Susan Dorman, MD, presented one of six research studies during the Late-Breaking Clinical Trials session.
ATS 2011 participants got a glimpse of the newest possible therapies in pulmonary care when expert researchers shared results during the May 17 “Late-Breaking Clinical Trials.” Investigators shed new light on potential treatments for people with chronic obstructive pulmonary disease (COPD), TB, asthma (pregnant women), lymphangioleiomyomatosis (LAM) and emphysema. Another looked at the safety of physician- vs. nurse-led transport teams for critically ill patients.
“This diverse session of clinical trials is the cream of the crop of what’s come out in the field of pulmonary critical care in the last few months. We’re fortunate to have speakers participating from all over the world,” said Marc Moss, MD, professor of medicine at the University of Colorado in Denver, who chairs the ATS International Conference Committee.
Azithromycin in COPD Exacerbations
One study, “Chronic Azithromycin Decreases Frequency of COPD Exacerbations,” sought to reduce the frequency of acute exacerbations of COPD with a macrolide antibiotic, azithromycin, taken daily for one year in addition to usual therapy.
Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) increase the morbidity, mortality and cost of care of patients with COPD. Macrolide antibiotics have antimicrobial and immunomodulatory effects and, when taken chronically, are efficacious in patients with cystic fibrosis and a variety of other inflammatory airways diseases. Seven small studies evaluating the effect of macrolides on AECOPDs report conflicting results. Researchers performed a prospective, randomized, double-blind, placebo-controlled trial to determine if azithromycin decreased AECOPDs.
Richard Albert, MD, of Denver Health, noted that adding azithromycin 250 mg a day for one year to the usual treatment of patients with an increased risk of COPD exacerbations decreased the frequency of these exacerbations and improved quality of life. However, it caused hearing decrements in a small fraction of patients.
He cautioned that the study enrolled only patients with resting heart rates of less than 100, those who had no apparent risk for QTc prolongation and those whose hearing was less then the 95th percentile for age.
“I cannot comment on the importance of azithromycin on macrolide resistance in the community bacterial flora but there certainly would be effect as has been shown worldwide over the last 10 years,” he added.
Rifampin vs. Rifapentine for TB Treatment
Another study, submitted by Susan Dorman, MD, of Johns Hopkins University in Baltimore, examined the efficacy of rifampin vs. rifapentine in treating TB. Rifapentine administered five days/week has potent activity in a mouse model of anti-tuberculosis (TB) chemotherapy, but data on efficacy and safety in humans are limited. In this study, researchers compared the antimicrobial activity and safety of rifapentine versus rifampin administered five days/week during the first eight weeks of combination therapy for pulmonary TB.
In “A Phase II Study of a Rifapentine-Containing Regimen for Intensive Phase Treatment of Pulmonary TB: Preliminary Results for TB Trials Consortium Study 29,” the investigators found that a regimen containing rifapentine administered at 10 mg/kg, five days per week without concomitant food for approximately eight weeks, was safe and well-tolerated.
“The activity of the rifapentine regimen was not superior to that of the rifampin regimen, based on the endpoint of culture status at completion of intensive phase treatment,” Dr. Dorman said. “There was a trend toward superiority of the rifapentine regimen in the subset of patients with non-cavitary pulmonary disease.
She added that overall additional trials are needed and are being planned to define the optimal dose of rifapentine and its role in TB treatment.
Asthma Management in Pregnancy
Asthma exacerbations during pregnancy are common and associated with significant maternal and fetal morbidity. Inflammometry using induced sputum reduces exacerbations in non-pregnant asthmatic adults, but results from FENO-guided management are equivocal.
Researchers from Australia identified a way for pregnant women with asthma to avoid exacerbations. Their randomized, controlled trial tested a management algorithm for asthma in pregnancy based on fractional exhaled nitric oxide (FENO), which indicates level of inflammation, and symptoms, and compared this to standard, guideline-based care.
Peter Gibson, MD, of the University of Newcastle, presented “Asthma Exacerbations During Pregnancy are Reduced by Inflammometry (FENO)-Guided Asthma Management,” for Heather Powell, MMedSci, of the Hunter Medical Research Institute at John Hunter Hospital in Newcastle, Australia and colleagues. They enrolled 242 pregnant asthmatic women before 20 weeks’ gestation. They measured FENO, symptoms and lung function at monthly visits. For the women randomized to the algorithm-based treatment, FENO was used to increase or decrease their ICS medications. Long-acting beta agonists were used to treat symptoms when FENO was not elevated.
The researchers found that for every six women receiving treatment adjustment by the FENO-based algorithm, one was prevented from having an asthma exacerbation, making FENO-based care an effective way to reduce asthma exacerbations in pregnant women.
While controversy exists, he said that FENO guided treatment “does make a difference,” adding that it is an extension of the current guideline trends toward lower inhaled corticosteroid doses and earlier introduction of inhaled controller therapy.
“We think that further work should investigate the applications of this algorithm in routine antenatal care and other settings, but also the use of this algorithm outside of pregnancy,” Dr. Gibson said.
