A feasibility randomized controlled superiority trial of fluticasone-vilanterol once daily use for the treatment of mild asthma in adults

Trial design

This is a pilot parallel two arm randomized open-label controlled study conducted in a primary health care center in Bahrain.

Ethical considerations

The protocol was designed by the investigators and approved by various ethics committees including Kingdom of Bahrain Ministry of Health on 23/06/2020, number AURS/184/202; Royal College of Surgeons in Ireland – Bahrain (RCSI Bahrain) on 09/11/2021, number NCT04265105; and National Health Regulatory Authority of Bahrain on 16/09/2021. The trial is registered in https://clinicaltrials.gov/ (registration number NCT04265105) on 11^th February 2020.

We used the CONSORT checklist when writing our report (Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomized trials).¹⁶ Written informed consent was obtained from all the patients before commencement of trial. The clinical trial unit at RCSI Bahrain had overall responsibility for the conduct of the trial, data management, and safety monitoring. The first author had full access to the trial data and ensured the accuracy and completeness of the data and the fidelity of the trial to the protocol.

Participants

The main inclusion criteria were patients between the ages of 21 and 75 years with a diagnosis of mild asthma attending the participating primary health care center in Bahrain, being managed with usual care (short-acting beta agonists (SABA) or SABA and ICS combination) and no other asthma medications.

Mild asthma, often termed mild intermittent or mild persistent asthma, is defined by the GINA management strategy as patients who meet the criteria for step 1 and step 2 treatment strategies.⁷

Exclusion criteria were use of LABA documented by medical record or self-reported, leukotriene receptor agonist, theophylline, anticholinergic agent, oral corticosteroids or cromone for regular maintenance therapy in 3 months before entry to the trial [nasal corticosteroid was permitted], medical record or self-reported diagnosis of COPD, bronchiectasis, interstitial lung disease, lung cancer or significant other respiratory disease, history of admission to the ICU with life-threatening asthma at any time, 20 pack-year smoking history, pregnancy or breastfeeding at the time of enrolment, congestive heart failure, unstable coronary artery disease, atrial fibrillation or other clinically significant heart disease, any known or suspected contraindication or allergy to the Investigational Medical Products and currently enrolled in other clinical trials.

Randomization and treatment

Recruitment was done by physicians who were blinded to the allocation of the treatment and control groups. The research coordinator allocated patients to either arm using randomizer.com. The research coordinator who is independent of the project, was aware of the allocation of the patients 1:1 to the control vs treatment group. The intervention arm received fluticasone furoate/vilanterol, Relvar) Ellipta(100 μg/25 μg inhalation powder (30 doses) once daily use. The control arm received usual care which is albuterol (Ventolin, GlaxoSmithKline), 100 μg, two inhalations from a pressurized metered-dose inhaler as needed for symptom relief with or without Fluticasone propionate (Flixotide Evohaler) 125 μg two inhalations from a pressurized metered-dose inhaler.

Procedure

Participants were approached by their physicians who then referred them to the research coordinator. Outcome was assessed at two intervals: Baseline week 0 at randomization (during a health center visit) and at 32 weeks (8 months) (via phone call) (Figure 1).

Figure 1. CONSORT flow diagram.

Primary outcome measures

The feasibility of this pilot study was assessed by evaluation of recruitment, randomization, intervention, retention, and acceptability.

Secondary outcome measures

We investigated patients’ experience of asthma, including their quality of life, asthma control, and the incidence of exacerbations.

The Asthma Quality of Life Questionnaire (AQLQ-S)⁸ consists of 32 questions that assess the quality of life of asthma patients, scored on a 7-point scale ranging from 1 (all of the time) to 7 (none of the time). Higher scores indicate better quality of life.

The Asthma Control Questionnaire (6 items) (ACQ-6): consists of 6 questions that assess asthma symptoms in the previous week, scored on a 7-point scale that ranges from 0 (no symptoms) to 6 (very severe symptoms) in which a 0.5-unit change represents the minimal clinically important difference. Higher scores indicate worse asthma control.

We investigated asthma exacerbations which we defined as worsening asthma that resulted in one or more of the following: an urgent medical care consultation (e.g., a primary care visit, an emergency department [ED] visit, or hospital admission); a prescription of systemic glucocorticoids for any duration, or an episode of high β2-agonist use, which was defined as more than 16 puffs of albuterol or more than 8 puffs of budesonide–formoterol over the course of 24 hours.

Statistical analysis

Statistical analysis was an intention-to-treat superiority analysis. Descriptive analysis used frequencies and percentages for categorical variables, mean, standard deviation (SD) and median for continuous variables. The treatment effect was measured using the mean difference between study arms scores at baseline and 32 weeks. We used SPSS statistical software version 28.0.0.0 for analyses.

