As-needed combo-drug inhaler a viable treatment solution in mild asthma

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AshmainhalerA large international trial has found an as-needed combined-drug inhaler treatmet that is a viable option with mild asthma, where up to 80% of patients do not follow the daily treatment regime. The findings were essentially confirmed in parallel ‘real world study’ conducted by the University of Cape Town.

People with mild asthma are often prescribed a daily treatment regimen, but up to 80% do not follow the routine, using inhalers only when they have an asthma attack. Now the researchers have found an as-needed combined-drug inhaler is a viable treatment option.

Paul O’Byrne is the principal investigator on the study that suggests an inhaler with a combination of budesonide, a steroid that controls inflammation, and formoterol, a beta2-agonist that helps to open airways and make breathing easier, may be an alternative to conventional treatment strategies.

O’Byrne is a respirologist, a professor of medicine at McMaster University’s Michael G DeGroote School of Medicine and a clinician scientist at the Firestone Institute for Respiratory Health at St Joseph’s Healthcare Hamilton.

“Short-acting beta-agonists, also known as rescue inhalers, work quickly but they do not treat the underlying problem of inflammation,” said O’Byrne of the first study. “The secret in this new approach is that it not only relieves symptoms but at the same time delivers steroids required for overall control of asthma.”

According to Statistics Canada, 8% of Canadians, or 2.4m people have been diagnosed with asthma by a health professional. Approximately 50% to 75% of patients diagnosed with the chronic disease have mild asthma. While symptoms may not always be burdensome, airway inflammation is usually present, and mild asthma patients are at risk of severe exacerbations, commonly called asthma attacks, which can result in emergency care or even asthma-related death.

“In clinical practice, poor adherence to asthma medications, particularly inhaled steroids as maintenance therapy, is a major problem across all severities of asthma,” said O’Byrne. “As such, patients rely on as-needed inhalers for symptom relief, which doesn’t actually help improve their overall condition.”

O’Byrne and his team worked with researchers around the world to conduct a 52-week trial with patients aged 12 years of age of older with clinically-diagnosed mild asthma.

More than 3,800 patients participated from countries including Canada, China, the UK, Australia, Brazil and South Africa, among others. The trial was conducted between July 2014 and August 2017.

Patients were randomly assigned one of three regimens and were closely monitored. One group took a twice-daily placebo plus as-needed terbutaline, a relief beta agonist used to prevent and treat wheezing; a second group was on a twice-daily placebo plus budesonide-formoterol used as needed, while a third group was on twice-daily maintenance budesonide plus terbutaline used as needed. All patients received an electronic reminder to take their maintenance treatment twice daily.

The trial results showed budesonide-formoterol used as needed was superior to terbutaline alone as needed for improving asthma symptom control, as well as reducing the risk of an asthma attacks by more than 60% but was inferior to the twice-daily budesonide maintenance therapy for symptom control.

“If patients could remember to take their maintenance budesonide treatment and follow it carefully, they would get the best day-to-day symptom control, but the risk of exacerbation was the same as if they used the combined budesonide and formoterol as needed,” said O’Byrne. “In addition, the amount of steroids used was much less when the combined inhaler was used, because the patient did not need to take it every day.”

O’Byrne is also an author on a parallel study led by Eric Bateman at the University of Cape Town in South Africa. In that study patients were randomly assigned a twice-daily placebo plus budesonide-formoterol used as needed or twice-daily budesonide plus terbutaline used as needed. The trial involved more than 4,200 patients on a 52-week trial in 25 countries between November 2014 and August 2017. As with the other study, participants had mild asthma and were aged 12 and older.

The results showed that in patients with mild asthma, budesonide-formoterol used as needed was comparable to twice-daily budesonide in relation to the rate of severe asthma attacks during 52 weeks of treatment but was inferior in controlling symptoms.

“This was more of a real-world study, without the electronic monitoring twice a day or reminders to use medication, and fewer study visits, so it is more comparable to managing patients in a real facility with a lower adherence to the daily treatment course,” said O’Byrne.

“There was no short-acting beta-agonists comparator group in this trial, just the comparison of the maintenance budesonide to the reliever that contained budesonide-formoterol, but the trial outcomes were essentially identical.”

Both studies were sponsored by AstraZeneca and are being presented at the American Thoracic Society conference in San Diego.

