Randomized Trials Confirm Safety and Efficacy of TRE Treatment for PAH

SAN DIEGO—According to two separate studies, inhaled treprostinil (TRE) and oral treprostinil diethanolamine (UT-15C)—the latter used adjunctively with an endothelin receptor agonist (ERA) and/or a phosphodiesterase 5 inhibitor (PDE5-I)—are safe and effective treatments for patients with pulmonary arterial hypertension (PAH), suggested research presented at the 2009 International Conference of the American Thoracic Society.

“There was a significant improvement in trough six-minute walking distance (6MWD) of around 14 m—which is really unique in the inhaled therapy world,” Raymond L. Benza, MD, of the Allegheny General Hospital in Pittsburgh, Pennsylvania pointed out. His study was a two-year follow-up analysis of the TRIUMPH-1 trial—an open-label double-blind, placebo-controlled, parallel study evaluating the effects of inhaled TRE in patients with functional class III and IV PAH on stable doses of oral background therapies bosentan or sildenafil.

Adjunct administration of UT-15C with an ERA and/or a PDE5-I was assessed in a double-blind, placebo-controlled, international phase III safety and efficacy trial—called the FREEDOM-C study—conducted by Victor F. Tapson, MD, from the Department of Medicine/Pulmonary, Allergy, and Critical Care, at Duke School of Medicine, and colleagues.

“Change in 6MWD at week 16 trended, but was not significant,” Dr. Tapson pointed out. “There were significant treatment effects for 6MWD at week 12.”

CONTINUING AND DURABLE BENEFITS

In the TRIUMPH-1 follow-up analysis, patients were randomized to receive up to 72 μg of TRE four times daily; 143 patients were on bosentan and 63 patients were on sildenafil.

Efficacy end points of interest included exercise capacity (measured by 6MWD), change in New York Heart Association (NYHA) classification, and quality of life (Minnesota Living with Heart Failure Questionnaire). Clinical laboratory analysis and adverse events were secondary end points.

Of 206 patients enrolled in the study, data for 131 were included in the ongoing analysis. As is typical for many PAH trials, the mean age was 53.6 years, there was a higher female-to-male ratio, and most of the patients had idiopathic PAH and were in NYHA class III (ie, marked limitation of physical activity), Dr. Benza explained. Time on background therapy was approximately 90 weeks and mean 6MWD at baseline was approximately 349 m.

Median 6MWD significantly improved at 12, 18, and 24 months of therapy (31 m, 34 m, and 50 m, respectively). “Over the course of two years, patients maintained statistically significant improvement in their walking distances,” Dr. Benza emphasized. About a third of patients experienced an improvement from baseline in functional class while most patients maintained their functional class.

In addition, improvements in quality of life global, physical, and emotional scores were observed. Ninety percent of the patients survived two years and 68% of the patients were free from events associated with discontinuation of therapy. Adverse events included cough (34%), headache (22%), dyspnea (16%), and nausea (15%). “Importantly, none of our patients had a significant change in clinical chemistry or hematologic parameters,” Dr. Benza noted.

According to the researchers, “Inhaled TRE continues to provide durable benefit to patients currently receiving oral therapies for PAH over 24 months, and offers several advantages including patient convenience, targeted drug delivery, and a favorable systemic safety profile.”

ADJUNCT THERAPY

In the FREEDOM-C Study, 350 patients were randomized to receive UT-15C or placebo twice daily for 16 weeks, in addition to an ERA alone (30%), a PDE5-I alone (25%), or both (45%).

“The study drug was titrated up to a maximum of 16 mg twice daily based on clinical response and study drug tolerability,” Dr. Tapson and colleagues noted. The mean dose of UT-15C was 2.5 mg twice daily at week 16.

Change in 6MWD at week 16 was the primary endpoint of interest; secondary end points included time to clinical worsening, Borg dyspnea score, dyspnea- fatigue index, and safety. Patients were included in the study on the basis of age (range, 12 to 70), 6MWD (100 to 450 meters), and confirmed diagnosis of PAH.

Overall, 66% of the patients enrolled had idiopathic PAH or familial PAH, 26% had PAH associated with connective tissue disease, 7% had repaired congenital systemic-to-pulmonary shunt, and 1% had HIV. Of the total patient population, 81% were female and 76% were in WHO functional class III (ie, dyspnea, fatigue, chest pain, or near syncope with minimal exertion). The mean baseline 6MWD was 346 m.

A total of 174 patients were on UT-15C and 176 patients were on placebo; 78% completed the study for the active group, compared with 86% for the placebo group. Twenty-two percent of patients discontinued the study drug prematurely in the active group mostly due to prostacyclin-related adverse events, compared with 14% of patients in the placebo group. “I think that it is an important point: The number of dropouts affected the study results,” Dr. Tapson acknowledged.

The change in 6MWD was not significant at week 4, reached significance by week 12, but then lost significance again at 16 weeks.

“There was a change in standard deviation from 75 m to 88 m, from week 12 to week 16, based on six discontinuations,” Dr. Tapson noted.

“In addition, there was a change in median 6MWD by dose achieved at week 16,” he emphasized. Walk distance changed 3.8 m in patients titrated to receive a dose of up to 1.25 mg, compared with 18.0 m at 3.25 mg. “You need to keep the dose up for efficacy,” he further pointed out.

With regard to adverse events, almost twice as many patients reported nausea in the active study group, compared with the placebo group. Diarrhea was reported in more than twice as many patients in the active drug group than in the placebo group.

Symptom-related secondary end points, combined walked, Borg dyspnea score, dyspnea fatigue index, showed significant treatment effects at week 16, Dr. Tapson observed.

“While the primary end point wasn’t achieved, the exploratory analyses indicate getting the dose above 1 mg twice daily in small increments with a 0.25-mg table—or perhaps in the future with a 0.125 mg tablet—an improvement in exercise capacity occurs,” he concluded.

—Frederique H. Theuvenin

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