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Study to Evaluate R2R01 Plus Terlipressin Versus Terlipressin Alone in Patients With Hepatorenal Syndrome

Primary Purpose

Hepatorenal Syndrome, Acute Kidney Injury

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
R2R01
Terlipressin
Sponsored by
River 2 Renal Corp.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatorenal Syndrome focused on measuring HRS-AKI, HRS, Renal Failure, Kidney Failure, Single-blind, Open-Label, Phase 2, R2R01

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Patient is able to communicate well with the Investigator, understands and is willing to comply with all requirements of the study, and understands and signs the written informed consent form (ICF). At least 18 years of age. Cirrhosis and ascites. AKI stage 2 or 3. AKI defined by any of the following: 1) increase in SCr (SCr) ≥ 0.3 mg/dl (or ≥ 26.5 micromolar/L) within 48 h, or 2) increase ≥ 50% in baseline SCr, which is known or presumed to have occurred within the prior seven days. QLY SCr ≥ to 1.5 mg/dl. No sustained improvement in renal function (less than 20% decrease in SCr and SCr => 1.5 mg/dL) after 48 h of diuretic withdrawal and the beginning of plasma volume expansion with albumin. Female patients as well as female partners of male patients must be willing to avoid pregnancy for the duration of the study (>90 days). Exclusion Criteria: Significant co-morbidities that in the opinion of the Investigator would preclude study participation. QLY SCr level > 5 mg/dL. AKI stage 1. ACLF stage 3. Model for End-Stage Liver Disease (MELD) score >35. At least one event of large volume paracentesis (LVP) > 4 Liters in the last 4 days before enrollment. Current or recent (within 4 weeks) treatment with nephrotoxic drugs (e.g., aminoglycosides, amphotericin, cyclosporine, NSAIDS (e.g., ibuprofen, naproxen, celecoxib), significant exposure to radiographic contrast agents (large doses or multiple injections of iodinated contrast media). Shock (hypovolemic-, cardiogenic-, or vasodilatory/distributive shock) with mean arterial blood pressure (MAP) ≤70 mmHg or systolic blood pressure ≤90 mmHg along with hypoperfusion. Sepsis or uncontrolled bacterial infection (e.g., persisting bacteremia, persisting ascitic fluid leucocytosis, fever, increasing leucocytosis with vasomotor instability) as measured with the quick sepsis-related organ dysfunction assessment (qSOFA) score. Fewer than two days of anti-infective therapy for documented or suspected infection. Superimposed acute liver injury induced by drugs, herbal preparation or dietary supplements, with the exception of alcoholic hepatitis. Estimated life expectancy less than 5 days. Hypoxia (<90%) or worsening respiratory symptoms. Proteinuria > 500 mg/day. Tubular epithelial casts, heme granular casts. Haematuria or microhaematuria (more than 50 red blood cells per high power field). Abnormal renal ultra-sonography unless there is a known chronic structural disease (e.g., diabetic or hypertensive nephropathy). Current or recent (within 4 weeks) renal replacement therapy (RRT). Severe cardiovascular and pulmonary diseases including, but not limited to, unstable angina, pulmonary edema, congestive heart failure requiring increasing doses of drug therapy, persisting symptomatic peripheral vascular disease, or any other cardiovascular disease judged by the Investigator to be severe. Transjugular intra-hepatic systemic shunt (TIPS) unless it is known to be non-functioning or occluded. Ongoing use of vasopressors, unless used for only 48 h before screening; in this case a wash-out period of 8 h before enrollment will be necessary. Patients receiving midodrine and octreotide may be enrolled but treatment must be discontinued prior to enrollment. Known allergy or hypersensitivity to terlipressin or other component of the study treatment. Subject is not suitable to participate in the study for any reason (including, but not limited to co-morbidities, history of non-compliance with study visits, procedures, or drug administration) in the opinion of the Investigator. Females of childbearing potential (those who are not surgically sterilized or post-menopausal for at least 1 year) are excluded from participation in the study unless they agree to use highly effective contraception. Males who have no sterilization history and whose female partners have child-bearing potential must agree to use a highly effective method of contraception during the period from the time of signing the informed consent form (ICF) through 90 days after the last dose of study drug. A male patient must agree to immediately inform the Investigator if his partner becomes pregnant during the study.

