October 2010
Est. completion date May 2013

Study information

Verified date October 2014
Source Otsuka Pharmaceutical Development & Commercialization, Inc.
Contact n/a
Is FDA regulated No
Health authority United States: Food and Drug Administration
Study type Interventional

Clinical Trial 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.


Recruitment information / eligibility

Status Terminated
Enrollment 124
Est. completion date May 2013
Est. primary completion date May 2013
Accepts healthy volunteers No
Gender Both
Age group 18 Years and older
Eligibility 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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment


Intervention

Drug:
tolvaptan
15 mg titrated to 30 mg then 60 mg once daily as oral tablet for up to 7 days based on response.
Other:
Fluid Restriction
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"

Locations

Country Name City State
United States Otsuka Investigational Site Azusa California
United States Otsuka Investigational Site Baltimore Maryland
United States Otsuka Investigational Site Banning California
United States Otsuka Investigational Site Bethleham Pennsylvania
United States Otsuka Investigational Site Birmingham Alabama
United States Otsuka Investigational Site Birmingham Alabama
United States Otsuka Investigational Site Bronx New York
United States Otsuka Investigational Site Buffalo New York
United States Otsuka Investigational Site Buffalo New York
United States Otsuka Investigational Site Cincinnati Ohio
United States Otsuka Investigational Site Cleveland Ohio
United States Otsuka Investigational Site Columbus Ohio
United States Otsuka Investigational Site Culver City California
United States Otsuka Investigational Site Denver Colorado
United States Otsuka Investigational Site Elizabethtown Kentucky
United States Otsuka Investigational Site Fairfax Virginia
United States Otsuka Investigational Site Fairfield Ohio
United States Otsuka Investigational Site Fountain Valley California
United States Otsuka Investigational Site Galveston Texas
United States Otsuka Investigational Site Grand Island Nebraska
United States Otsuka Investigational Site Haddon Heights New Jersey
United States Otsuka Investigational Site Houston Texas
United States Otsuka Investigational Site Jackson Mississippi
United States Otsuka Investigational Site Jacksonville Florida
United States Otsuka Investigational Site Jacksonville Florida
United States Otsuka Investigational Site Jacksonville Florida
United States Otsuka Investigational Site Jamaica New York
United States Otsuka Investigational Site Los Angeles California
United States Otsuka Investigational Site Los Angeles California
United States Otsuka Investigational Site Madison Wisconsin
United States Otsuka Investigational Site Minneapolis Minnesota
United States Otsuka Investigational Site Mission Texas
United States Otsuka Investigational Site Mobile Alabama
United States Otsuka Investigational Site New York New York
United States Otsuka Investigational Site Newark New Jersey
United States Otsuka Investigational Site Northridge California
United States Otsuka Investigational Site Oklahoma City Oklahoma
United States Otsuka Investigational Site Omaha Nebraska
United States Otuska Investigational Site Orange California
United States Otsuka Investigational Site Orlando Florida
United States Otsuka Investigational Site Philadelphia Pennsylvania
United States Otsuka Investigational Site Philadelphia Pennsylvania
United States Otsuka Investigational Site Port Charlotte Florida
United States Otsuka Investigational Site Providence Rhode Island
United States Otsuka Investigational Site Rochester Minnesota
United States Otsuka Investigational Site Saginaw Michigan
United States Otsuka Investigational Site San Antonio Texas
United States Otsuka Investigational Site San Antonio Texas
United States Otsuka Investigational Site Savannah Georgia
United States Otsuka Investigational Site Southfield Michigan
United States Otsuka Investigational Site Springfield Massachusetts
United States Otsuka Investigational Site St. Louis Missouri
United States Otsuka Investigational Site Toledo Ohio
United States Otsuka Investigational Site Washington District of Columbia
United States Otsuka Investigational Site West Reading Pennsylvania
United States Otsuka Investigational Site Yorba Linda California

