Inhaled cyclosporine cut posttransplant deaths: enrollment criteria excluded fungal infections, bronchial stenosis, and mechanical ventilation.
Although the study results were clear, the small size triggered some skepticism about the findings. "It sounds too good to be true," commented Gregory I. Snell, M.D., a physician with the lung transplantation service at Alfred Hospital, Melbourne (Australia).
The study, which was funded by the National Institutes of Health and received no commercial support, is scheduled for review by the pulmonary-allergy drugs advisory committee of the Food and Drug Administration in June. Recommendations from this panel will likely determine whether the formulation goes straight to FDA review or to additional testing, Dr. Iacono said.
He spearheaded a multiyear effort at the University of Pittsburgh on a shoestring budget to develop an inhaled formulation of cyclosporine and then launched a study in 1998 to test the concept's safety and efficacy. Much of the development process focused on the technically challenging problem of placing cyclosporine in a safe vehicle that could be aerosolized. The material that finally worked was propylene glycol.
Once the clinical study began, during 5 years of enrollment only 56 transplant patients received the study medication or placebo, about half the number planned. The low numbers were attributed in part to enrollment criteria that excluded patients with fungal infections, bronchial stenosis, and those who needed mechanical ventilation.
Only patients who were free of these complications and stable for 30 days after receiving one or two allogeneic lungs were eligible.
All of the patients were started on a standard immunosuppressive regimen of tacrolimus, azathioprine, and prednisone immediately after receiving their new lungs.
Once they entered the study, patients received 30 minutes of inhaled treatment daily with a nebulizer for 10 days. The 26 patients randomized to cyclosporine began on a dosage of 100 mg daily, which was titrated as tolerated during the initial 10 days to a maximum daily dosage of 300 mg.
The 30 patients randomized to placebo only inhaled propylene glycol. After the first 10 days, all patients were scaled back to treatment 3 days a week with their maximum tolerated daily dose.
The study's protocol called for continuing treatment on this schedule for 2 years, but the actual treatment duration was an average of about 400 days.
The last dose was administered in August 2003, and Dr. Iacono reported on results through June 2004, an average follow-up of 4.5 years from transplantation.
Of the 30 patients treated with placebo, 15 (50%) died, whereas among the 26 patients treated with inhaled cyclosporine there were 5 deaths (19%), a statistically significant difference, reported Dr. Iacono, who is now medical director for the lung transplant program at the University of Maryland, Baltimore.
Success was also measured in terms of whether patients developed histologically proven obliterative bronchiolitis or bronchiolitis obliterans syndrome, both of which flag chronic rejection. The incidence of this complication was 50% among the placebo-treated patients and 27% among patients who received inhaled cyclosporine. The rate of obliterative bronchiolitis, bronchiolitis obliterans syndrome, or death was 73% in the placebo group and 31% in the patients treated with cyclosporine.
But both survival and chronic rejection were prespecified as secondary end points for the study. The study's primary end point was the cumulative rate of acute rejection episodes, which occurred 35 times among the placebo patients and 36 times among the cyclosporine-treated patients, with no significant difference between the two groups.
Hence, this technically was a negative study, as judged by its primary end point, said Dr. Iacono, although he noted that the incidence of acute episodes may have been skewed against the cyclosporine group because many more patients died in the placebo group. Once patients are dead they cannot manifest episodes of acute rejection.
It's not clear why inhaled cyclosporine was effective at preventing chronic rejection but may have been ineffective for stopping acute rejection. It's possible that acute rejection is a vascular event, while chronic rejection occurs in the airways. Inhaled cyclosporine would be expected to have an effect in the airways, but since little of the drug enters the blood it wouldn't be as effective on mechanisms that occur within blood vessels, Dr. Iacono said.
Inhaled cyclosporine was well tolerated; there were no indications of systemic effects, nor was there evidence of nephrotoxicity, opportunistic infections, or malignancies in the treated patients.
Respiratory symptoms included cough, dyspnea, wheezing, and pharyngeal soreness. About half of the patients in the cyclosporine group had some of these respiratory effects, but only two of the 26 patients dropped out because of adverse effects.
Chiron Corp. purchased a patent license for inhaled cyclosporine from the University of Pittsburgh and is now funding further development of the formulation.
BY MITCHEL L. ZOLER
|Printer friendly Cite/link Email Feedback|
|Author:||Zoler, Mitchel L.|
|Publication:||Internal Medicine News|
|Date:||Jun 1, 2005|
|Previous Article:||IgE levels validate rise in allergy.|
|Next Article:||Primary graft dysfunction redefined by infiltrates, oxygen ratio.|