FDA Gives Green Light to Human Transplant Study Using Ex Vivo Liver Perfusion

Cleveland Clinic transplant specialists recently gained FDA approval to conduct a human trial involving transplantation of deceased donor livers preserved using normothermic ex vivo machine perfusion.

If they begin enrollment before the end of 2015, as planned, they could be the first in the U.S. to transplant a human liver using the innovative practice.

“The trial aligns with broader efforts by the Cleveland Clinic health system to create a comprehensive Organ Recovery Center where donor organs for all types of transplants can undergo normothermic ex vivo machine perfusion prior to transplantation,” says John Fung, MD, PhD.

Creating in vivo conditions outside the body

Normothermic ex vivo perfusion involves the circulation of oxygenated warm blood — along with nutrients and medications —to the donor organ to keep it metabolically active while awaiting transplant. As such, it represents a dramatic advance from traditional cold-storage preservation of donor organs.

“This is a paradigm shift in how we preserve organs,” says liver transplant and hepatobiliary surgeon Cristiano Quintini, MD, who is leading Cleveland Clinic’s human trial of normothermic ex vivo liver perfusion. “We’re trying to recreate as closely as possible ex vivo the same conditions that exist in the body.”

Liver transplantation presents a good case study of the benefits to be gained from normothermic ex vivo perfusion. Currently, many donor livers are deemed marginal for any number of reasons — they come from older donors, they contain fat, they have sustained damage — and are discarded for fear of graft failure.

“We believe about 20 percent of livers we currently need to leave unused could be transplanted successfully because of this technology,” says Dr. Quintini. “It has potential to substantially reduce organ discard and thereby reduce mortality on the waiting list.”

Path cleared for first U.S. application in human liver transplant

Dr. Quintini’s study in humans will build on insights gained from four years of lab studies of ex vivo liver perfusion done by his team using animal and discarded human livers. Those experiments shaped the ex vivo liver perfusion device Cleveland Clinic has designed — and which the FDA has approved for use in human studies under an investigational device exemption (IDE).

“We used some components off the shelf and built the rest ourselves,” Dr. Quintini explains. “It’s essentially a cardiopulmonary bypass machine that circulates oxygenated warm blood to the liver.”

The human study will consist of two phases. The first phase will be a safety and efficacy trial in which suitable deceased donor livers are placed on the Cleveland Clinic-designed ex vivo liver perfusion device and then transplanted to patients. The second phase will involve rehabilitating marginal donor livers through ex vivo perfusion on the machine and then transplanting them to patients after excellent recovery is demonstrated on the machine.

The study promises to be the first of its kind in the U.S., although studies involving transplantation of human livers following ex vivo perfusion have been conducted in Europe for more than 18 months, most notably by the OrganOx spinoff company affiliated with the U.K.’s Oxford Biomedical Research Centre.

Key pillar of the larger Organ Recovery Center

The same inventive spirit behind the development of Dr. Quintini’s machine for livers lies at the heart of the comprehensive Organ Recovery Center project to offer normothermic ex vivo perfusion for multiple organ types.

The effort involves remodeling an operating room space at the heart of Cleveland Clinic’s main campus housing approximately eight stations with machines that use extracorporeal membrane oxygenation for normothermic preservation of various organs for all types of transplants.

Construction of the Organ Recovery Center is projected to start before January 2016, although widespread clinical use of the center will depend on when the machines and proprietary solutions for normothermic ex vivo perfusion receive FDA approval for various organ types. “As FDA approvals are granted, we will be ready to proceed with this technology on a large scale across all organs,” says Cleveland Clinic Transplant Center Director Kareem Abu-Elmagd, MD, PhD.

It promises to be one of the nation’s first centers for multiorgan normothermic ex vivo perfusion, he adds.

Minimizing ischemia-reperfusion injury

Across all organ types, normothermic ex vivo perfusion aims to minimize the ischemia-reperfusion injury that occurs in organs harvested from brain-dead donors and to allow repair of damage that does occur. Potential benefits include:

• Further improving the condition of currently usable donor organs, promising reduced length of stay and recovery times and a lower overall cost of transplant care
• Enabling repair or reconditioning of marginal donor organs that currently are not usable, thereby combating the organ shortage and reducing mortality on the waiting list
• Extending the time that donor organs can be preserved compared with traditional cold-storage preservation, allowing better viability testing and opportunities to share organs across more miles

Progress on another front: Ex vivo lung perfusion

Cleveland Clinic is among a small number of U.S. centers studying and developing normothermic ex vivo perfusion across multiple organ types. In addition to the liver, Cleveland Clinic clinicians and researchers have so far tested the technology in the lungs, kidney and pancreas (as well as participated in the PROCEED II multicenter trial of TransMedics’ OCS™ Heart ex vivo perfusion system for the heart).

Ex vivo lung perfusion has been among the most active areas of study. That is fortuitous, since lung transplantation is an area with some of the greatest needs for more usable organs: Currently up to 80 percent of donor lungs are rejected for transplantation.

Cleveland Clinic is beginning participation in a multicenter phase 2 trial of the Toronto EVLP System™ from Perfusix USA. The study is comparing the safety of receiving a lung treated with that proprietary system of ex vivo lung perfusion vs. standard lung transplantation.

This human clinical trial follows on more than three years of extensive Cleveland Clinic research comparing various systems for normothermic ex vivo perfusion of pig lungs and unusable human lungs that were not ultimately transplanted. Efforts to publish results of those comparative studies are underway.

“These studies are helping us pinpoint the best system and approach for using ex vivo lung perfusion to evaluate donor lungs for transplant and to guide related clinical decision-making,” says Transplant Center Clinical Associate Toshihiro Okamoto, MD, PhD.