Sponsors (1)

Lead Sponsor Collaborator
Otsuka Pharmaceutical Development & Commercialization, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Primary 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 No
Secondary Change From Baseline to 48 Hour Post Dose in Clinical Global Impression-Severity (CGI-S) of Hyponatremia Symptoms. Change from baseline in blinded rater assessed CGI-S at 48 hours post-first dose or at discharge/rescue therapy, if earlier was assessed.
The CGI-S is a one-question rating scale which was as follows: "Considering your total clinical experience with hyponatremia symptoms in this particular population, how symptomatic is the patient at this time?" 0=not assessed; 1=normal, not at all symtpmatic; 2=borderline symptomatic; 3=mildly symptomatic; 4=moderately symptomatic; 5=markedly symptomatic; 6=severely symptomatic; 7=among the most severly symptomatic patients.
Baseline to 48 hours post dose No
Secondary Change From Baseline to 24 and 72 Hours Post Dose in CGI-S of Hyponatremia Symptoms. Change in CGI-S of hyponatremia symptoms from pretreatment baseline at 24 and 72 hours post-first dose, or at discharge/rescue therapy if earlier was assessed.
The CGI-S is a one-question rating scale which was as follows: "Considering your total clinical experience with hyponatremia symptoms in this particular population, how symptomatic is the patient at this time?" 0=not assessed; 1=normal, not at all symtpmatic; 2=borderline symptomatic; 3=mildly symptomatic; 4=moderately symptomatic; 5=markedly symptomatic; 6=severely symptomatic; 7=among the most severly symptomatic patients.
Baseline to 24 and 72 hours post dose No
Secondary Change From Baseline to 48 Hours Post Dose in Clinical Global Impression - Improvement (CGI-I) Score of Hyponatremia Symptoms. Change in CGI-I score at 48 hours post-first dose or discharge/rescue therapy, if earlier was assessed.
The CGI-I is a one-question rating scale where the participant is asked to rate total improvement whether or not, in their judgment, it is due entirely to trial treatment. Compared to his/her condition at admission to the trial, how much has he/she changed? 0=not assessed; 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse
Baseline to 48 hours post dose No
Secondary Change From Baseline in Serum Sodium Concentration (24 Hour Area Under the Curve [AUC]). Average 24 hour AUC of serum sodium concentration change from baseline, from Day 1 Hour 0 up to 72 hours post-first dose was assessed.
A serum sodium sample was drawn at pre-treament and 8, 24, 48, and 72 hours post-first dose. Serum sodium was also assessed between 36 and 72 hours after the last dose.
Analysis of AUC was for daily average AUC, hence the units or AUC are mEq/L/24 hours.
0 to 72 hours No
Secondary Time to First 2-point Improvement in CGI-S Score. CGI-S data up to 72 hours were used to identify 2-point improvements. Please refer to outcome measure 2 for details on the scale. For the analysis of time to first 2-point improvement in CGI-S, CGI-S data up to Hour 72 were used to identify 2-point improvements. Data for participants who received rescue therapy were censored at the time of receiving rescue therapy. For participants who were discharged before Hour 72 without reaching 2-point improvement in CGI-S, data were censored at the time of discharge. Other participants who did not reach the 2-point improvement during the 72 hours also had their data censored at their last CGI-S observations within 72 hours. Up to 72 hours No
Secondary Percentage of Participants With Clinical Global Impression-Improvement (CGI-I) Score Improved to a Score of 1 or 2. Percentage of responders (defined as CGI-I score of 1 = very much improved or 2 = much improved) at 48 hours post-first dose, or at discharge/rescue therapy, if earlier. Participants given rescue therapy were given a score of 7. 48 hours post dose No
Secondary Percentage of Participants Requiring Rescue Therapy for Hyponatremia Percentage of participants requiring rescue therapy within first 7 days of treatment for hyponatremia. 7 days No
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