Introduction
Asthma has become one of the most common chronic medical conditions and about 300 million people globally are estimated to suffer from asthma [1–3]. Asthma is also regarded as the most common chronic disorder in children [4, 5]. This disease can result in considerable morbidity and remarkably reduced quality of life in paediatric populations, and hospitalizations and urgent medical care is sometimes required for these patients [6, 7]. Inhaled corticosteroid (ICS) is currently accepted as the most effective anti-inflammatory medications for the treatment of paediatric asthma and is recommended by international guidelines [8].
Mometasone furoate, a potent ICS has high binding affinity to the glucocorticoid receptor in order to inhibit production of inflammatory mediators and cytokines [9–12]. Mometasone furoate has the features of low systemic bioavailability by inhalation, and high plasma protein binding because of slow diffusion from the bloodstream into other tissues throughout the body [13]. In adults and children as young as aged 4 years, mometasone furoate is reported to have efficacy in improving the lung function, reducing symptoms, and reducing the frequency and severity of exacerbations [14–17].
Recently, several studies reporting mometasone furoate for paediatric asthma have been published, but their efficacy has not been well established.
Aim
With accumulating evidence, we therefore have performed a systematic review and meta-analysis of RCTs to compare the efficacy and safety of mometasone furoate versus placebo for paediatric asthma patients.
Material and methods
Ethical approval and patient consent were not required because this was a systematic review and meta-analysis of previously published studies. The systematic review and meta-analysis was conducted and reported in adherence to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [18].
Search strategy and study selection
Two investigators have independently searched the following databases (inception to October 2019): PubMed, Embase, Web of science, EBSCO, and Cochrane library databases. The electronic search strategy has been conducted using the following key words: mometasone furoate, and asthma, and paediatric or children. We have also checked the reference lists of the screened full-text studies to identify other potentially eligible trials.
The inclusion criteria were as follows: (i) population: children patients diagnosed with asthma; (ii) intervention treatments: mometasone furoate versus placebo; (iii) the study design was RCT.
Data extraction and outcome measures
We have extracted the following information: the author, number of patients, age, female, weight, duration of asthma and detailed methods in each group etc. Data have been extracted independently by two investigators, and discrepancies were resolved by consensus. We have also contacted the corresponding author to obtain the data when necessary.
The primary outcome was predicted forced expiratory volume in 1 s (FEV1) and FEV1. Secondary outcomes included morning peak expiratory flow (AM PEF), pharyngitis, upper respiratory tract infection, and adverse events.
Quality assessment in individual studies
Methodological quality of the included studies was independently evaluated using the modified Jadad scale [19]. There are 3 evaluation items for Jadad scale: randomization (0–2 points), blinding (0–2 points), dropouts and withdrawals (0–1 points). The score of Jadad scale varies from 0 to 5 points. An article with Jadad score ≤ 2 is considered to be of low quality. If the Jadad score ≥ 3, the study is thought to be of high quality [20].
Statistical analysis
We estimated the difference (MD) with 95% confidence interval (CI) for continuous outcomes (predicted FEV1, FEV1, and AM PEF) and risk ratio (RR) with 95% CI for dichotomous outcomes (pharyngitis, upper respiratory tract infection, and adverse events). A random-effects model was used regardless of heterogeneity [21]. Heterogeneity was reported using the I2 statistic, and I2 > 50% indicated significant heterogeneity [21, 22]. Whenever significant heterogeneity was present, we searched for potential sources of heterogeneity via omitting one study in turn for the meta-analysis or performing subgroup analysis. All statistical analyses were performed using Review Manager Version 5.3 (The Cochrane Collaboration, Software Update, Oxford, UK).
Results
Literature search, study characteristics and quality assessment
A detailed flowchart of the search and selection results is shown in Figure 1. Two hundred and sixty-nine potentially relevant articles were identified initially. Finally, four articles that meet our inclusion criteria were included in the meta-analysis [14, 23–25].
