Clinical trial NCT05875948: 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
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Hepatorenal Syndrome
Acute Kidney Injury
Keywords: HRS-AKI
HRS
Renal Failure
Kidney Failure
Single-blind
Open-Label
Phase 2
R2R01
Lead sponsor: River 2 Renal Corp.
Sponsor class: INDUSTRY
First posted: 2023-05-25
Enrollment: 95
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. 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).
2. At least 18 years of age.
3. Cirrhosis and ascites.
4. 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.
5. QLY SCr ≥ to 1.5 mg/dl.
6. 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.
7. 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:

1. Significant co-morbidities that in the opinion of the Investigator would preclude study participation.
2. QLY SCr level \> 5 mg/dL.
3. AKI stage 1.
4. ACLF stage 3.
5. Model for End-Stage Liver Disease (MELD) score \>35.
6. At least one event of large volume paracentesis (LVP) \> 4 Liters in the last 4 days before enrollment.
7. 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).
8. Shock (hypovolemic-, cardiogenic-, or vasodilatory/distributive shock) with mean arterial blood pressure (MAP) ≤70 mmHg or systolic blood pressure ≤90 mmHg along with hypoperfusion.
9. 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.
10. Fewer than two days of anti-infective therapy for documented or suspected infection.
11. Superimposed acute liver injury induced by drugs, herbal preparation or dietary supplements, with the exception of alcoholic hepatitis.
12. Estimated life expectancy less than 5 days.
13. Hypoxia (\<90%) or worsening respiratory symptoms.
14. Proteinuria \> 500 mg/day.
15. Tubular epithelial casts, heme granular casts.
16. Haematuria or microhaematuria (more than 50 red blood cells per high power field).
17. Abnormal renal ultra-sonography unless there is a known chronic structural disease (e.g., diabetic or hypertensive nephropathy).
18. Current or recent (within 4 weeks) renal replacement therapy (RRT).
19. 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.
20. Transjugular intra-hepatic systemic shunt (TIPS) unless it is known to be non-functioning or occluded.
21. 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.
22. Known allergy or hypersensitivity to terlipressin or other component of the study treatment.
23. 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.
24. 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.
25. 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.

Primary outcomes:
measure: Safety Evaluation Criteria - Treatment Emergent Adverse Events (TEAEs)
timeFrame: From first dose of study drug to 30 days post last dose
measure: Safety Evaluation Criteria - Change in Weight
timeFrame: Change from screening through Day 30
measure: Safety Evaluation Criteria - Vital Signs - Respiration Rate
timeFrame: Change from screening through Day 30
measure: Safety Evaluation Criteria - Vital Signs - Body Temperature
timeFrame: Change from screening through Day 30
measure: Safety Evaluation Criteria - Vital Signs - Continuous pulse oximetry (SpO2)
timeFrame: Change from baseline through Day 30
measure: Safety Evaluation Criteria - Vital Signs - Systolic Blood Pressure (SBP)
timeFrame: Change from screening through Day 30
measure: Safety Evaluation Criteria - Vital Signs - Diastolic Blood pressure (DBP)
timeFrame: Change from screening through Day 30
measure: Safety Evaluation Criteria - Vital Signs - Heart Rate (HR)
timeFrame: Change from screening through Day 30
measure: Safety Evaluation Criteria - ECGs - PR interval
timeFrame: Change from screening to Day 14 or hospital discharge
measure: Safety Evaluation Criteria - ECGs - RR interval
timeFrame: Change from screening to Day 14 or hospital discharge
measure: Safety Evaluation Criteria - ECGs - QRS duration
timeFrame: Change from screening to Day 14 or hospital discharge
measure: Safety Evaluation Criteria - ECGs - QT interval
timeFrame: Change from screening to Day 14 or hospital discharge
measure: Safety Evaluation Criteria - ECGs - QTcF interval
timeFrame: Change from screening to Day 14 or hospital discharge
measure: Safety Evaluation Criteria - ECGs - QTcB interval
timeFrame: Change from screening to Day 14 or hospital discharge
measure: The incidence of Responders
timeFrame: 90 days
Secondary outcomes:
measure: Mortality Rate
timeFrame: 30, 60, 90 days
measure: Liver Transplant Rates
timeFrame: 30, 60, 90 days
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Atlanta
country: United States
facility: Piedmont Healthcare, Inc
state: Georgia
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Fort Worth
country: United States
facility: Baylor Scott and White All Saints Medical Center
state: Texas
Study officials:
References: