Researchers at Michigan Medicine have teamed up to launch a study to test the safety and efficacy of the agent defibrotide to treat patients with COVID-19 illnesses.
Dr. Gregory Yanik, Leland and Elaine Blatt Family Professor of Pediatric Hematology/Oncology, Clinical Director of Pediatric Marrow Transplantation, was out walking with his wife one Saturday afternoon in early April, when he received a call from colleague Dr. Vibha Lama, Henry Sewall Research Professor of Pulmonary and Critical Care Medicine and Professor of Internal Medicine at Michigan Medicine.
Dr. Lama and her colleagues at Michigan Medicine were caring for patients with COVID-19 pneumonia at the time, and were noting a high incidence of blood clots in affected patients. Could this infection damage both the lungs and blood vessels, she asked? Dr. Yanik spoke about a similar condition seen in their bone marrow transplant patients, and how an agent called defibrotide was often used to “stabilize” the blood vessels in affected patients. Dr. Lama asked if defibrotide could be considered for the treatment of patients with COVID-19 infections as well.
By that Sunday evening, Dr. Lama and Yanik had already formed an investigator team, spoken with the pharma supplier, and designed a protocol concept. Within the upcoming month, a protocol was written, the concept approved by the COVID-research committee and is now under review at IRBMED.
Defibrotide was initially discovered in the 1980s, and has been used by Dr. Yanik and his transplant colleagues at Michigan Medicine over the past 15 years to treat patients with severe liver injury after a hematopoietic cell transplant. Approximately 5% of patients undergoing hematopoietic cell transplantation develop acute inflammation in their liver, the inflammation associated with severe clotting within small blood vessels at that site. Defibrotide was developed to stabilize the blood vessels in affected patients, and has now undergone multiple clinical trials in this setting over the past two decades. The agent was FDA approved in 2016 for the treatment severe liver dysfunction (termed sinusoidal obstruction syndrome, SOS) following hematopoietic cell transplants.
Dr. Yanik explained that SOS is really a “thrombo-inflammatory” disorder, one in which an initial inflammatory insult leads to the development of blood clots in small and medium sized blood vessels after transplant. Physicians are now beginning to realize that COVID-19 infections also may be thrombo-inflammatory in nature. Dr. Lama made the connection that Saturday in April and reached out to Dr. Yanik. It has been a great partnership to date.
“Once the lungs of affected patients become infected by the COVID-19 virus, blood vessels (within the lungs) become inflamed as well. This inflammation then leads to the formation of small blood clots within the lungs, with the inflammation and clotting then spreading out to impact blood vessels in other organs. Approximately, 30% of patients with severe COVID-19 pneumonia are known to develop clinically significant blood clots, either pulmonary emboli, deep venous thrombosis or just microvascular clots within small veins and arteries in other organs,” according to Dr. Yanik.
Dr. Lama, Dr. Yanik and their research teams have now initiated a pilot study to test the effectiveness of using defibrotide to treat patients with COVID-19 pneumonia. The study is designed as an open label, single center pilot study, with 12 patients to be treated. If the study is successful, a multi-site study with a larger patient population is planned. Per Dr. Yanik, this will be the third trial worldwide currently using defibrotide to treat patients with COVID-19 pneumonia. The first two trials are currently open in Italy and Spain, with Harvard University opening the fourth clinical trial later this summer.
Dr. Yanik stated, “We have built a great team, a multidisciplinary effort from the Blood and Marrow Transplant Program, Pulmonary and Critical Care Medicine, Infectious Disease, Cardiovascular Medicine and our Pharmacy. MICHR has been a key partner throughout the process.”
Rivka Siden from MICHR’s IND/IDE Investigator Assistance Program (MIAP) team has been instrumental in the process, participating in the initial protocol development, IND application, and streamlining communication between the FDA and Dr. Yanik and Dr. Lama’s study team.
“The study was allowed to proceed by the FDA one week after the submission, which is very fast turnaround,” Rivka explained.
MIAP connected the study team with MICHR’s Clinical Research Management team for monitoring, clinicaltrials.gov registration, and database development. Lori Kempf is the study monitor; Monika Benedict-Blue registered the study on clinicaltrials.gov; and Mariann Christy is helping with the development of the database.
“I don’t know where this clinical trial would be without MICHR’s assistance. Rivka Siden, Sue Burhop, Mariann Christy, Monika Benedict-Blue, and Lori Kempf have been integral to the entire process. We cannot thank them enough for their expertise, collegiality and kindness,” Dr. Yanik said. “MICHR was instrumental in helping us build this protocol. This protocol will enable us to treat the patients of today, and will lay the foundation to help the patients of tomorrow, both at Michigan Medicine and nationally.”