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

A Multi-Center, Randomized, Placebo-controlled, Double-Blind Study to Confirm the Reversal of Hepatorenal Syndrome Type 1 With Lucassin® (Terlipressin) (The REVERSE Study)

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01143246

Enrollment

196

Registered

2010-06-14

Start date

2010-10-11

Completion date

2013-05-10

Last updated

2022-11-29

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hepatorenal Syndrome

Keywords

Hepatorenal syndrome, Renal failure, Cirrhosis, Alcoholic hepatitis, Ascites

Brief summary

This study is designed to evaluate the efficacy and safety of intravenous terlipressin versus placebo for the treatment of type 1 hepatorenal syndrome (HRS) in participants 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.

Interventions

DRUGTerlipressin

Each 6 mL vial contains 1 mg lyophilized terlipressin acetate and 10 mg mannitol in sterile 0.9% sodium chloride solution.

DRUGPlacebo

11 mg mannitol reconstituted with 5 ml of sterile 0.9% sodium chloride solution.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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: * Serum creatinine (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 International Ascites Club (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. SCr \> 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

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With Confirmed Hepatorenal Syndrome (HRS) Reversal	within 14 days	Confirmed HRS Reversal: The percentage of participants with two serum creatinine (SCr) values of ≤ 1.5 mg/dL at least 48 hours apart, on treatment, and without intervening renal replacement therapy or liver transplant.

Secondary

Measure	Time frame	Description
Percentage of Participants With HRS Reversal	within 14 days	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).
Percentage of Participants With Transplant-free Survival	Up to 90 days	Transplant-Free Survival up to 90 days, defined as the time (in days) that each participant survives without liver transplantation from the day of randomization.
Percentage of Participants With Overall Survival	Up to 90 days	Overall Survival up to 90 days, defined as the time (in days) that each participant survives from the day of randomization.
Percentage of Participants With Serious Adverse Events	Up to 30 days post treatment (within 44 days)	Clinically significant changes in vital signs, height, weight, immunogenicity and laboratory assessments which qualified for the definition of serious adverse event are reported.

Countries

Canada, United States

Participant flow

Recruitment details

The study was conducted at 52 active sites in the United States and Canada.

Participants by arm

Arm	Count
Terlipressin Participants receive matching placebo intravenously as a bolus injection, followed by a saline flush. Dose, duration, retreatment and/or discontinuation may be modified by the investigator, per protocol.	97
Placebo Participants receive matching placebo intravenously as a bolus injection, followed by a saline flush. Dose, duration, retreatment and/or discontinuation may be modified by the investigator, per protocol.	99
Total	196

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	24	28
Overall Study	Death	16	15
Overall Study	Lost to Follow-up	0	1
Overall Study	Participant Withdrew Informed Consent	2	2
Overall Study	Reason not Specified	3	5

Baseline characteristics

Characteristic	Terlipressin	Total	Placebo
Age, Continuous	55.8 years STANDARD_DEVIATION 8.38	55.3 years STANDARD_DEVIATION 8.43	54.8 years STANDARD_DEVIATION 8.5
Ethnicity (NIH/OMB) Hispanic or Latino	10 Participants	25 Participants	15 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	86 Participants	170 Participants	84 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	2 Participants	1 Participants
Race (NIH/OMB) Asian	3 Participants	3 Participants	0 Participants
Race (NIH/OMB) Black or African American	7 Participants	13 Participants	6 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) White	85 Participants	177 Participants	92 Participants
Region of Enrollment Canada	5 participants	9 participants	4 participants
Region of Enrollment United States	92 participants	187 participants	95 participants
Sex: Female, Male Female	45 Participants	77 Participants	32 Participants
Sex: Female, Male Male	52 Participants	119 Participants	67 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	41 / 97	45 / 99
other Total, other adverse events	87 / 93	82 / 95
serious Total, serious adverse events	62 / 93	59 / 95

Arm	Measure	Value (NUMBER)
Terlipressin	Percentage of Participants With Transplant-free Survival	30.9 percentage of participants
Placebo	Percentage of Participants With Transplant-free Survival	26.3 percentage of participants

Source: ClinicalTrials.gov · Data processed: Mar 14, 2026