Treprostinil for Ischemia-Reperfusion Injury During Kidney Transplantation

Overseen By Nisanne Ghonem, PharmD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Rhode Island Hospital

Must not be taking: Investigational drugs, Prostanoid therapy

Disqualifiers: BMI > 40, Gastroparesis, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: 2 days

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a medication called treprostinil to determine if it protects kidneys from damage during a transplant. Researchers believe treprostinil improves blood flow and reduces injury in the new kidney. The trial seeks participants undergoing a deceased donor kidney transplant, particularly those with diabetes. Participants will receive the medication through an IV starting a few hours before surgery and continuing for two days after. The study focuses on the treatment's safety and effectiveness. As a Phase 1, Phase 2 trial, it aims to understand how treprostinil works in people and measure its effectiveness in an initial group, offering participants a chance to contribute to important medical research.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are on any investigational drugs, prostanoid therapy for portopulmonary hypertension, or non-standard immunosuppression protocols.

Is there any evidence suggesting that treprostinil is likely to be safe for humans?

Research has shown that treprostinil has been safely used in other situations. For example, it was administered to liver transplant patients with high blood pressure in the lungs without any negative effects, indicating that treprostinil is usually well-tolerated.

This trial tests whether treprostinil can help reduce kidney damage during transplants. The drug is administered through an IV for about two days around the time of the transplant. As this is an early-stage trial, researchers closely monitor participants to ensure safety. The FDA has already approved the drug for other uses, which provides some confidence in its safety. Prospective participants should consult the research team to understand the possible risks and benefits before joining the trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Treprostinil is unique because it targets ischemia-reperfusion injury during kidney transplantation through its vasodilatory effects, which can improve blood flow and protect the kidney tissue. Unlike current treatments that primarily focus on immunosuppression to prevent organ rejection, treprostinil offers a different approach by directly addressing the blood flow issues that occur during transplantation. Researchers are excited about treprostinil because it has the potential to enhance the success of kidney transplants and improve overall outcomes by reducing injury to the transplanted organ.

What evidence suggests that treprostinil might be an effective treatment for ischemia-reperfusion injury during kidney transplantation?

Research has shown that treprostinil, which participants in this trial will receive, might protect kidneys during transplants by improving blood flow. In animal studies, treprostinil improved kidney function after restoring blood supply due to its effect on certain biological processes. People who have used treprostinil for other conditions, such as high blood pressure in the lungs during liver transplants, did not experience major side effects. This suggests that treprostinil could safely enhance kidney function after a transplant and possibly reduce complications with the new kidney. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

Adults aged 18-65 eligible for a deceased donor kidney transplant can join this trial. They must be on the RIH transplant list, able to follow study requirements, and have documented diabetes. Exclusions include inflammatory bowel disease, treprostinil hypersensitivity, recent failed kidney transplant, pregnancy or nursing women, extreme obesity (BMI > 40), certain GI surgeries or conditions, other drug trials participation, specific heart diseases.

Inclusion Criteria

I am between 18 and 65 years old, waiting for a kidney transplant from a deceased donor.

Written informed consent obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study

You have been diagnosed with diabetes based on clinical signs and symptoms.

Exclusion Criteria

I am on medication for portopulmonary hypertension.

I am not taking any experimental drugs except for treprostinil.

I frequently vomit due to severe gastroparesis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a two-day peri-operative course of treprostinil to reduce ischemia-reperfusion injury during kidney transplantation

2 days

Continuous monitoring during hospitalization

Follow-up

Participants are monitored for safety and effectiveness after treatment, including evaluation of biochemical and clinical endpoints

4 weeks

Regular follow-up visits, including assessments on Day 7 and Day 30

What Are the Treatments Tested in This Trial?

Interventions

• Treprostinil

Trial Overview

The trial is testing Treprostinil's safety and effectiveness in reducing injury from blood supply restoration during kidney transplants. Participants will receive an IV infusion of Treprostinil before and for two days after surgery to see if it helps protect the new kidney.

How Is the Trial Designed?

Group I: Trepostinil Experimental Treatment 1 Intervention

Treprostinil (Remodulin) will be administered IV by a standard 3 + 3 dose-escalation approach. This dosing model will be followed until a target dose of 15 mg/kg/min is achieved or if it is medically determined that side effects prevent dose escalation. IV infusion will commence approximately 2-3 hours before transplantation of the kidney graft and will continue for approximately 48 hours after completion of surgery, unless hemodynamic changes or tolerability require discontinuation of treprostinil.

Treprostinil is already approved in United States, European Union for the following indications:

Approved in United States as Remodulin for:

• Pulmonary Arterial Hypertension

Approved in European Union as Remodulin for:

• Pulmonary Arterial Hypertension

Who Is Running the Clinical Trial?

Rhode Island Hospital

Lead Sponsor

Trials

275

Recruited

71,400+

University of Rhode Island

Collaborator

Trials

57

Recruited

22,400+

United Therapeutics

Industry Sponsor

Trials

112

Recruited

14,500+

Dr. Martine Rothblatt

United Therapeutics

Chief Executive Officer since 1996

PhD in Medical Ethics from the Royal London College of Medicine and Dentistry, JD and MBA from UCLA

Dr. Michael Benkowitz

United Therapeutics

Chief Medical Officer since 2023

MD from Harvard Medical School

Published Research Related to This Trial

Treprostinil significantly improved kidney function in rats after renal ischemia-reperfusion injury (IRI) by reducing serum creatinine and blood urea nitrogen levels, indicating its potential as a protective treatment against acute kidney injury.

The treatment also inhibited inflammation and apoptosis in kidney cells, as shown by reduced expression of injury biomarkers and pro-inflammatory cytokines, suggesting that treprostinil could be an effective therapeutic agent for preventing renal damage during IRI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treprostinil, a prostacyclin analog, ameliorates renal ischemia-reperfusion injury: preclinical studies in a rat model of acute kidney injury. Ding, M., Tolbert, E., Birkenbach, M., et al.[2021]

Treprostinil significantly improved kidney function in rats with renal ischemia-reperfusion injury (IRI) by reducing peak serum creatinine levels and accelerating recovery compared to a placebo, indicating its potential efficacy as a treatment.

The treatment with treprostinil also protected against mitochondrial damage by reducing renal apoptosis and preserving ATP levels, suggesting it enhances mitochondrial recovery and function during IRI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treprostinil reduces mitochondrial injury during rat renal ischemia-reperfusion injury. Ding, M., Tolbert, E., Birkenbach, M., et al.[2022]

In a phase 1/2 study involving liver transplant recipients, continuous intravenous infusion of treprostinil was safely tolerated at doses up to 5 ng/kg/min, showing no primary graft non-function and improved liver function post-transplant.

The use of treprostinil minimized the need for ventilation support and reduced hospitalization time, suggesting its potential to enhance outcomes in liver transplantation and warranting further studies on its efficacy in preventing ischemia and reperfusion injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of the safety and preliminary efficacy of peri- and post-operative treprostinil in preventing ischemia and reperfusion injury in adult orthotopic liver transplant recipients. Almazroo, OA., Miah, MK., Pillai, VC., et al.[2021]

Olprinone, a phosphodiesterase III inhibitor, significantly improved renal blood flow and reduced tubular damage in a rat model of renal ischemic reperfusion injury, indicating its potential as a protective agent during kidney transplantation.

Both systemic and local administration of olprinone were effective, and it also inhibited inflammatory responses in kidney cells, suggesting it could be beneficial for both donor kidneys and recipients in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of olprinone, a phosphodiesterase III inhibitor, on ischemic acute renal failure. Anas, C., Ozaki, T., Maruyama, S., et al.[2012]

Treprostinil, a synthetic analog of prostaglandin I2, has shown promising results in improving liver and kidney function during hepatic ischemia-reperfusion syndrome, which is critical in liver surgeries and transplants.

The drug works by reducing oxidative stress, inflammation, and apoptosis in the liver, while also restoring ATP levels, suggesting it could effectively minimize damage during ischemia-reperfusion injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatic ischemia-reperfusion syndrome and its effect on the cardiovascular system: The role of treprostinil, a synthetic prostacyclin analog. Mouratidou, C., Pavlidis, ET., Katsanos, G., et al.[2023]

The addition of Vectisol®, an antioxidant encapsulating resveratrol, to kidney preservation solutions significantly improved early recovery of kidney function and reduced chronic loss of function in a preclinical pig model of kidney autotransplantation.

Using Vectisol® during machine perfusion decreased oxidative stress and apoptosis, leading to better organ quality and long-term outcomes, suggesting it could be a crucial component in future therapies for organ transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vectisol Formulation Enhances Solubility of Resveratrol and Brings Its Benefits to Kidney Transplantation in a Preclinical Porcine Model. Soussi, D., Danion, J., Baulier, E., et al.[2020]

Treprostinil, a prostacyclin analog, effectively reduced ischemia-reperfusion injury (IRI) in liver transplantation, as shown in a study with Lewis rats, where it decreased liver damage markers and improved energy levels post-transplant.

The treatment with treprostinil maintained normal hepatic blood flow and preserved liver graft integrity, suggesting its potential as a therapeutic option for protecting liver grafts during transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treprostinil, a prostacyclin analog, ameliorates ischemia-reperfusion injury in rat orthotopic liver transplantation. Ghonem, N., Yoshida, J., Stolz, DB., et al.[2023]

Supplementing preservation solutions with the Sigma-1 receptor agonist fluvoxamine (FLU) significantly reduces cold and warm ischemic injury in kidney transplants, improving post-transplant kidney function and reducing histological damage in rodent models.

FLU treatment leads to decreased renal inflammation and apoptosis, suggesting it can enhance organ preservation and potentially extend the viability of transplantable kidneys, addressing the shortage of available organs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Sigma-1 Receptor Is a Novel Target for Improving Cold Preservation in Rodent Kidney Transplants. Hosszu, A., Toth, AR., Lakat, T., et al.[2023]

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