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

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ClinicalTrials.gov Identifier: NCT01227512
Recruitment Status : Terminated (Recruitment challenges and results of interim futility analysis, which showed less than likely to achieve primary endpoint goal-length of hospital stay.)
First Posted : October 25, 2010
Results First Posted : October 17, 2014
Last Update Posted : October 30, 2014
Sponsor:
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Tracking Information
First Submitted Date  ICMJE October 22, 2010
First Posted Date  ICMJE October 25, 2010
Results First Submitted Date  ICMJE May 29, 2014
Results First Posted Date  ICMJE October 17, 2014
Last Update Posted Date October 30, 2014
Study Start Date  ICMJE October 2010
Actual Primary Completion Date May 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 10, 2014)
Length of Hospital Stay (LoS) [ Time Frame: 45 days ]
LoS was time to clinically ready to be hospital discharged (CRBD) from study treatment initiation, disregarding prolonged hospitalization due solely to social factors.
Original Primary Outcome Measures  ICMJE
 (submitted: October 22, 2010)
Compare treatment with tolvaptan without fluid restriction to placebo with fluid restriction [ Time Frame: 14 days ]
The primary efficacy endpoint for this trial is to compare treatment with tolvaptan without fluid restriction to placebo with fluid restriction on time to hospital discharge from trial treatment initiation through Day 14 post-dose.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 10, 2014)
  • Change From Baseline to 48 Hour Post Dose in Clinical Global Impression-Severity (CGI-S) of Hyponatremia Symptoms. [ Time Frame: Baseline to 48 hours post dose ]
    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.
  • Change From Baseline to 24 and 72 Hours Post Dose in CGI-S of Hyponatremia Symptoms. [ Time Frame: Baseline to 24 and 72 hours post dose ]
    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.
  • Change From Baseline to 48 Hours Post Dose in Clinical Global Impression - Improvement (CGI-I) Score of Hyponatremia Symptoms. [ Time Frame: Baseline to 48 hours post dose ]
    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
  • Change From Baseline in Serum Sodium Concentration (24 Hour Area Under the Curve [AUC]). [ Time Frame: 0 to 72 hours ]
    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.
  • Time to First 2-point Improvement in CGI-S Score. [ Time Frame: Up to 72 hours ]
    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.
  • Percentage of Participants With Clinical Global Impression-Improvement (CGI-I) Score Improved to a Score of 1 or 2. [ Time Frame: 48 hours post dose ]
    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.
  • Percentage of Participants Requiring Rescue Therapy for Hyponatremia [ Time Frame: 7 days ]
    Percentage of participants requiring rescue therapy within first 7 days of treatment for hyponatremia.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 22, 2010)
  • Key secondary: Change in CGI-S of hyponatremia symptoms from pretreatment baseline to 48 hours post first dose, or at discharge/rescue therapy if earlier [ Time Frame: 48 hours ]
  • 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 [ Time Frame: 24 and 72 hours ]
  • Clinical Global Impression - Improvement scale (CGI-I) score at 48 hours post first dose or discharge/rescue therapy, if earlier. [ Time Frame: 48 hours ]
  • Percentage of subjects requiring rescue therapy for hyponatremia through Day 7 post first dose [ Time Frame: 7 days ]
  • Time to 2-point improvement in CGI-S score [ Time Frame: 7 days ]
  • Percentage of responders (CGI-I score of 1 = very much improved or 2 = much improved) at 48 hours post first dose or discharge/rescue therapy, if earlier [ Time Frame: 48 hours ]
  • Descriptive summary statistics for standard safety assessments [ Time Frame: 24, 48, and 72 hours ]
    Adverse events, vital signs, laboratory tests, and physical examinations
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effects of Tolvaptan vs Fluid Restriction in Hospitalized Subjects With Dilutional Hyponatremia
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Condition  ICMJE
  • Hyponatremia
  • Dilutional Hyponatremia
  • Inappropriate ADH Syndrome
Intervention  ICMJE
  • 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 Names:
    • SAMSCA
    • OPC-41061
    • OPC-156
  • 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"

Study Arms  ICMJE
  • Experimental: Tolvaptan 15-60mg
    Oral tablet without fluid restriction. After the initial dose, daily dose may be titrated based on response.
    Intervention: Drug: tolvaptan
  • Active Comparator: Fluid Restriction
    Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may titrated based response.
    Intervention: Other: Fluid Restriction
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 6, 2013)
124
Original Estimated Enrollment  ICMJE
 (submitted: October 22, 2010)
400
Actual Study Completion Date  ICMJE May 2013
Actual Primary Completion Date May 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01227512
Other Study ID Numbers  ICMJE 156-08-275
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Otsuka Pharmaceutical Development & Commercialization, Inc.
Study Sponsor  ICMJE Otsuka Pharmaceutical Development & Commercialization, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Ann Dandurand, MD Otsuka Pharmaceutical Development & Commercialization, Inc.
PRS Account Otsuka Pharmaceutical Development & Commercialization, Inc.
Verification Date October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP