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

Trial Summary

What is the purpose of this trial?

The objectives of this study are to test the preliminary safety and efficacy of a two-day peri-operative course of treprostinil in reducing ischemia-reperfusion injury in adult patients receiving a deceased donor kidney transplantation. Treprostinil, a prostacyclin analog, is expected to facilitate the restoration of blood supply to the revascularized kidney graft via its vasodilatory actions, well characterized protective effects, and longer elimination half-life. These properties and actions of treprostinil make it a strong drug candidate to reduce kidney graft dysfunction during kidney transplantation. An anticipated 20 participants undergoing deceased donor kidney transplant will be hospitalized and intensively monitored during an entire two-day Treatment Phase. An IV infusion using a dedicated central venous line will be used to administer treprostinil commencing approximately 2-3 hours before transplantation of the kidney graft and will continue for approximately 48 hours after completion of the transplant surgery. The primary endpoints include the safety and efficacy of treprostinil, with secondary endpoints including the evaluation of both biochemical and clinical endpoints post-transplantation.

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.

What data supports the effectiveness of the drug Treprostinil for ischemia-reperfusion injury during kidney transplantation?

Research shows that Treprostinil, a drug similar to natural substances in the body, helps protect kidneys from damage caused by interrupted blood flow and its return (ischemia-reperfusion injury) in animal studies. It improves energy production in cells and reduces tissue damage, suggesting it could be beneficial in kidney transplants. ^{1 2 3 4 5}

What makes the drug Treprostinil unique for treating ischemia-reperfusion injury during kidney transplantation?

Treprostinil is unique because it is a prostacyclin analog that helps protect against kidney damage by improving mitochondrial function and reducing inflammation, which are not addressed by any existing treatments for ischemia-reperfusion injury. ^{1 5 6 7 8}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

References

1. France pubmed.ncbi.nlm.nih.gov

Treprostinil reduces mitochondrial injury during rat renal ischemia-reperfusion injury. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Vectisol Formulation Enhances Solubility of Resveratrol and Brings Its Benefits to Kidney Transplantation in a Preclinical Porcine Model. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Treprostinil, a prostacyclin analog, ameliorates ischemia-reperfusion injury in rat orthotopic liver transplantation. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

The Sigma-1 Receptor Is a Novel Target for Improving Cold Preservation in Rodent Kidney Transplants. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Treprostinil, a prostacyclin analog, ameliorates renal ischemia-reperfusion injury: preclinical studies in a rat model of acute kidney injury. [2021]

6. Denmark 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. [2021]

7. Australia pubmed.ncbi.nlm.nih.gov

Effects of olprinone, a phosphodiesterase III inhibitor, on ischemic acute renal failure. [2012]

8. United States pubmed.ncbi.nlm.nih.gov

Hepatic ischemia-reperfusion syndrome and its effect on the cardiovascular system: The role of treprostinil, a synthetic prostacyclin analog. [2023]