A Single-blind, Phase 2, Multi-center, Randomized Study to Assess Safety, Tolerability, Efficacy and Pharmacokinetics of the Relaxin Agonist R2R01 Plus Terlipressin Versus Terlipressin Alone in Patients with Hepatorenal Syndrome – Acute Kidney Injury

Overview

Sponsor-declared trial summary

Key facts

Sponsor

River 2 Renal Corp.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Pathological Conditions, Signs and Symptoms [C23]

Trial duration

13 May 2024 → 29 Mar 2025

Decision date (initial)

2023-10-17

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

River 2 Renal Corp.

External identifiers

EU CT number

2023-503504-88-00

ClinicalTrials.gov

NCT05875948

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the tolerability and safety R2R01 in combination with terlipressin versus terlipressin alone. To evaluate the efficacy of R2R01 in combination with terlipressin versus terlipressin alone based on the number of responding patients. Established HRS reversal (clinical responders) are defined as patients with a Full or Partial HRS response based on SCr and AKI stage AND are alive without Renal Replacement Therapy (RRT) for at least 30 days after the first dose of study medication. To evaluate the efficacy of the addition of R2R01 to terlipressin in terlipressin-non-responders.

Secondary objectives 1

1. To evaluate the efficacy of R2R01 in combination with terlipressin versus terlipressin alone on mortality, liver transplant rates, RRT rates, durability of HRS reversal, HRS recurrence, worsening of acute on chronic liver failure (ACLF) to stage 3, on change in Model for End-Stage Liver Disease (MELD) at Days 30, 60, and 90 after the start of treatment.

Conditions and MedDRA coding

Hepatorenal Syndrome – Acute Kidney Injury

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

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 μmol/L) within 48 h, or 2) increase ≥ 50% in BL SCr, which is known or presumed to have occurred within the prior seven days. - Stage 2 is defined as an increase in sCr > 2 fold to 3 fold from baseline. - Stage 3 is defined as increase of sCr > 3 fold from baseline or sCr ≥ 4.0 mg/dl (353.6 μmol/L) with an or initiation acute increase ≥ 0.3 mg/dl (26.5 μmol/L)
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 25

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 (see Table 13).
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 as described in Section 11.3.
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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Safety and tolerability will be assessed by occurrence of AEs, changes in physical examinations, vital signs, ECGs, and clinical laboratory parameters.
2. 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.
3. Patients who are undergoing liver transplant during the first 30 days after treatment start will have their SCr and AKI stage evaluated before the transplant and will be considered responders if meeting the criteria for SCr/AKI stage for HRS response (Full or Partial) before the liver transplant and are alive and without RRT at day 30 after treatment start.
4. In case of recurrence and retreatment during the first 30 days, the second treatment period will be evaluated for response.

Secondary endpoints 11

1. Number of patients who died (mortality rate) at day 30, 60, and 90.
2. Number of patients with renal and/or liver transplant at day 30, 60, and 90.
3. Number of patients with RRT at day 30, 60, and 90.
4. Number of patients with durable Established HRS reversal (number of patients with a Full or Partial HRS Response and without RRT by day 45, 60, and 90), the two response categories evaluated in a separate and combined manner.
5. Number of patients with HRS recurrence.
6. Number of patients with an HRS response based on SCr/AKI stage as Full, Partial, and Combined.
7. Number of patients with worsening of ACLF 1 or 2 to stage 3, or improvement from stage 2 to stage 1.
8. Mean change from baseline in MELD score at day 30, 60, and 90.
9. The number of responding patients with an Established HRS reversal where the clinical definition is patient alive without RRT 10 days after the achievement of HRS response (i.e., as per the CONFIRM study).
10. Mean change from baseline in serum and urine biomarkers (including Cystatin C, Endothelin-1, vWF, NGAL, KIM 1).
11. Population PK analysis will be performed to derive primary PK parameters (e.g., absorption rate (ka), apparent Clearance (CI/F) and apparent volume of distribution (V/F)) and secondary PK parameters (maximum concentrations (Cmax), time of Cmax (tmax), minimum plasma concentrations (Cmin), area under the concetration time curve over the dosing interval (AUC 024b), elimination halft life(t1/2), and accumulation ratio (Racc).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

River 2 Renal Corp.

Sponsor organisation

River 2 Renal Corp.

Address

1 Rockefeller Plaza Suite 1204

City

New York

Postcode

10020-2070

Country

United States

Scientific contact point

Organisation

River 2 Renal Corp.

Contact name

Richard Woodward

Public contact point

Organisation

River 2 Renal Corp.

Contact name

Richard Woodward

Third parties 5

Sponsor responsibilities

Article 77 compliance

River 2 Renal Corp.

Locations

2 EU/EEA countries · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 19 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications