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

Acute Kidney Injury Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05875948
• Other study ID #: R2R01-HRS-201
• Status: Recruiting
• Phase: Phase 2
• Start date: June 30, 2023
• Est. completion date: December 2024

Study information

• Verified date: May 2023
• Source: River 2 Renal Corp.
• Contact: Guido Magni, MD, PHD
• Phone: +41 794563810
• Email: magniguido[@]yahoo.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 95
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Kidney Injury
• Hepatorenal Syndrome
• Syndrome

Intervention

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

Locations

Country	Name	City	State
United States	Piedmont Healthcare, Inc	Atlanta	Georgia
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Baylor Scott and White All Saints Medical Center	Fort Worth	Texas
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	California Pacific Medical Center	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
River 2 Renal Corp.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	From first dose of study drug to 30 days post last dose
Primary	Safety Evaluation Criteria - Change in Weight	Safety and tolerability will be assessed by change in body weight	Change from screening through Day 30
Primary	Safety Evaluation Criteria - Vital Signs - Respiration Rate	Safety and tolerability will be assessed by change in respiration rate	Change from screening through Day 30
Primary	Safety Evaluation Criteria - Vital Signs - Body Temperature	Safety and tolerability will be assessed by change in body temperature	Change from screening through Day 30
Primary	Safety Evaluation Criteria - Vital Signs - Continuous pulse oximetry (SpO2)	Safety and tolerability will be assessed by change in SpO2	Change from baseline through Day 30
Primary	Safety Evaluation Criteria - Vital Signs - Systolic Blood Pressure (SBP)	Safety and tolerability will be assessed by change in SBP	Change from screening through Day 30
Primary	Safety Evaluation Criteria - Vital Signs - Diastolic Blood pressure (DBP)	Safety and tolerability will be assessed by change in DBP	Change from screening through Day 30
Primary	Safety Evaluation Criteria - Vital Signs - Heart Rate (HR)	Safety and tolerability will be assessed by change in Heart Rate (HR)	Change from screening through Day 30
Primary	Safety Evaluation Criteria - ECGs - PR interval	Safety and tolerability will be assessed by occurrence of ECGs	Change from screening to Day 14 or hospital discharge
Primary	Safety Evaluation Criteria - ECGs - RR interval	Safety and tolerability will be assessed by occurrence of ECGs	Change from screening to Day 14 or hospital discharge
Primary	Safety Evaluation Criteria - ECGs - QRS duration	Safety and tolerability will be assessed by occurrence of ECGs	Change from screening to Day 14 or hospital discharge
Primary	Safety Evaluation Criteria - ECGs - QT interval	Safety and tolerability will be assessed by occurrence of ECGs	Change from screening to Day 14 or hospital discharge
Primary	Safety Evaluation Criteria - ECGs - QTcF interval	Safety and tolerability will be assessed by occurrence of ECGs	Change from screening to Day 14 or hospital discharge
Primary	Safety Evaluation Criteria - ECGs - QTcB interval	Safety and tolerability will be assessed by occurrence of ECGs	Change from screening to Day 14 or hospital discharge
Primary	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	90 days
Secondary	Mortality Rate	Number of patients who died at day 30, 60, and 90.	30, 60, 90 days
Secondary	Liver Transplant Rates	Number of patients undergoing a liver transplant at day 30, 60, and 90.	30, 60, 90 days