The study, which was the first double-blind, placebo-controlled trial ever conducted in lung transplant patients, tested an inhaled form of cyclosporine, a widely used medicine to prevent organ rejection following a transplant. The study, conducted from 1998 to 2001, was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health.
"Inhaled cyclosporine is the first drug ever to show a decline in the incidence of chronic rejection--the leading cause of death following a lung transplant," says lead author Aldo T. Iacono, M.D., medical director of lung transplantation at the University of Maryland Medical Center and associate professor of medicine at the University of Maryland School of Medicine.
"In our study, the patients who took the inhaled cyclosporine had a two-thirds reduction in chronic rejection compared to those who had the placebo," says Dr. Iacono. "The risk of death, adjusting for all other variables, was five times greater in the group of patients who took the placebo than among those on the inhaled cyclosporine," he adds.
The study included 56 people who had received either a single or a double lung transplant. Within one month following their transplants, they were randomly assigned to take either the inhaled cyclosporine or an inhalable placebo along with traditional anti-rejection therapy. The patients took the inhaled drugs at home three times a week and were followed by the researchers for at least two years.
"The results of this study are exceedingly important for lung transplant patients," says Bartley Griffith, M.D., professor of surgery and chief of the Division of Cardiac Surgery at the University of Maryland School of Medicine.
"Conventional anti-rejection drugs, which are given orally, do not get into the small air sacs of the lungs where chronic rejection takes place. It just makes a lot more sense to give a higher concentration of the drug right into the area you are trying to treat. Organ-specific immune suppression is almost a new paradigm for transplantation," according to Dr. Griffith, who is also director of Heart and Lung Transplantation at the University of Maryland Medical Center and the senior author of the article in the New England Journal of Medicine. Of the 26 patients in the study who received the inhaled cyclosporine, 23 were still alive two years later. However, of the 30 patients in the placebo group, only 16 were alive at the two-year point. The researchers report that the death rate in the cyclosporine group was 11 percent during the study compared to 47 percent for the placebo group.
"Our study shows for the first time that inhaled cyclosporine, taken in conjunction with oral anti-rejection medication, can protect patients from chronic rejection, which is the main reason that the average three-year survival rate from lung transplantation is only 55 percent--a much lower rate than for other solid organ transplants, including liver and kidney transplants," says Dr. Iacono.
Years of work led up to the clinical study. Dr. Griffith began doing basic research on the concept of an inhaled form of cyclosporine in 1988 while he was on the faculty of the University of Pittsburgh School of Medicine. He was the principal investigator on two federal grants, including one from the NIH for $1.7 million in 1998, which funded the clinical study now published in the New England Journal.
Dr. Iacono began working with Dr. Griffith at the University of Pittsburgh in 1992. When Dr. Griffith went to the University of Maryland in 2001, Dr. Iacono continued the studies of inhaled cyclosporine and became principal investigator of the now-published clinical trial that evaluated the drug's ability to prevent rejection. Dr. Iacono joined Dr. Griffith in Baltimore in February 2005.
One of the major challenges the researchers faced early on was finding a substance that could be mixed with the cyclosporine to enable patients to safely inhale the drug without irritating their throat or lungs. They decided to combine the cyclosporine with propylene glycol, which allowed the drug to be administered as an aerosol. Novartis Pharmaceuticals provided the cyclosporine powder, which was then compounded by the researchers.
The formula enabled patients to breathe in high doses of the anti-rejection drug without hurting other organs. Such high doses, if given orally, would have a toxic impact on the kidneys. About half of the people in the study, in both the cyclosporine and the placebo groups, experienced some respiratory irritation, but many developed a tolerance for the inhaled drug after a few treatments.
The University of Pittsburgh licensed its data on inhaled cyclosporine to Novartis in 2001. In April 2003, Chiron Corporation obtained rights to the data through an in-licensing agreement with Novartis. The inhaled drug has not been approved by the Food and Drug Administration, and therefore, is not yet available to lung transplant patients.
"My hope is that one day soon our patients will have access to this therapy," says Dr. Iacono. "As our study demonstrated, patients who took the inhaled cyclosporine had a substantially better chance of survival because they were free from chronic rejection," he adds.
In addition to Drs. Iacono and Griffith, other authors of the study include: from the University of Pittsburgh, Bruce A. Johnson, M.D.; Wayne F. Grgurich; J. Georges Youssef, M.D.; Timothy E. Corcoran, Ph.D.; Diedre A. Seiler, M.S.N., C.C.R.C.; James H. Dauber, M.D.; Adriana Zeevi, Ph.D.; Samuel A. Yousem, M.D.; and Kenneth R. McCurry, M.D.; Gerald C. Smaldone, M.D., Ph.D., from State University of New York at Stony Brook; John J. Fung, M.D., Ph.D., formerly of the University of Pittsburgh and now at the Cleveland Clinic Foundation; and Gilbert J. Burckart, Pharm.D., formerly of the University of Pittsburgh and now at the University of Southern California.