The ATS 2010 International Conference in New Orleans will feature a special section of late-breaking clinical trials, to be presented Tuesday, May 18 at 1:30 p.m. Results are summarized below.
The BUILD-3 Trial: A Prospective, Randomized, Double-Blind Placebo-Controlled Study of Bosentan in Idiopathic Pulmonary Fibrosis (IPF). http://www.thoracic.org/newsroom/press-releases/resources/king.pdf
A Phase III trial of a promising drug for idiopathic pulmonary fibrosis failed to demonstrate significant improvements in morbidity or mortality among IPF patients.
IPF is a progressive scarring lung disease that is commonly fatal. The median survival time after diagnosis is only two to three years, and there are no treatments available for patients outside of Japan. Currently, no pharmacological therapy has been definitively shown to improve survival or quality of life in this disease.
Researchers had identified bosentan, a dual endothelin receptor antagonist, as a strong pharmaceutical candidate for the treatment of this intractable disease. They randomized 407 patients with mild to moderate IPF to receive treatment with bosentan and 209 to receive placebo twice a day. The primary endpoint was time to occurrence of IPF worsening or death. IPF worsening was determined by a composite of a change in FVC and diffusing capacity or the development of an acute exacerbation of IPF. Bosentan was well tolerated; the observed safety profile was consistent with previous clinical trials using this agent.
However, after median follow-up duration of 21 months, while there was trend in favor of bosentan over placebo, there was no statistically significant difference. At this time there are no further studies of bosentan planned in IPF. Further investigation of the role of dual endothelin receptor antagonism in IPF is ongoing with the MUSIC study where macitentan, a highly potent, tissue targeting dual endothelin receptor antagonist, is being used in Phase II trial of patients with IPF (Clinical trials identifier: NCT00903331)
Two Day Neuromuscular Blocking Agent Therapy in Early Severe ARDS http://www.thoracic.org/newsroom/press-releases/resources/papazian.pdf
In patients with severe acute respiratory distress syndrome (ARDS), early administration of neuromuscular blocking agents (NMBAs) improved adjusted 90-day survival and increased time off the ventilator without increasing muscle weakness.
In patients receiving mechanical ventilation for ARDS, reducing ventilator-associated injuries is a key clinical goal, but because of their potential to increase muscle weakness, there is some concern about using NMBAs in this population.
Laurent Papazian, M.D., Ph.D., Director of the Medical ICU, and colleagues at the North Hospital in Marseille, France evaluated whether two days of NMBA therapy in early severe ARDS improved clinical outcomes.
The researchers recruited patients with onset of severe ARDS within the past 48 hours and enrolled them in the multicenter, double-blind randomized trial of cisatracurium besylate (n=178) versus placebo (n=162) for 48 hours. The primary outcome was 90-day in-hospital mortality. 20 French ICUs participated to the study.
After 90 days, crude mortality was 31.6 percent in the NMBA group and 40.7 percent in the placebo group. The hazard ratio for the NMBA group was .68 that of the placebo group. (That is, they had about two-thirds the risk of dying in the hospital within 90 days.)
Mortality at 28 days was 23.7 percent in the NMBA group and 33.3 percent in the placebo group.
Additionally, the NMBA group also had more ventilator-free and organ-failure-free days during the first 28 days and less than half the cases of pneumothorax compared to the placebo group, but the rate of muscle weakness was the same for the two groups.
Oral Iloprost for the Chemoprevention of Lung Cancer http://www.thoracic.org/newsroom/press-releases/resources/keith.pdf
Oral iloprost showed promise for preventing lung cancer in former, but not current, smokers in a phase II clinical trial. Ilioprost is an analogue of prostacyclin, which has been shown to prevent lung cancer in a variety of mouse models.
Researchers recruited 152 subjects, consisting of both former and current smokers. Each subject was scored on bronchial biopsies on a scale from 1-8, based on WHO criteria. The subjects also underwent bronchoscopies to assess worst biopsy score, dysplasia index—a measure of abnormal or pre-cancerous cells-- and average of all biopsy scores.
Former smokers had baseline average biopsy scores that were significantly better than current smokers, but there were no baseline differences between the treatment and placebo groups.
At the end of six months, however, former smokers showed significant improvements on all measures, indicating that treatment with iloprost may reduce the risk of developing lung cancer among former smokers. Interestingly, current smokers did not show any significant improvements.
Efficacy and Safety of Omalizumab in Patients with Moderate-to-Severe Asthma Poorly Controlled on High-Dose Inhaled Corticosteroids and Long-Acting Beta-Agonists—Results of a Phase IIIb Randomized Controlled Trial http://www.thoracic.org/newsroom/press-releases/resources/busse.pdf
Omalizumab significantly reduced the rate of protocol-defined asthma exacerbations by 25 percent in moderate-to-severe allergic asthma patients already receiving a high-dose inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), and in nearly two-thirds of patients, a third controller medication including chronic oral corticosteroids.
Researchers recruited 850 patients with moderate to severe asthma as defined by having had at least one asthma exacerbation in the past year despite treatment with high-dose ICS and a LABA. Patients were randomized to receive placebo or omalizumab for 48 weeks.