Sites / Locations

  • California Pacific Medical Center
  • Piedmont Healthcare, IncRecruiting
  • Beth Israel Deaconess Medical Center
  • Mayo ClinicRecruiting
  • Hospital of the University of PennsylvaniaRecruiting
  • Vanderbilt University Medical CenterRecruiting
  • Baylor Scott and White All Saints Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Experimental

Arm Label

An Open-Label Safety Run-In Part

Single-blind Placebo-controlled Randomized period

An Open-Label Terlipressin Non-Responder Cohort

Arm Description

Three initial cohorts (Cohort 1, N=3 patients, Cohorts 2 and 3, N=6 patients, each) will be treated with an open-label combination of terlipressin and R2R01 to ascertain the safety of the combination therapy. A Safety Review Committee (SRC) will review the safety of Cohort 1 patients based on the adverse events and laboratory abnormalities up until Day 14, prior to the start of recruitment of Cohort 2 patients, as well as the safety of Cohorts 1 and 2 patients up until Day 14 prior to the start of recruitment of Cohort 3 patients. Data from all Cohorts 1, 2, and 3 patients up until Day 14 will be reviewed by the SRC before starting the randomized part of the study (Cohorts 4 and 5), so that the SRC can decide and confirm the most appropriate R2R01 dose schedule for patients in Cohorts 4 and 5. Patients enrolled in Cohorts 1, 2, or 3 will remain in their Cohort until study completion (Day 90) or study discontinuation.

After conclusion of the open-label safety run-in part, and after the SRC has determined the appropriate R2R01 dose schedule, approximately 80 patients will receive terlipressin and be randomized 1:1 to either R2R01 (Cohort 4) or placebo (Cohort 5). At randomization, patients will be stratified by the presence of systemic inflammatory response syndrome (SIRS), since patients with SIRS have shown a better response to terlipressin than patients without SIRS.

In Cohort 5, if patients do not respond to terlipressin, they must discontinue Cohort 5. After discontinuation, they will be allowed to enter Cohort 6 (Terlipressin Non-Responder Part) to receive R2R01 with the same dosing and schedule as that for Cohort 4. No patient from any Cohort other than Cohort 5 will be allowed to enter Cohort 6.

Outcomes

Primary Outcome Measures

Safety Evaluation Criteria - Treatment Emergent Adverse Events (TEAEs)
Safety and tolerability will be assessed by occurrence of TEAEs. Outcome will be reported as the count of participant experiencing TEAEs.
Safety Evaluation Criteria - Change in Weight
Safety and tolerability will be assessed by change in body weight
Safety Evaluation Criteria - Vital Signs - Respiration Rate
Safety and tolerability will be assessed by change in respiration rate
Safety Evaluation Criteria - Vital Signs - Body Temperature
Safety and tolerability will be assessed by change in body temperature
Safety Evaluation Criteria - Vital Signs - Continuous pulse oximetry (SpO2)
Safety and tolerability will be assessed by change in SpO2
Safety Evaluation Criteria - Vital Signs - Systolic Blood Pressure (SBP)
Safety and tolerability will be assessed by change in SBP
Safety Evaluation Criteria - Vital Signs - Diastolic Blood pressure (DBP)
Safety and tolerability will be assessed by change in DBP
Safety Evaluation Criteria - Vital Signs - Heart Rate (HR)
Safety and tolerability will be assessed by change in Heart Rate (HR)
Safety Evaluation Criteria - ECGs - PR interval
Safety and tolerability will be assessed by occurrence of ECGs
Safety Evaluation Criteria - ECGs - RR interval
Safety and tolerability will be assessed by occurrence of ECGs
Safety Evaluation Criteria - ECGs - QRS duration
Safety and tolerability will be assessed by occurrence of ECGs
Safety Evaluation Criteria - ECGs - QT interval
Safety and tolerability will be assessed by occurrence of ECGs
Safety Evaluation Criteria - ECGs - QTcF interval
Safety and tolerability will be assessed by occurrence of ECGs
Safety Evaluation Criteria - ECGs - QTcB interval
Safety and tolerability will be assessed by occurrence of ECGs
The incidence of Responders
The incidence of Responders (Established HRS reversal defined as patients with a Full or Partial HRS response (based on SCr/AKI stage) AND are alive without Renal Replacement Therapy (RRT) for at least 30 days after the first dose of study medication), evaluated separately as two different outcome groups and combined. In case of recurrence and retreatment during the first 30 days, the second treatment period will be evaluated for response