Abstract 1
Background: Patients with mild asthma often rely on inhaled short-acting β2-agonists for symptom relief and have poor adherence to maintenance therapy. Another approach might be for patients to receive a fast-acting reliever plus an inhaled glucocorticoid component on an as-needed basis to address symptoms and exacerbation risk.
Methods: We conducted a 52-week, double-blind, multicenter trial involving patients 12 years of age or older who had mild asthma and were eligible for treatment with regular inhaled glucocorticoids. Patients were randomly assigned to receive twice-daily placebo plus budesonide–formoterol (200 μg of budesonide and 6 μg of formoterol) used as needed or budesonide maintenance therapy with twice-daily budesonide (200 μg) plus terbutaline (0.5 mg) used as needed. The primary analysis compared budesonide–formoterol used as needed with budesonide maintenance therapy with regard to the annualized rate of severe exacerbations, with a prespecified noninferiority limit of 1.2. Symptoms were assessed according to scores on the Asthma Control Questionnaire–5 (ACQ-5) on a scale from 0 (no impairment) to 6 (maximum impairment).
Results: A total of 4215 patients underwent randomization, and 4176 (2089 in the budesonide–formoterol group and 2087 in the budesonide maintenance group) were included in the full analysis set. Budesonide–formoterol used as needed was noninferior to budesonide maintenance therapy for severe exacerbations; the annualized rate of severe exacerbations was 0.11 (95% confidence interval [CI], 0.10 to 0.13) and 0.12 (95% CI, 0.10 to 0.14), respectively (rate ratio, 0.97; upper one-sided 95% confidence limit, 1.16). The median daily metered dose of inhaled glucocorticoid was lower in the budesonide–formoterol group (66 μg) than in the budesonide maintenance group (267 μg). The time to the first exacerbation was similar in the two groups (hazard ratio, 0.96; 95% CI, 0.78 to 1.17). The change in ACQ-5 score showed a difference of 0.11 units (95% CI, 0.07 to 0.15) in favor of budesonide maintenance therapy.
Conclusions: In patients with mild asthma, budesonide–formoterol used as needed was noninferior to twice-daily budesonide with respect to the rate of severe asthma exacerbations during 52 weeks of treatment but was inferior in controlling symptoms. Patients in the budesonide–formoterol group had approximately one quarter of the inhaled glucocorticoid exposure of those in the budesonide maintenance group.

Authors
Eric D Bateman, Helen K Reddel, Paul M O’Byrne, Peter J Barnes, Nanshan Zhong, Christina Keen, Carin Jorup, Rosa Lamarca, Agnieszka Siwek-Posluszna, J Mark FitzGerald

Abstract 2
Background: In patients with mild asthma, as-needed use of an inhaled glucocorticoid plus a fast-acting β2-agonist may be an alternative to conventional treatment strategies.
Methods: We conducted a 52-week, double-blind trial involving patients 12 years of age or older with mild asthma. Patients were randomly assigned to one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed (terbutaline group), twice-daily placebo plus budesonide–formoterol (200 μg of budesonide and 6 μg of formoterol) used as needed (budesonide–formoterol group), or twice-daily budesonide (200 μg) plus terbutaline used as needed (budesonide maintenance group). The primary objective was to investigate the superiority of as-needed budesonide–formoterol to as-needed terbutaline with regard to electronically recorded weeks with well-controlled asthma.
Results: A total of 3849 patients underwent randomization, and 3836 (1277 in the terbutaline group, 1277 in the budesonide–formoterol group, and 1282 in the budesonide maintenance group) were included in the full analysis and safety data sets. With respect to the mean percentage of weeks with well-controlled asthma per patient, budesonide–formoterol was superior to terbutaline (34.4% vs. 31.1% of weeks; odds ratio, 1.14; 95% confidence interval [CI], 1.00 to 1.30; P=0.046) but inferior to budesonide maintenance therapy (34.4% and 44.4%, respectively; odds ratio, 0.64; 95% CI, 0.57 to 0.73). The annual rate of severe exacerbations was 0.20 with terbutaline, 0.07 with budesonide–formoterol, and 0.09 with budesonide maintenance therapy; the rate ratio was 0.36 (95% CI, 0.27 to 0.49) for budesonide–formoterol versus terbutaline and 0.83 (95% CI, 0.59 to 1.16) for budesonide–formoterol versus budesonide maintenance therapy. The rate of adherence in the budesonide maintenance group was 78.9%. The median metered daily dose of inhaled glucocorticoid in the budesonide–formoterol group (57 μg) was 17% of the dose in the budesonide maintenance group (340 μg).
Conclusions: In patients with mild asthma, as-needed budesonide–formoterol provided superior asthma-symptom control to as-needed terbutaline, assessed according to electronically recorded weeks with well-controlled asthma, but was inferior to budesonide maintenance therapy. Exacerbation rates with the two budesonide-containing regimens were similar and were lower than the rate with terbutaline. Budesonide–formoterol used as needed resulted in substantially lower glucocorticoid exposure than budesonide maintenance therapy.

Authors
Paul M O’Byrne, J Mark FitzGerald, Eric D Bateman, Peter J Barnes, Nanshan Zhong, Christina Keen, Carin Jorup, Rosa Lamarca, Stefan Ivanov, Helen K Reddel

McMaster University material
New England Journal of Medicine abstract 1
New England Journal of Medicine abstract 2


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