Characteristics of participants at baseline

A total of 18 patients were recruited and randomized into the intervention (n=10) and usual care (n=8) groups and randomly allocated to intervention and control groups. No participants withdrew from the trial. The mean (SD) age of the patients was 40.40 (17.32) years old among the intervention group and 54.88 (17.92) in the control group. Half of the participants were male in the intervention arm and 75% in the control arm. All recruited patients had mild asthma with a baseline mean asthma control score of 2.91 for the intervention and 3.26 among control groups. The mean quality of life score was 4.56 was for the intervention group, and 5.08 for the control group. There were no statistically significant differences at baseline between the intervention and control groups in age (p-value=0.102), sex (p-value=0.367), asthma control (p-value 0.547) and quality of life scores (p-value=0.861) (Table 1).

Primary outcome - feasibility of the trial

This feasibility trial was designed with the intention of recruiting 100 participants – 50 allocated to treatment regimen of Fluticasone – Vilanterol (ICS + LABA) and 50 allocated to the control group of ICS + SABA. We were only able to recruit 18 participants in total. This was due to factors including strict inclusion criteria and hesitancy of participation in experimental studies. However, the retention rate was 100% despite an 8-month timeline and 3 different outcome assessments: asthma control score, QoL score, and exacerbation survey.

Secondary outcomes

The mean asthma control score in the fluticasone-vilanterol intervention group was significantly lower after 8 months compared to the baseline, indicating better control of asthma (mean difference: 1.58; 95% confidence interval [CI], 0.72 to 2.44, p=0.003). Additionally, quality-of-life mean scores were higher in the intervention group after 8 months compared to the baseline, indicating better quality of life, but this difference was not statistically significant (mean difference: -0.75; 95% confidence interval [CI], -1.98 to -0.48, p=0.197) (Table 2). In the control group, asthma control and the quality-of-life scores were both lower at 8 months (32 weeks) than at baseline which indicates better asthma control but worse quality of life. However, neither were statistically significant (Table 2).

Table 3 shows that there was no statistical difference in post-intervention asthma control mean score (p-value=0.361) or QoL mean score (p-value=0.337) between the two arms after adjustment for pre-intervention scores.

Asthma exacerbations were assessed at 32 weeks (8 months) in both arms and showed insignificant differences across the two arms: We asked, “did you visit the hospital or the emergency department for asthma or SOB from the beginning of the study?” (p value=0.64), “did you need to use cortisone tablets from the beginning of the study?” (p value=0.41), “did you need to use Ventolin more than 16times a day from the beginning of the study?” (p value=0.55), “did you need to use inhaler more than 8 times a day since the beginning of the study?” (p value=0.16), “did you need to use nebulizer more than 3times a day since the beginning of the study?” (p value=0.55).

Adverse events

No serious adverse events were recorded.

Limitations and strengths

Our trial has several limitations. It indicates that LABA+ICS treatment for mild asthma is feasible and safe with no negative impact on quality of life, but long-term safety and generalizability are not clear as there were only 18 participants recruited from one health center. Our study encountered challenges in recruitment due to the recent COVID-19 pandemic, and research during the pandemic was difficult. Worldwide, many medical research activities including recruitment, visitations, and assessments stopped.¹⁴

Further, patients with mild asthma tend to manage their condition at home and not present at health facilities where the trial recruitment took place. Additionally, this is one of few randomized controlled trials (RCTs) to be conducted in this part of the world where many patients may be reluctant to participate in experimental studies due to fear and unfamiliarity with this type of research.¹⁵ These factors resulted in the small sample of patients. Finally, this study investigated once daily dose of LABA+ICS and did not investigate the as needed protocol which could be the future direction of further research.

Our study has several strengths. This is one of the few interventional trials in this region where many patients are reluctant to participate in experimental studies for reasons discussed.¹⁵ Further, it is one of the few trials investigating the new shift in mild asthma treatment to update the existing treatment guidelines, and this trial has utilized structured validated questionnaires to test outcomes and establishes a baseline for future RCTs. Despite the small sample size, it is worth emphasizing that it demonstrated significant results favoring the intervention and this may impact future policy decisions and create a foundation for further study.

Underlying data

Dryad: The underlying data for ‘A feasibility randomized controlled superiority trial of fluticasone-vilanterol once daily use for the treatment of mild asthma in adults’, https://doi.org/10.5061/dryad.bnzs7h4gq.¹⁶

Reporting guidelines

Dryad: CONSORT checklist for ‘A feasibility randomized controlled superiority trial of fluticasone-vilanterol once daily use for the treatment of mild asthma in adults’, https://doi.org/10.5061/dryad.bnzs7h4gq.¹⁶

Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).