What is the mechanism of action of this treatment?

Terlipressin, a vasopressin analog, is commonly used in the treatment of Hepatorenal Syndrome (HRS) due to its vasoconstrictive properties, which help to increase renal perfusion. It works by constricting the splanchnic circulation, thereby reducing portal hypertension and improving blood flow to the kidneys. This is crucial for HRS patients as it addresses the underlying circulatory dysfunction that leads to renal failure. The combination of Terlipressin with other agents, such as the investigational R2R01, aims to enhance therapeutic outcomes, although the exact mechanism of R2R01 remains unknown.

What side effects are associated with this type of intervention?

Terlipressin, a vasopressin analog commonly used in the treatment of Hepatorenal Syndrome, is associated with several side effects. These include abdominal pain, diarrhea, and cardiovascular issues such as hypertension and bradycardia. More severe but less common side effects can include ischemic events, such as myocardial infarction and peripheral ischemia. Patients may also experience hyponatremia and fluid retention. Monitoring for these adverse effects is crucial during treatment.

What prior FDA approvals exist?

The FDA has approved Terlipressin, a vasopressin analog, for the treatment of Hepatorenal Syndrome (HRS). Terlipressin works by constricting blood vessels, which helps improve kidney function in patients with HRS. Other treatments for HRS have included vasopressin and its analogs, but Terlipressin is the primary drug in this category that has received FDA approval. The combination of R2R01 with Terlipressin is currently being studied to evaluate its safety and efficacy, but R2R01's mechanism remains unknown.

What other types of research exist?

Promising novel alternatives to R2R01 combined with Terlipressin for Hepatorenal Syndrome patients include selective V2 receptor antagonists like RWJ-351647 and dual V1a/V2 receptor antagonists like Conivaptan. These agents have shown efficacy in improving renal function and managing water retention in cirrhotic patients with ascites.

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R2R01 + Terlipressin for Hepatorenal Syndrome

Phase 2

Recruiting

Research Sponsored by River 2 Renal Corp.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Cirrhosis and ascites.

At least 18 years of age.

Must not have

AKI stage 1.

ACLF stage 3.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 30, 60, 90 days

Summary

This trial is testing a new drug called R2R01 combined with an existing drug, terlipressin, to treat patients with severe kidney problems related to liver disease (HRS-AKI). The goal is to see if this combination works better than using terlipressin alone. Terlipressin helps improve blood flow to the kidneys, and R2R01 might make this treatment even more effective. Terlipressin has been used for many years in Europe and has shown to be effective in improving kidney function.

Who is the study for?

Adults with cirrhosis, ascites, and severe kidney injury related to liver disease (HRS-AKI) can join this trial. They must understand the study and agree to its rules, including avoiding pregnancy. People with allergies to terlipressin or other serious health issues, recent infections without proper treatment, high MELD scores (>35), or those on certain medications are excluded.

What is being tested?

The trial is testing a combination of R2R01 and terlipressin against using just terlipressin for treating HRS-AKI. The goal is to see if adding R2R01 improves safety, tolerability, and effectiveness in patients compared to the standard treatment alone.

What are the potential side effects?

Possible side effects include allergic reactions to medication components, potential worsening of cardiovascular or pulmonary conditions due to drug interactions or underlying diseases. Specific side effects of R2R01 aren't listed but may be similar or additive to those known for terlipressin.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have cirrhosis and fluid buildup in my abdomen.

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I am 18 years old or older.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have mild kidney injury.

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My liver disease is in its most severe stage.

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I do not have sepsis or any uncontrolled infection.

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I do not have severe heart or lung diseases.

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I am using or agree to use effective birth control if I can have children.

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I haven't taken kidney-damaging drugs or had certain scans, and my blood pressure hasn't been very low recently.

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I have taken antibiotics for an infection for less than two days.

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I have low oxygen levels or my breathing is getting worse.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 30, 60, 90 days

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~30, 60, 90 days

This trial's timeline: 3 weeks for screening, Varies for treatment, and 30, 60, 90 days for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Safety Evaluation Criteria - Change in Weight

Safety Evaluation Criteria - ECGs - PR interval

Safety Evaluation Criteria - ECGs - QRS duration

+12 more

Secondary study objectives

Liver Transplant Rates

Mortality Rate

Trial Design

3Treatment groups

Experimental Treatment

Placebo Group

Group I: An Open-Label Terlipressin Non-Responder CohortExperimental Treatment2 Interventions

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.

Group II: An Open-Label Safety Run-In PartExperimental Treatment2 Interventions

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.

Group III: Single-blind Placebo-controlled Randomized periodPlacebo Group2 Interventions

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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Terlipressin

2020

Completed Phase 4

~2660

0 / 10Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Terlipressin, a vasopressin analog, is commonly used in the treatment of Hepatorenal Syndrome (HRS) due to its vasoconstrictive properties, which help to increase renal perfusion. It works by constricting the splanchnic circulation, thereby reducing portal hypertension and improving blood flow to the kidneys. This is crucial for HRS patients as it addresses the underlying circulatory dysfunction that leads to renal failure. The combination of Terlipressin with other agents, such as the investigational R2R01, aims to enhance therapeutic outcomes, although the exact mechanism of R2R01 remains unknown.