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

• ClinicalTrials.gov Identifier: NCT05875948
• Recruitment Status: Recruiting
• First Posted: May 25, 2023
• Last Update Posted: October 3, 2023
• Sponsor: River 2 Renal Corp.
• Information provided by (Responsible Party): River 2 Renal Corp.

Tracking Information

• First Submitted Date: May 1, 2023
• First Posted Date: May 25, 2023
• Last Update Posted Date: October 3, 2023
• Actual Study Start Date: June 30, 2023
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 16, 2023)

• Safety Evaluation Criteria - Treatment Emergent Adverse Events (TEAEs) [ Time Frame: From first dose of study drug to 30 days post last dose ]
  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 [ Time Frame: Change from screening through Day 30 ]
  Safety and tolerability will be assessed by change in body weight
• Safety Evaluation Criteria - Vital Signs - Respiration Rate [ Time Frame: Change from screening through Day 30 ]
  Safety and tolerability will be assessed by change in respiration rate
• Safety Evaluation Criteria - Vital Signs - Body Temperature [ Time Frame: Change from screening through Day 30 ]
  Safety and tolerability will be assessed by change in body temperature
• Safety Evaluation Criteria - Vital Signs - Continuous pulse oximetry (SpO2) [ Time Frame: Change from baseline through Day 30 ]
  Safety and tolerability will be assessed by change in SpO2
• Safety Evaluation Criteria - Vital Signs - Systolic Blood Pressure (SBP) [ Time Frame: Change from screening through Day 30 ]
  Safety and tolerability will be assessed by change in SBP
• Safety Evaluation Criteria - Vital Signs - Diastolic Blood pressure (DBP) [ Time Frame: Change from screening through Day 30 ]
  Safety and tolerability will be assessed by change in DBP
• Safety Evaluation Criteria - Vital Signs - Heart Rate (HR) [ Time Frame: Change from screening through Day 30 ]
  Safety and tolerability will be assessed by change in Heart Rate (HR)
• Safety Evaluation Criteria - ECGs - PR interval [ Time Frame: Change from screening to Day 14 or hospital discharge ]
  Safety and tolerability will be assessed by occurrence of ECGs
• Safety Evaluation Criteria - ECGs - RR interval [ Time Frame: Change from screening to Day 14 or hospital discharge ]
  Safety and tolerability will be assessed by occurrence of ECGs
• Safety Evaluation Criteria - ECGs - QRS duration [ Time Frame: Change from screening to Day 14 or hospital discharge ]
  Safety and tolerability will be assessed by occurrence of ECGs
• Safety Evaluation Criteria - ECGs - QT interval [ Time Frame: Change from screening to Day 14 or hospital discharge ]
  Safety and tolerability will be assessed by occurrence of ECGs
• Safety Evaluation Criteria - ECGs - QTcF interval [ Time Frame: Change from screening to Day 14 or hospital discharge ]
  Safety and tolerability will be assessed by occurrence of ECGs
• Safety Evaluation Criteria - ECGs - QTcB interval [ Time Frame: Change from screening to Day 14 or hospital discharge ]
  Safety and tolerability will be assessed by occurrence of ECGs
• The incidence of Responders [ Time Frame: 90 days ]
  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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 16, 2023)

• Mortality Rate [ Time Frame: 30, 60, 90 days ]
  Number of patients who died at day 30, 60, and 90.
• Liver Transplant Rates [ Time Frame: 30, 60, 90 days ]
  Number of patients undergoing a liver transplant at day 30, 60, and 90.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Sequential Assignment
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.

Masking: Single (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

Primary Purpose: Treatment

Condition

• Hepatorenal Syndrome
• Acute Kidney Injury

Intervention

• Drug: R2R01
  Pharmaceutical form: sterile 2R vials containing 10 mg of R2R01.
• Drug: Terlipressin

  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.

Study Arms

• Experimental: An Open-Label Safety Run-In Part

  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.

  Interventions:

  • Drug: R2R01
  • Drug: Terlipressin
• Placebo Comparator: Single-blind Placebo-controlled Randomized period

  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.

  Interventions:

  • Drug: R2R01
  • Drug: Terlipressin
• Experimental: An Open-Label Terlipressin Non-Responder Cohort
  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.
  Interventions:

  • Drug: R2R01
  • Drug: Terlipressin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 16, 2023): 95
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2024
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Guido Magni, MD, PHD; +41 794563810; magniguido@yahoo.com

Contact: Kathie Gabriel, RN, MFT; 610-937-1932; kgabriel@narrowrivermgmt.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05875948
• Other Study ID Numbers: R2R01-HRS-201
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: River 2 Renal Corp.
• Original Responsible Party: Same as current
• Current Study Sponsor: River 2 Renal Corp.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: River 2 Renal Corp.
• Verification Date: May 2023