Secondary Outcome Measures

Mortality Rate
Number of patients who died at day 30, 60, and 90.
Liver Transplant Rates
Number of patients undergoing a liver transplant at day 30, 60, and 90.

Full Information

First Posted
May 1, 2023
Last Updated
September 29, 2023
Sponsor
River 2 Renal Corp.
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1. Study Identification

Unique Protocol Identification Number
NCT05875948
Brief Title
Study to Evaluate R2R01 Plus Terlipressin Versus Terlipressin Alone in Patients With Hepatorenal Syndrome
Official Title
A Single-blind, Phase 2, Multi-center, Randomized Study to Assess Safety, Tolerability, Efficacy and Pharmacokinetics of the R2R01 Plus Terlipressin Versus Terlipressin Alone in Patients With Hepatorenal Syndrome - Acute Kidney Injury
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 30, 2023 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
River 2 Renal Corp.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study aims to evaluate the safety, tolerability and efficacy of R2R01 combined with terlipressin as compared to terlipressin alone in the treatment of patients with HRS-AKI
Detailed Description
This is a phase 2 randomized, single-blind, placebo-controlled, two group, multicenter trial preceded by a safety run-in, in patients with Hepatorenal Syndrome (HRS) - Acute Kidney Injury (HRS-AKI). The study consists of: A. an Open-Label Safety Run-In Part with 3 Cohorts of patients, followed by B. a Single-Blind Placebo-Controlled Randomized Part with two Cohorts of patients treated in parallel, and C. an Open-Label Terlipressin Non-Responder Cohort. All patients in all Cohorts will be treated with terlipressin, administered as a slow intravenous (IV) bolus 1 mg over 2 minutes every 6 hours (h) to be increased if clinically appropriate to 2.0 mg every 6 h. Terlipressin dosing should continue up to 24 h after achievement of an HRS response (either Partial or Full) based on Serum Creatinine (SCr)/AKI stage or up to day 14. For those Cohorts where terlipressin will be administered combined with R2R01 (i.e., Cohorts 1, 2, 3, 4, and 6), the first R2R01 administration will commence immediately following the first terlipressin administration. Like terlipressin treatment, R2R01 dosing should continue up to 24 h after achievement of an HRS response (either Partial or Full) based on SCr/AKI stage or up to day 14. All patients in all Cohorts will be followed for up to 90 days after the first dose of study drug. This study will be conducted across approximately 25 centers in EU, UK, US, and Canada. The screening period will occur within 14 days prior to the first dose administration. The treatment duration is up to 14 days with a follow-up period of approximately 76 days. The expected total duration of study participation is up to 15 weeks for each subject.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatorenal Syndrome, Acute Kidney Injury
Keywords
HRS-AKI, HRS, Renal Failure, Kidney Failure, Single-blind, Open-Label, Phase 2, R2R01

