Emma Hitt, PhD

May 30, 2012

May 30, 2012 (Florence, Italy) — Once-daily oral dual-release hydrocortisone (Plenadren, ViroPharma Incorporated) was shown to be safe and effective in patients with adrenal insufficiency who were treated for up to 27 months, according to a new study presented here at the Joint 15th International Congress of Endocrinology (ICE) and 14th European Congress of Endocrinology (ECE).

Plenadren (also called hydrocortisone, modified release tablet) was recently granted European Marketing Authorization for treatment of adrenal insufficiency in adults. The aim of the current study was to assess the safety and efficacy in maintaining improvements in cardiovascular risk factors during long-term treatment.

Gudmundur Johannsson, MD, PhD, from the Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden, and colleagues presented their findings here.

According to the researchers, there are limited prospective safety data on glucocorticoid replacement therapy in adrenal insufficiency.

These findings show us for the first time in humans "the importance of the serum cortisol profile (ie, cortisol exposure time profile) for the metabolic outcome in patients with adrenal insufficiency," Dr. Johannsson told Medscape Medical News.

The current study was an open-label, multicenter study involving 71 patients with adrenal insufficiency. Of these patients, 53 had been recruited from a previous controlled trial during which they had been treated with the same therapy for between 6 and 9 months.

Nearly all (94.6%) of the patients remained in the study after 18 months. According to the researchers, the high retention rate in the study helps confirm "the good tolerability reported in the study." In addition, 98.5% of the patients reported that they found the treatment acceptable or better at the end of the study.

Patients were receiving a median dose of 30 mg of the drug, with a range of 20 to 40 mg at the beginning of the study; 9 patients reduced their dose and 6 patients increased their dose during the 18 months.

Overall, significant increases were observed in total serum cholesterol (P = .03), low-density lipoprotein cholesterol (P = .03), and high-density lipoprotein cholesterol levels (P < .0001), whereas triglycerides decreased (P < .0001).

In 13 patients with diabetes mellitus, high-density lipoprotein cholesterol increased (P = .004), triglycerides decreased (P = .03), and glycated hemoglobin levels remained unchanged.

Decreases in blood pressure and body weight occurred when switching from conventional immediate-release hydrocortisone to the dual-release modified formulation. No significant differences were noted in systolic blood pressure, diastolic blood pressure, or body weight in the 18-month extension phase, the researchers report.

The most common adverse events (AEs) were nasopharyngitis (20%), fatigue (7%), and gastroenteritis (6%), which the authors note are similar to conventional hydrocortisone replacement.

"The frequency of AEs was similar in the beginning and at the end of the study," the authors note. A total of 13 nonfatal serious AEs were reported, which include 2 cases of Addison crisis, 6 cases of gastroenteritis, and 1 case each of pyelonephritis, gastritis/esophagitis, virosis, colitis, and ectopic pregnancy.

"No safety concerns were observed in this open prospective study using a new oral dual-release hydrocortisone replacement therapy," Dr. Johannsson and colleagues concluded. "Some continuing beneficial metabolic effects could be seen in particular in patients with concomitant DM," they added.

According to Dr. Johannsson, more focus should be put on the exposure time profile than before, and in particular on the importance of not overexposing patients to hydrocortisone in the evening and during the night, he said.

He added that it will be important to find out to what extent this new regimen influences sleep quality and body composition in terms of fat, muscle, and regional fat distribution.

Independent commentator Simon H.S. Pearce, MD, FRCP, professor of endocrinology at Newcastle University in the United Kingdom, noted that there is actually relatively sparse prospectively collected information about the long-term use of glucocorticoids in adrenal insufficiency, "so these safety data on Plenadren use extending to 27 months are welcome."

"The main significance of this study is that 95% of people with adrenal insufficiency given the choice of single daily dosing with Plenadren or multiple daily dosing with conventional hydrocortisone, chose to stay on the once-daily dose," Dr. Pearce said. "Thus, irrespective of any potential metabolic advantages of Plenadren, patients understandably prefer the convenience of a single dose."

"However, we do need to bear in mind that people will be on such medication for the rest of their lives, so 27 months is just a start," he told Medscape Medical News.

According to Dr. Pearce, the data are encouraging, "showing a modest improvement in several metabolic parameters compared to multiple daily-dosed hydrocortisone." In addition, he noted that the study extends the follow-up by a further 18 months and, by and large, these benefits appear to be maintained.

However, he pointed out that the median daily dose of 30 mg is significantly higher than the 20 mg or less that his patients and others in the United Kingdom receive, "so that it remains unknown whether these potential benefits will be meaningful."

Dr. Johannsson is a cofounder of DuoCort Pharma, which financially supported this study. Dr. Pearce has disclosed no relevant financial relationships.

Joint 15th International Congress of Endocrinology (ICE) and 14th European Congress of Endocrinology (ECE): Abstract P78. Presented May 6, 2011.

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