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

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

Tracking Information

• First Submitted Date: June 11, 2010
• First Posted Date: June 14, 2010
• Last Update Posted Date: September 23, 2016
• Study Start Date: September 2010
• Actual Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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.

Current Secondary Outcome Measures (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 (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: A Placebo-Controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Terlipressin
• Official Title: 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: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: HRS

Intervention

• 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

• Experimental: Terlipressin
  intravenous terlipressin (1 mg) every 6 hours with concomitant albumin
  Intervention: Drug: Terlipressin
• Placebo Comparator: Placebo
  lyophilized mannitol
  Intervention: Drug: Placebo

Publications *

• Sanyal AJ, Boyer TD, Frederick RT, Wong F, Rossaro L, Araya V, Vargas HE, Reddy KR, Pappas SC, Teuber P, Escalante S, Jamil K. Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies. Aliment Pharmacol Ther. 2017 Jun;45(11):1390-1402. doi: 10.1111/apt.14052. Epub 2017 Mar 29.
• Wong F, Pappas SC, Boyer TD, Sanyal AJ, Bajaj JS, Escalante S, Jamil K; REVERSE Investigators. Terlipressin Improves Renal Function and Reverses Hepatorenal Syndrome in Patients With Systemic Inflammatory Response Syndrome. Clin Gastroenterol Hepatol. 2017 Feb;15(2):266-272.e1. doi: 10.1016/j.cgh.2016.07.016. Epub 2016 Jul 25.
• Boyer TD, Sanyal AJ, Wong F, Frederick RT, Lake JR, O'Leary JG, Ganger D, Jamil K, Pappas SC; REVERSE Study Investigators. Terlipressin Plus Albumin Is More Effective Than Albumin Alone in Improving Renal Function in Patients With Cirrhosis and Hepatorenal Syndrome Type 1. Gastroenterology. 2016 Jun;150(7):1579-1589.e2. doi: 10.1053/j.gastro.2016.02.026. Epub 2016 Feb 16.

Recruitment Information

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

Eligibility Criteria

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

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT01143246
• Other Study ID Numbers: IK-4001-HRS-301
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Mallinckrodt
• Study Sponsor: Mallinckrodt
• Collaborators: Not Provided

Investigators

• Study Director: Khurram Jamil, MD; Mallinckrodt

• PRS Account: Mallinckrodt
• Verification Date: September 2016