SAN ANTONIO, TEX—A number of clinical trials have produced results supporting the use of inhaled corticosteroids for mild persistent asthma. But there is widespread concern that these results may not be applicable in clinical practice. Critics point out that the trials may have been so highly controlled that their findings cannot be replicated in day-to-day patient care. However, the newest and largest of these trials—the recently completed inhaled Steroid Treatment As Regular Therapy (START) study—may help to put such concerns to rest.[1]

START, which assessed early inhaled budesonide for mild persistent asthma, was a “real-world” study. Patients were allowed to discuss their symptoms with their doctors, who could then alter therapy as necessary, as often occurs in actual practice. Medications other than those studied could be used, if needed.

In addition, medication compliance was not measured. “Hence, the outcomes reflect the compliance that can be expected in normal clinical practice,” claimed Wan C. Tan, MD, who presented some of the data from START at the 60th Annual Meeting of the American College of Allergy, Asthma and Immunology in San Antonio, Texas. Dr. Tan, a principal investigator in START, is a Professor of Medicine at the National University of Singapore.

Despite the fact that the study had, by design, less control over patient care than occurs in standard clinical trials, the START results firmly uphold those from previous trials. “In these mild cases, budesonide reduces the risk of having a very severe asthma-related event by 44%,” reported Soren Pedersen, MD, another principal investigator in START and a Professor of Pediatric Respiratory Medicine at the University of Southern Denmark in Kolding.

Compared with placebo, inhaled budesonide also significantly slowed asthma-related lung function declines. It was no more likely to cause adverse events, and no unexpected effects on growth were seen.

PRIOR STUDY LIMITATIONS WERE ADDRESSED

Before START, there were about 150 studies (with a combined total of more than 20,000 patients) that suggested that inhaled corticosteroids can prevent exacerbations and preserve lung function. However, these studies typically involved fewer than 100 patients each and were less than eight weeks in duration. Clearly, larger, longer studies were needed. “The START study was specially designed to address this need,” said Dr. Tan. Indeed, more than 7,200 pediatric and adult patients at about 500 centers in 32 countries were recruited, and the study lasted five years.

To ensure that the investigators were actually evaluating the early use of inhaled corticosteroids, they enrolled only patients with newly diagnosed asthma who had had symptoms for two years or less. The patients had to have reversible airway obstruction, wheeze, cough, dyspnea, chest tightness, or nighttime awakening caused by asthma symptoms; these findings had to be present more than once per week but not daily. A history of wheeze during the first two years of life was not a reason for exclusion from the study.

The study was divided into two phases. In the first three years, patients were randomized in double-blind fashion to inhaled budesonide or placebo. In the budesonide group, the prescribed dosage was 400 µg/d for those 11 and older and 200 µg/d for younger children. The two groups also received “usual asthma therapy,” which could include inhaled ß2-agonists, leukotriene modifiers, other oral or inhaled corticosteroids, or other asthma medications.

The final two years of the trial were an open phase in which both groups received inhaled budesonide. Data analysis was recently completed for phase 1; the analysis for phase 2 is to be completed this year.

BENEFITS OF EARLY STEROID USE

During the study’s first three years, 3.3% of the inhaled budesonide group had at least one severe asthma exacerbation, compared with 5.6% of the placebo group. Nine patients in the budesonide group had a life-threatening exacerbation, versus 24 in the placebo group.

Early in the study, the budesonide group’s cumulative probability of severe exacerbations became significantly lower than that in the placebo cohort. Furthermore, it remained so until the trial’s end.

In addition, early use of inhaled corticosteroids had a positive effect on airway remodeling. Compared with placebo, inhaled budesonide slowed asthma-related lung function declines by 42% in adults and by 22% in children. Because children received only half the adult dose, this finding could suggest a dose response to budesonide, said Dr. Pedersen, but it is also possible that children simply respond to the drug differently, he acknowledged.

If there was any bad news in the START results, it is that no predictors of severe asthma exacerbations were identified. That, Dr. Pedersen explained, was because there were no differences in any of the results by age, sex, smoking habits, or other variables.

It is important to remember, he added, that these results are based not on budesonide plus placebo alone but on budesonide plus placebo and usual treatment. But the need for additional asthma medications was significantly lower in the budesonide group, the study also showed. For example, only about 20% of that group required an additional course of oral or inhaled corticosteroids during the study, compared with nearly 50% of the placebo cohort.

COMPARING START TO EARLIER STUDIES

The START study replicated previous results showing that inhaled budesonide did not raise the risk of adverse events nor did it cause long-term growth suppression in children. In an earlier study lasting 10 years, growth rates were significantly reduced only on a short-term basis.[2] The effect was most pronounced after one year, but this reduction did not affect the children’s attainment of full adult height. In the START study, growth was less inhibited during the first three years than it had been in the earlier study in which the patients reached their full adult height based on their mean predicted height.

The START findings are also comparable to those from previous highly controlled clinical trials for many other variables, including the incidence of severe and mild exacerbations, percentage of days with poor asthma control, rescue ß2-agonist use, and number of nocturnal awakenings caused by asthma symptoms. Thus, it appears that those trials did reflect real life after all, Dr. Pedersen concluded.

HOW MUCH DID THE TREATMENT COST?

When Sean D. Sullivan, PharmD, PhD, used the START data to perform an economic analysis, he found that in the study’s first three years, inhaled budesonide therapy reduced the number of emergency room visits and hospital days by about 70%, and it lowered work and school absences by nearly 40% per year. It also provided an additional 14 symptom-free days per patient annually.

The additional per-patient cost for these improvements: only 42 cents per day in the United States, said Dr. Sullivan, Professor and Director of the Pharmaceutical Outcomes Research and Policy Program at the University of Washington in Seattle. Inhaled budesonide also appeared to be cost-effective for the treatment of mild persistent asthma in China, the United Kingdom, Spain, France, Canada, Sweden, and Australia, other countries that participated in START.

When the savings from reduced work and school absences were factored into the equation, the US cost was even lower—only 14 cents per patient daily: “less than the cost of a newspaper,” Dr. Sullivan remarked.

—Timothy Begany