This study is to treat adult patients with hepatorenal syndrome (HRS) Type 1.

Out of every three participants, two will receive terlipressin and one will receive placebo.

Assignments will be made randomly.

The primary objective of this trial is to confirm the efficacy and safety of intravenous terlipressin versus placebo in the treatment of adult subjects with hepatorenal syndrome (HRS) Type 1.

Inclusion Criteria:

• Written informed consent by participant or legally authorized representative
• Cirrhosis and ascites
• Rapidly progressive worsening in renal function to a serum creatinine (SCr) at least 2.25 mg/dL and meeting a trajectory for SCr to double over 2 weeks
• No sustained improvement in renal function (less than 20% decrease in SCr and SCr at least 2.25 mg/dL) at least 48 hours after diuretic withdrawal and the beginning of plasma volume expansion with albumin
• Discontinues midodrine and octreotide before randomization if applicable

Exclusion Criteria:

• Serum creatinine level greater than 7.0 mg/dL
• At least 1 event of large volume paracentesis (LVP) at least 4 L within 2 days of randomization
• Sepsis and/or uncontrolled bacterial infection
• Less than 2 days anti-infective therapy for documented or suspected infection
• Shock
• Being treatment with or exposure to nephrotoxic agents, nonsteroidal anti-inflammatory drugs, or significant radiographic contrast agents (within the last 4 weeks)
• Estimated life expectancy of less than 3 days
• Superimposed acute liver injury due to drugs, dietary supplements, herbal preparations, viral hepatitis, or toxins, with the exception of acute alcoholic hepatitis
• Proteinuria greater than 500 mg/day
• Evidence of obstructive uropathy or parenchymal renal disease on ultrasound or other imaging
• Tubular epithelial casts, heme granular casts, hematuria or microhematuria (greater than 50 red blood cells per high power field in the absence of recent catheterization) on urinalysis
• Pregnancy; all women of child-bearing age and potential must have a negative pregnancy test
• Cardiovascular disease judged by the investigator to be severe
• Current or recent renal replacement therapy (RRT) within the past 4 weeks
• Participation in other clinical research involving investigational medicinal products within 30 days of randomization
• Transjugular intrahepatic portosystemic shunt (TIPS) within 30 days of randomization
• Use of vasopressors for at least 3 consecutive days within the 14-day screening period - patients receiving any vasopressor other than midodrine and octreotide within 24 hours of qualifying SCr are also excluded, ie, a 24-hour washout is required prior to enrollment
• Known allergy or sensitivity to terlipressin or another component of the study treatment

Discussion of statistical endpoints and analysis are included in manuscripts. Summary aggregate (basic) results (including adverse events information) and the study protocol are made available on clinicaltrials.gov (NCT02770716) when required by regulation. Individual de-identified patient data will not be disclosed. Requests for additional information should be directed to the company at medinfo@mnk.com.