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Model Description
A. An Open-Label Safety Run-In Part with 3 Cohorts of patients, followed by B. A Single-Blind Placebo-Controlled Randomized Part with two Cohorts of patients treated in parallel, and C. An Open-Label Terlipressin Non-Responder Cohort.
Masking
Participant
Masking Description
Patients in Cohorts 4 and 5 will be blinded to study treatment. Patients randomized to Cohort 4 will receive terlipressin and R2R01. Patients randomized to Cohort 5 will receive terlipressin and R2R01-matching placebo in the same schedule as Cohort 4. Study staff and Investigators will not be blinded
Allocation
Randomized
Enrollment
95 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
An Open-Label Safety Run-In Part
Arm Type
Experimental
Arm Description
Three initial cohorts (Cohort 1, N=3 patients, Cohorts 2 and 3, N=6 patients, each) will be treated with an open-label combination of terlipressin and R2R01 to ascertain the safety of the combination therapy. A Safety Review Committee (SRC) will review the safety of Cohort 1 patients based on the adverse events and laboratory abnormalities up until Day 14, prior to the start of recruitment of Cohort 2 patients, as well as the safety of Cohorts 1 and 2 patients up until Day 14 prior to the start of recruitment of Cohort 3 patients. Data from all Cohorts 1, 2, and 3 patients up until Day 14 will be reviewed by the SRC before starting the randomized part of the study (Cohorts 4 and 5), so that the SRC can decide and confirm the most appropriate R2R01 dose schedule for patients in Cohorts 4 and 5. Patients enrolled in Cohorts 1, 2, or 3 will remain in their Cohort until study completion (Day 90) or study discontinuation.
Arm Title
Single-blind Placebo-controlled Randomized period
Arm Type
Placebo Comparator
Arm Description
After conclusion of the open-label safety run-in part, and after the SRC has determined the appropriate R2R01 dose schedule, approximately 80 patients will receive terlipressin and be randomized 1:1 to either R2R01 (Cohort 4) or placebo (Cohort 5). At randomization, patients will be stratified by the presence of systemic inflammatory response syndrome (SIRS), since patients with SIRS have shown a better response to terlipressin than patients without SIRS.
Arm Title
An Open-Label Terlipressin Non-Responder Cohort
Arm Type
Experimental
Arm Description
In Cohort 5, if patients do not respond to terlipressin, they must discontinue Cohort 5. After discontinuation, they will be allowed to enter Cohort 6 (Terlipressin Non-Responder Part) to receive R2R01 with the same dosing and schedule as that for Cohort 4. No patient from any Cohort other than Cohort 5 will be allowed to enter Cohort 6.
Intervention Type
Drug
Intervention Name(s)
R2R01
Intervention Description
Pharmaceutical form: sterile 2R vials containing 10 mg of R2R01.
Intervention Type
Drug
Intervention Name(s)
Terlipressin
Intervention Description
In the US, terlipressin is supplied as a sterile, preservative-free, lyophilized, white-to- off-white powder for intravenous (IV) administration. Each vial contains 0.85 mg Terlivaz, equivalent to 1 mg terlipressin acetate, and 10.0 mg mannitol. Terlivaz requires reconstituting in saline (5mL). In the EU, terlipressin is supplied in a clear glass vial with 5 ml of injection solution, containing 1 mg terlipressin acetate corresponding to 0.85 mg terlipressin.
Primary Outcome Measure Information:
Title
Safety Evaluation Criteria - Treatment Emergent Adverse Events (TEAEs)
Description
Safety and tolerability will be assessed by occurrence of TEAEs. Outcome will be reported as the count of participant experiencing TEAEs.
Time Frame
From first dose of study drug to 30 days post last dose
Title
Safety Evaluation Criteria - Change in Weight
Description
Safety and tolerability will be assessed by change in body weight
Time Frame
Change from screening through Day 30
Title
Safety Evaluation Criteria - Vital Signs - Respiration Rate
Description
Safety and tolerability will be assessed by change in respiration rate
Time Frame
Change from screening through Day 30
Title
Safety Evaluation Criteria - Vital Signs - Body Temperature
Description
Safety and tolerability will be assessed by change in body temperature
Time Frame
Change from screening through Day 30
Title
Safety Evaluation Criteria - Vital Signs - Continuous pulse oximetry (SpO2)
Description
Safety and tolerability will be assessed by change in SpO2
Time Frame
Change from baseline through Day 30
Title
Safety Evaluation Criteria - Vital Signs - Systolic Blood Pressure (SBP)
Description
Safety and tolerability will be assessed by change in SBP
Time Frame
Change from screening through Day 30
Title
Safety Evaluation Criteria - Vital Signs - Diastolic Blood pressure (DBP)
Description
Safety and tolerability will be assessed by change in DBP
Time Frame
Change from screening through Day 30
Title
Safety Evaluation Criteria - Vital Signs - Heart Rate (HR)
Description
Safety and tolerability will be assessed by change in Heart Rate (HR)
Time Frame
Change from screening through Day 30
Title
Safety Evaluation Criteria - ECGs - PR interval
Description
Safety and tolerability will be assessed by occurrence of ECGs
Time Frame
Change from screening to Day 14 or hospital discharge
Title
Safety Evaluation Criteria - ECGs - RR interval
Description
Safety and tolerability will be assessed by occurrence of ECGs
Time Frame
Change from screening to Day 14 or hospital discharge
Title
Safety Evaluation Criteria - ECGs - QRS duration
Description
Safety and tolerability will be assessed by occurrence of ECGs
Time Frame
Change from screening to Day 14 or hospital discharge
Title
Safety Evaluation Criteria - ECGs - QT interval
Description
Safety and tolerability will be assessed by occurrence of ECGs
Time Frame
Change from screening to Day 14 or hospital discharge
Title
Safety Evaluation Criteria - ECGs - QTcF interval
Description
Safety and tolerability will be assessed by occurrence of ECGs
Time Frame
Change from screening to Day 14 or hospital discharge
Title
Safety Evaluation Criteria - ECGs - QTcB interval
Description
Safety and tolerability will be assessed by occurrence of ECGs
Time Frame
Change from screening to Day 14 or hospital discharge
Title
The incidence of Responders
Description
The incidence of Responders (Established HRS reversal defined as patients with a Full or Partial HRS response (based on SCr/AKI stage) AND are alive without Renal Replacement Therapy (RRT) for at least 30 days after the first dose of study medication), evaluated separately as two different outcome groups and combined. In case of recurrence and retreatment during the first 30 days, the second treatment period will be evaluated for response
Time Frame
90 days
Secondary Outcome Measure Information:
Title
Mortality Rate
Description
Number of patients who died at day 30, 60, and 90.
Time Frame
30, 60, 90 days
Title
Liver Transplant Rates
Description
Number of patients undergoing a liver transplant at day 30, 60, and 90.
Time Frame
30, 60, 90 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patient is able to communicate well with the Investigator, understands and is willing to comply with all requirements of the study, and understands and signs the written informed consent form (ICF). At least 18 years of age. Cirrhosis and ascites. AKI stage 2 or 3. AKI defined by any of the following: 1) increase in SCr (SCr) ≥ 0.3 mg/dl (or ≥ 26.5 micromolar/L) within 48 h, or 2) increase ≥ 50% in baseline SCr, which is known or presumed to have occurred within the prior seven days. QLY SCr ≥ to 1.5 mg/dl. No sustained improvement in renal function (less than 20% decrease in SCr and SCr => 1.5 mg/dL) after 48 h of diuretic withdrawal and the beginning of plasma volume expansion with albumin. Female patients as well as female partners of male patients must be willing to avoid pregnancy for the duration of the study (>90 days). Exclusion Criteria: Significant co-morbidities that in the opinion of the Investigator would preclude study participation. QLY SCr level > 5 mg/dL. AKI stage 1. ACLF stage 3. Model for End-Stage Liver Disease (MELD) score >35. At least one event of large volume paracentesis (LVP) > 4 Liters in the last 4 days before enrollment. Current or recent (within 4 weeks) treatment with nephrotoxic drugs (e.g., aminoglycosides, amphotericin, cyclosporine, NSAIDS (e.g., ibuprofen, naproxen, celecoxib), significant