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A Placebo-Controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Terlipressin

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ClinicalTrials.gov Identifier: NCT01143246
Recruitment Status : Completed
First Posted : June 14, 2010
Last Update Posted : September 23, 2016
Sponsor:
Information provided by (Responsible Party):
Mallinckrodt

Tracking Information
First Submitted Date  ICMJE June 11, 2010
First Posted Date  ICMJE June 14, 2010
Last Update Posted Date September 23, 2016
Study Start Date  ICMJE September 2010
Actual Primary Completion Date February 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 19, 2010)
Confirmed Hepatorenal syndrome reversal [ Time Frame: Baseline and 14 days ]
Confirmed HRS Reversal: The percentage of subjects with two serum creatinine (SCr) values of ≤ 1.5 mg/dL at least 48 hours apart, on treatment, and without intervening RRT or liver transplant.
Original Primary Outcome Measures  ICMJE
 (submitted: June 11, 2010)
Confirmed Hepatorenal syndrome reversal [ Time Frame: 14 days ]
Confirmed HRS Reversal: The percentage of subjects with two serum creatinine (SCr) values of ≤ 1.5 mg/dL at least 48 hours apart, on treatment, and without intervening RRT or liver transplant.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 19, 2010)
  • Hepatorenal syndrome reversal [ Time Frame: 14 days ]
    Incidence of HRS Reversal is defined as at least one SCr value of ≤ 1.5 mg/dL on treatment (up to 24 hours after the last dose of study medication).
  • Transplant-free survival [ Time Frame: Up to 90 days ]
    Transplant-Free Survival up to 90 days, defined as the time (in days) that each subject survives without liver transplantation from the day of randomization.
  • Overall Survival [ Time Frame: Up to 90 days ]
    Overall Survival up to 90 days, defined as the time (in days) that each subject survives from the day of randomization.
  • Serious Adverse Events [ Time Frame: Up to 30 days post treatment ]
Original Secondary Outcome Measures  ICMJE
 (submitted: June 11, 2010)
  • Renal Function [ Time Frame: baseline through end of treatment (14 days) ]
    Repeated measures analysis of change from baseline through end of treatment in renal function assessed by the daily serum creatinine values.
  • Hepatorenal syndrome reversal [ Time Frame: 14 days ]
    Incidence of HRS Reversal is defined as at least one SCr value of ≤ 1.5 mg/dL on treatment (up to 24 hours after the last dose of study medication).
  • Transplant-free survival [ Time Frame: Up to 90 days ]
    Transplant-Free Survival up to 90 days, defined as the time (in days) that each subject survives without liver transplantation from the day of randomization.
  • Overall Survival [ Time Frame: Up to 90 days ]
    Overall Survival up to 90 days, defined as the time (in days) that each subject survives from the day of randomization.
  • Serious Adverse Events [ Time Frame: Up to 30 days post treatment ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Placebo-Controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Terlipressin
Official Title  ICMJE Phase 3, Multi-Center Randomized, Placebo-Controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Lucassin® (Terlipressin) (REVERSE Trial)
Brief Summary This study is designed to evaluate the efficacy and safety of intravenous Lucassin® (terlipressin) versus placebo for the treatment of type 1 hepatorenal syndrome (HRS) in subjects receiving standard of care albumin therapy.
Detailed Description Hepatorenal syndrome is a rare syndrome of marked renal dysfunction in patients with cirrhosis, decompensated liver disease, and portal hypertension. Hepatorenal syndrome type 1 is characterized by a rapid progressive renal impairment and has a very poor prognosis with > 80% mortality within 3 months. At present, there are no approved drug therapies for HRS type 1 in the US, Australia, or Canada. The only curative treatment for HRS type 1 and the underlying end-stage cirrhosis is liver transplantation. However, many patients will not survive long enough to receive a liver transplant and therapy, which may provide a bridge to transplantation, is badly needed. Increased understanding of the pathophysiology of HRS type 1 has demonstrated that vasoconstrictive drug therapy may reverse HRS type 1. Substantial data available from many published clinical investigations in the literature provide compelling evidence suggesting that administration of terlipressin improves renal function in patients with HRS.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE HRS
Intervention  ICMJE
  • Drug: Terlipressin
    Blinded terlipressin reconstituted with 5 mL of sterile 0.9% sodium chloride solution for injection will be administered intravenously as a slow bolus injection over 2 minutes at a dose of 1 mg (1 vial) every 6 hours (4 mg/day).
    Other Name: Lucassin®
  • Drug: Placebo
    Lyophilized mannitol reconstituted with 5 mL of sterile 0.9% sodium chloride solution administered intravenously as a slow bolus injection over 2 minutes at a dose of 1 mg (1 vial) every 6 hours (4 mg/day).
    Other Name: Saline
Study Arms  ICMJE
  • Experimental: Terlipressin
    intravenous terlipressin (1 mg) every 6 hours with concomitant albumin
    Intervention: Drug: Terlipressin
  • Placebo Comparator: Placebo
    lyophilized mannitol
    Intervention: Drug: Placebo
Publications *