Treatment of LAM with Sirolimus
LAM is a rare, cystic lung disease of women, caused by mutations in tuberous sclerosis complex (TSC) genes that regulate mammalian target of rapamycin (mTOR) signaling. Sirolimus, which suppresses mTOR activation that occurs when TSC genes are corrupted, has shown promise for patients with TSC or LAM in pilot trials.
In a discussion of the ” Multicenter International LAM Efficacy of Sirolimus (MILES) Trial,” Francis X. McCormack, MD, of the University of Cincinnati School of Medicine School of Medicine, described a two-year double-blind trial at 13 National Institutes of Health Rare Lung Disease Consortium sites to determine whether sirolimus improves lung function in patients with LAM.
Patients were given sirolimus or placebo for the first year and monitored for changes in spirometry, lung volumes, diffusing capacity, six-minute walk distance, serum levels of vascular endothelial growth factor (VEGF-D) and quality of life scores. In the second year, the same parameters were followed off all therapy.
The authors showed that in patients with moderately severe LAM, treatment with sirolimus stabilized FEV1 and improved FVC. By the end of the 12-month treatment period, FEV1 had stabilized or improved in 46 percent of patients on sirolimus compared to only 12 percent on placebo. Treatment also improved quality of life and functional performance measures, and it markedly reduced serum levels of VEGF-D. Use of sirolimus did not improve measures of exercise tolerance (6MWD) or gas exchange (DLCO). Side effects were more common on sirolimus, but serious events were balanced between groups. The benefits of sirolimus were only sustained while the drug treatment continued. Dr. McCormack concluded that sirolimus may be a reasonable therapy for selected LAM patients.
Palovarotene for Emphysema
Another trial, submitted by Alexis Rames, MD, of Switzerland, investigated the use of a selective retinoid agonist in the treatment of emphysema. Palovarotene is an oral gamma-selective retinoid agonist that reduces inflammation, and promotes structural and functional improvement in animal models of emphysema.
Paul W. Jones, MD, PhD, of St. George’s, University of London, described the results of “Treatment of Emphysema with a Selective Retinoid Agonist (TERSA).”
TESRA was a two-year phase-2 double-blind, randomized, placebo-controlled multi-center (69 centers in 12 countries) study to assess the safety and efficacy of a 5 mg/day regimen of palovarotene in 492 patients with cigarette smoke-induced emphysema. In addition to the study treatment, all patients were given standardized inhaled treatment with an inhaled steroid, beta2-agonist and tiotropium.
Patients were randomly assigned to placebo or palovarotene and matched for all baseline characteristics. After two years, while there was no significant effect of palovarotene overall. “Palvoratene appears to have low toxicity, and that was a great relief because we had worried a great deal about that,” Dr. Jones said.
However, in placebo treated patients, investigators identified some regions of interest.
“Patients whose emphysema was predominantly in the lower half or lowest quartile of their lungs showed faster disease progression across most the measures that we used,” he added. “In these patients, palvarotene was associated with less worsening over time in nearly all outcomes that were measured.”
Dr. Jones noted that these observations are preliminary and require confirmation using more detailed analysis of emphysema progression in different parts of the lung, but, if confirmed, would suggest that this agent may modify disease progression in selected patients with emphysema.
Physician- Versus Nurse-based Critical Care Transport
A third study submitted by Erik van Lieshout, MD, of the Netherlands, examined the effect of physician-versus qualified nurse-based critical care transport by ambulance. Researchers found that nurse-led transport groups had outcomes that equaled the physician-led groups, suggesting that, at least among less severely critical ill patients, nurse-led transport is a safe option.
This prospective, randomized (stratified for distance), open-label, blinded-endpoint, non-inferiority trial looked at critical care patients transported by the mobile intensive care unit in the Amsterdam region with exclusion criteria. In “Intensive Care Physician- Versus Qualified Nurse- Based Critical Care Transport—A Randomized Controlled (IQ-Transport Trial),” researchers prospectively assigned critical care patients to be transported by physician- or nurse-led transport teams, both assisted by a paramedic. They used stored digital monitoring data to determine whether patients underwent critical events during transport.
Of a total of 618 eligible transported critically ill patients, 307 were randomized and allocated to the nurse group (n=147 patients) or physician group (n=151 patients). The median transport distance was 30 km in both groups, and the median transport time was 66 versus 65 minutes.
In the nurse group, 23 critical events occurred versus 28 in the physician group. There was also no difference in number or size of adjustments in inotropic/vasoactive medication or ventilator settings.
Dr. van Lieshout noted that they did not study air-medical transport, they investigated a select group of critically ill patients (e.g., pf ratio of 20-40 kpa(= ±225 mmHg), limited dosage of inotropics/vasopressors), and they did not standardize the stabilization periods pre-transport.
He suggested that future studies involve sicker patients and the potential role of telemedicine. “The level of vasopressors and inotropical and ventilatory support could be tailor-made to staffing of ground critical transport and possibly air-medical transport,” he added.