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

NCT05875948 | Unknown Phase 2 DMC FDA Drug

• 1 other identifier: R2R01-HRS-201
• Study Type: interventional
• Target: 95
• Locations: 1 country
• Sites: 7

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

Conditions

Hepatorenal Syndrome; Acute Kidney Injury

Keywords

HRS-AKI; HRS; Renal Failure; Kidney Failure; Single-blind; Open-Label; Phase 2; R2R01

Outcome Measures

Primary Outcomes (15)

• 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

• Safety Evaluation Criteria - Change in Weight

  Safety and tolerability will be assessed by change in body weight

  Change from screening through Day 30

• Safety Evaluation Criteria - Vital Signs - Respiration Rate

  Safety and tolerability will be assessed by change in respiration rate

  Change from screening through Day 30

• Safety Evaluation Criteria - Vital Signs - Body Temperature

  Safety and tolerability will be assessed by change in body temperature

  Change from screening through Day 30

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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 Outcomes (2)

• Mortality Rate

  30, 60, 90 days

• Liver Transplant Rates

  30, 60, 90 days

Study Arms (3)

An Open-Label Safety Run-In Part

EXPERIMENTAL

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.

Drug: R2R01; Drug: Terlipressin

Single-blind Placebo-controlled Randomized period

PLACEBO COMPARATOR

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.

Drug: R2R01; Drug: Terlipressin

An Open-Label Terlipressin Non-Responder Cohort

EXPERIMENTAL

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.

Drug: R2R01; Drug: Terlipressin

Interventions

R2R01 DRUG

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

An Open-Label Safety Run-In Part; An Open-Label Terlipressin Non-Responder Cohort; Single-blind Placebo-controlled Randomized period

Terlipressin DRUG

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.

An Open-Label Safety Run-In Part; An Open-Label Terlipressin Non-Responder Cohort; Single-blind Placebo-controlled Randomized period

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• River 2 Renal Corp.: lead

Study Sites (7)

California Pacific Medical Center

San Francisco, California, 94114, United States

NOT YET RECRUITING

Piedmont Healthcare, Inc

Atlanta, Georgia, 30309, United States

RECRUITING

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

NOT YET RECRUITING

Mayo Clinic

Rochester, Minnesota, 55905, United States

RECRUITING

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

RECRUITING

Baylor Scott and White All Saints Medical Center

Fort Worth, Texas, 76104, United States

RECRUITING

MeSH Terms

Conditions

Hepatorenal Syndrome; Acute Kidney Injury; Renal Insufficiency

Interventions

Terlipressin

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Lypressin; Vasopressins; Pituitary Hormones, Posterior; Pituitary Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins

Central Study Contacts

Guido Magni, MD, PHD

CONTACT

+41 794563810; magniguido@yahoo.com

Kathie Gabriel, RN, MFT

CONTACT

610-937-1932; kgabriel@narrowrivermgmt.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: 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
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: May 1, 2023
• First Posted: May 25, 2023
• Study Start: June 30, 2023
• Primary Completion: December 1, 2024
• Study Completion: December 1, 2024
• Last Updated: October 3, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)