At the end of the 48 weeks, patents who had received omalizumab had fewer exacerbations than patients who received the placebo (.66 percent vs. .88 percent) and used less albuterol per day. Patients on omalizumab also experienced a statistically significant improvement in asthma-related quality of life questionnaire scores over patients who took the placebo.
Furthermore, the effect of treatment on the fractional concentration of exhaled nitric oxide (FeNO), a marker of inflammation in asthma, was evaluated as an exploratory endpoint. Adding omalizumab to baseline therapy of ICS/LABA ± additional controllers led to a significant reduction of FeNO at all visits.
Although omalizumab is indicated for patients with allergic asthma that are inadequately controlled by inhaled corticosteroids, the current standard of care for these patients is to add a LABA and/or an additional controller medication. Patients who fail these therapies are often treated with chronic oral corticosteroids as a last resort. Subgroup analyses from previous clinical trials suggested that omalizumab would prove safe and effective in this patient population with substantial need for additional therapy; however, these results had not been demonstrated definitively.
These findings demonstrate that omalizumab treatment reduced risk and impairment for patients with uncontrolled allergic asthma. Other controller medications, including corticosteroids and leukotriene modifiers did not limit the effect of, or interact with, omalizumab.
The STEP-IPF Trial: Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis http://www.thoracic.org/newsroom/press-releases/resources/zisman.pdf
Sildenafil, a phosphodiesterase-5 inhibitor, may preferentially improve blood flow to well-ventilated regions of the lung in patients with advanced idiopathic pulmonary fibrosis, which could result in improvements in gas exchange. Researchers tested the hypothesis that treatment with sildenafil would improve walk distance, dyspnea, and quality of life in patients with advanced idiopathic pulmonary fibrosis, defined as a carbon monoxide diffusion capacity of less than 35 percent of the predicted value.
Sildenifil was tested in a double-blind, randomized, placebo-controlled trial of sildenafil in two periods. The first period consisted of 12 weeks of a double-blind comparison between sildenafil and a placebo control. The primary outcome was the proportion of patients with an increase in the 6-minute walk distance of 20 percent or more. Key secondary outcomes included changes in oxygenation, degree of dyspnea, and quality of life. The second period was a 12-week open-label evaluation involving all patients receiving sildenafil.
A total of 180 patients were enrolled in the study. The difference in the primary outcome was not significant, with 9 of 89 patients (10 percent) in the sildenafil group and 6 of 91 (7percent) in the placebo group showing an improvement of 20 percent or more in the 6-minute walk distance (P = 0.39). There were small but significant differences in arterial oxygenation, carbon monoxide diffusion capacity, degree of dyspnea, and quality of life favoring the sildenafil group. Serious adverse events were similar in the two study groups.
The researchers concluded that while this study did not show a benefit for sildenafil in the primary outcome, the presence of some positive secondary outcomes justifies the pursuit of further research. (ClinicalTrials.gov number, NCT00517933.)
CPAP and Cardiovascular Outcomes in Non-Sleepy OSAS Patients http://www.thoracic.org/newsroom/press-releases/resources/barbe.pdf
Please note that this abstract will be presented prior to the Late Breaking Clinical Trial Session and is also the subject a press conference on May 18 at 11:15 a.m. in the ATS Press Room.
The embargo for this release expires on May 18 at 11:15 a.m.
In non-sleepy patients with obstructive sleep apnea (OSA), treatment with continuous positive airway pressure (CPAP) can reduce the incidence of cardiovascular events and hypertension, according to researchers from Spain.
Obstructive sleep apnea is a common condition characterized by repeated episodes of upper airway obstruction during sleep, nocturnal hypoxemia and excessive daytime sleepiness. OSA is also known to be associated with cardiovascular disease and stroke.
CPAP is the current standard of treatment for patients with symptomatic OSA. CPAP improves daytime sleepiness, and quality of life in patients with OSA. Although daytime sleepiness is one of the main symptoms of sleep apnea, not all patients with OSAS complain of it. Therefore, CPAP usage for OSA subjects without sleepiness is unclear.
To determine whether CPAP could reduce cardiovascular risks in OSA patients without daytime sleepiness, Dr. Barbé Illa and colleagues recruited 724 patients with moderate to severe sleep apnea (AHI>20) and Epworth sleep scores of less than 10, indicating minimal daytime sleepiness despite significant OSA. The patients were randomized to be treated with CPAP or conservative treatment (in which their doctors provided advice on weight control and sleep) and followed for four years.
At the end of four years, Dr. Barbé Illa and colleagues found that the risk of a having cardiovascular event—such as stroke, angor pectoris, cardiac arrhythmia or peripheral ischemia—or developing hypertension among patients who used CPAP for at least four hours a night was reduced by 25 percent compared to those who did not use CPAP. Among those who had baseline hypertension and used CPAP for four or more hours a night, the risk of a cardiovascular event declined to nearly half of those who did not use CPAP.
More research is necessary for a better understanding of OSAS physiopathology and to determine the CPAP treatment effects are evident in the entire range of OSAS patients.