exposure to radiographic contrast agents (large doses or multiple injections of iodinated contrast media). Shock (hypovolemic-, cardiogenic-, or vasodilatory/distributive shock) with mean arterial blood pressure (MAP) ≤70 mmHg or systolic blood pressure ≤90 mmHg along with hypoperfusion. Sepsis or uncontrolled bacterial infection (e.g., persisting bacteremia, persisting ascitic fluid leucocytosis, fever, increasing leucocytosis with vasomotor instability) as measured with the quick sepsis-related organ dysfunction assessment (qSOFA) score. Fewer than two days of anti-infective therapy for documented or suspected infection. Superimposed acute liver injury induced by drugs, herbal preparation or dietary supplements, with the exception of alcoholic hepatitis. Estimated life expectancy less than 5 days. Hypoxia (<90%) or worsening respiratory symptoms. Proteinuria > 500 mg/day. Tubular epithelial casts, heme granular casts. Haematuria or microhaematuria (more than 50 red blood cells per high power field). Abnormal renal ultra-sonography unless there is a known chronic structural disease (e.g., diabetic or hypertensive nephropathy). Current or recent (within 4 weeks) renal replacement therapy (RRT). Severe cardiovascular and pulmonary diseases including, but not limited to, unstable angina, pulmonary edema, congestive heart failure requiring increasing doses of drug therapy, persisting symptomatic peripheral vascular disease, or any other cardiovascular disease judged by the Investigator to be severe. Transjugular intra-hepatic systemic shunt (TIPS) unless it is known to be non-functioning or occluded. Ongoing use of vasopressors, unless used for only 48 h before screening; in this case a wash-out period of 8 h before enrollment will be necessary. Patients receiving midodrine and octreotide may be enrolled but treatment must be discontinued prior to enrollment. Known allergy or hypersensitivity to terlipressin or other component of the study treatment. Subject is not suitable to participate in the study for any reason (including, but not limited to co-morbidities, history of non-compliance with study visits, procedures, or drug administration) in the opinion of the Investigator. Females of childbearing potential (those who are not surgically sterilized or post-menopausal for at least 1 year) are excluded from participation in the study unless they agree to use highly effective contraception. Males who have no sterilization history and whose female partners have child-bearing potential must agree to use a highly effective method of contraception during the period from the time of signing the informed consent form (ICF) through 90 days after the last dose of study drug. A male patient must agree to immediately inform the Investigator if his partner becomes pregnant during the study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Guido Magni, MD, PHD
Phone
+41 794563810
Email
magniguido@yahoo.com
First Name & Middle Initial & Last Name or Official Title & Degree
Kathie Gabriel, RN, MFT
Phone
610-937-1932
Email
kgabriel@narrowrivermgmt.com
Facility Information:
Facility Name
California Pacific Medical Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94114
Country
United States
Individual Site Status
Not yet recruiting
Facility Name
Piedmont Healthcare, Inc
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30309
Country
United States
Individual Site Status
Recruiting
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Individual Site Status
Not yet recruiting
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Individual Site Status
Recruiting
Facility Name
Hospital of the University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Individual Site Status
Recruiting
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Individual Site Status
Recruiting
Facility Name
Baylor Scott and White All Saints Medical Center
City
Fort Worth
State/Province
Texas
ZIP/Postal Code
76104
Country
United States
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
No

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Study to Evaluate R2R01 Plus Terlipressin Versus Terlipressin Alone in Patients With Hepatorenal Syndrome

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