*   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 Completed
Actual Enrollment  ICMJE
 (submitted: July 11, 2013)
196
Original Estimated Enrollment  ICMJE
 (submitted: June 11, 2010)
150
Actual Study Completion Date  ICMJE May 2013
Actual Primary Completion Date February 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Written informed consent by subject or legally authorized representative
  2. At least 18 years of age
  3. Cirrhosis and ascites
  4. Rapidly progressive reduction in renal function characterized by:

    • SCr ≥ 2.5 mg/dL
    • Doubling of SCr within 2 weeks (or for observations of shorter duration, SCr values over time meeting slope-based criteria for proportional increases likely to be representative of at least a doubling within 2 weeks
  5. No sustained improvement in renal function (< 20% decrease in SCr and SCr ≥ 2.25 mg/dL) 48 hours after both diuretic withdrawal and the beginning of plasma volume expansion with albumin:

Note: Albumin doses recommended by the IAC are 1 g/kg on the first day (Maximum 100 g) and 20 - 40 g/day thereafter as clinically indicated.It is recommended (if clinically appropriate) that the albumin dose is kept constant during the study drug administration period.

Note: The qualifying SCr value is the SCr value at least 48 hrs after both diuretic withdrawal (if applicable) and the beginning of albumin fluid challenge. The qualifying SCr value must be ≥ 2.25 mg/dL AND at least 80% of the diagnostic (pre-fluid challenge) SCr value.

Exclusion Criteria:

  1. Serum creatinine > 7 mg/dL
  2. Shock Note: Hypotension (Mean Arterial Pressure < 70 mm Hg or a decrease > 40 mm Hg in systolic blood pressure from baseline) with evidence of hypoperfusion abnormalities despite adequate fluid resuscitation.
  3. Sepsis or systemic inflammatory response syndrome (SIRS)

    Note: SIRS: Presence of 2 or more of the following findings:

    Temperature > 38°C or < 36°C; heart rate > 90/min; respiratory rate of > 20/min or a PaCO2 of < 32 mm Hg; white blood cell count of > 12,000 cells/µL or < 4,000/ µL.

    Note: Sepsis: Documented infection and systemic inflammatory response syndrome.

  4. < 2 days anti-infective therapy for documented or suspected infection
  5. Proteinuria > 500 mg/day
  6. Hematuria or microhematuria (> 50 red blood cells per high power field)
  7. Clinically significant casts on urinalysis, including granular casts

    Note: Urine sediment examination is required to exclude presence of granular casts and other clinically significant casts (e.g., red blood cell [RBC] casts).

  8. Evidence of intrinsic or parenchymal renal disease (including acute tubular necrosis)
  9. Obstructive uropathy or other renal pathology on ultrasound or other medical imaging
  10. Current or recent treatment (within 4 weeks) with nephrotoxic drugs, e.g., aminoglycosides, nonsteroidal anti-inflammatory drugs (NSAID) Note: Up to 3 doses of an NSAID within the prior month (prescription or over the counter) is acceptable Note: Use of short-term (< 2 weeks) oral neomycin for acute encephalopathy is acceptable.
  11. Current or recent (within 4 weeks) renal replacement therapy
  12. Superimposed acute liver failure/injury due to factors other than alcoholic hepatitis, including acute viral hepatitis, drugs, medications (e.g., acetaminophen), or other toxins (e.g., mushroom [Amanita] poisoning)
  13. Current or recent treatment (within 48 hours) with octreotide, midodrine, vasopressin, dopamine or other vasopressors
  14. Severe cardiovascular disease as judged by investigator
  15. Estimated life expectancy of less than 3 days
  16. Confirmed pregnancy
  17. Known allergy or sensitivity to terlipressin or another component of the study treatment
  18. Participation in other clinical research studies involving the evaluation of other investigational drugs or devices within 30 days of randomization.
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 Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01143246
Other Study ID Numbers  ICMJE IK-4001-HRS-301
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mallinckrodt
Study Sponsor  ICMJE Mallinckrodt
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Khurram Jamil, MD Mallinckrodt
PRS Account Mallinckrodt
Verification Date September 2016

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