The baseline characteristics of the four eligible RCTs in the meta-analysis are summarized in Table 1. The four studies were published between 2006 and 2017, and sample sizes ranged from 89 to 225 with a total of 704. Two studies report mometasone furoate 100 μg once daily [14, 25], while the other two studies report mometasone furoate 100 μg twice daily [23, 24].
Table 1
Characteristics of included studies
Among the four studies included here, three studies report predicted FEV1 [14, 23, 25], two studies report FEV1 [14, 25], two studies report AM PEF [23, 25], three studies report pharyngitis and upper respiratory tract infection [14, 23, 24], and two studies report adverse events [14, 23, 25]. Jadad scores of the four included studies vary from 3 to 5, and all four studies are considered to be high-quality ones according to quality assessment.
Primary outcomes: predicted FEV1 and FEV1
These outcome data were analysed using the random-effects model, and compared to the control group for paediatric asthma, mometasone furoate can significantly improve predicted FEV1 (MD = 7.53; 95% CI: 7.02–8.04; p < 0.00001) with no heterogeneity among the studies (I2 = 0%, heterogeneity p = 0.66) (Figure 2) and FEV1 (MD = 0.11; 95% CI: 0.10–0.12; p < 0.00001) with no heterogeneity among the studies (I2 = 0%, heterogeneity p = 0.70) (Figure 3).
Sensitivity analysis
No heterogeneity was observed for the primary outcomes, and thus we have not performed the sensitivity analysis by omitting one study in turn to detect the heterogeneity.
Secondary outcomes
In comparison with placebo for paediatric asthma, mometasone furoate demonstrates an increase in AM PEF (MD = 17.70; 95% CI: 9.91–25.49; p < 0.00001; Figure 4), but has no obvious impact on pharyngitis (RR = 0.96; 95% CI: 0.59–1.58; p = 0.89; Figure 5), upper respiratory tract infections (RR = 0.73; 95% CI: 0.50–1.05; p = 0.09; Figure 6), or adverse events (RR = 1.05; 95% CI: 0.84–1.31; p = 0.69; Figure 7).
Discussion
Inhaled corticosteroids are widely used to decrease the symptoms and the risk of asthma exacerbations, and initiation of ICS treatment or in combination with short-acting β2-agonists (SABA) is recommended in patients with the risk of exacerbations for inhibiting a long-term decline in lung function [26–29]. Mometasone furoate is a highly potent topical corticosteroid with negligible systemic bioavailability, and is available in a dry-powder inhaler for the treatment of asthma. Several trials found that mometasone furoate was efficacious and well tolerated in adolescent and adult patients who were receiving ICS maintenance therapy or only SABA [16, 30–32].
Our meta-analysis suggests that mometasone furoate can substantially improve predicted FEV1, FEV1 and AM PEF for children with asthma to a greater extent than placebo. In addition, mometasone furoate at a dose of 100 µg qd resulted in a significant improvement in quality of life compared to placebo, as evidenced by the Paediatric Asthma Quality of Life Questionnaire with Standardized Activities scores, with a difference of 0.22 points (p = 0.014) [23]. Regarding the sensitivity analysis, although there is no significant heterogeneity analysis, different doses of mometasone furoate and treatment duration may have some impact on the pooling results.
In a 12-week, multicentre, double-blind, parallel-group, placebo-controlled study evaluating 2 dosing regimens of mometasone furoate DPI (100 µg every evening and 100 µg twice daily) in 296 children aged 4 to 11 years with asthma, predicted FEV1 were 4.73 and 5.52 percentage points for mometasone furoate at a dose of 100 µg daily and 100 µg twice daily, respectively. Both of these two doses demonstrated an important improvement in lung function to a higher extent than placebo. However, the difference of two doses was not significant [14]. In one RCT involving children with asthma included in this meta-analysis, all three doses of mometasone furoate treatment (50 µg BID, 100 µg BID, 200 µg BID) demonstrated statistically significant differences of predicted FEV1 compared to placebo. Mometasone furoate at doses of 100 µg BID and 200 µg BID induced the efficacy by increasing predicted FEV1 approximating a five percentage-point difference compared to placebo, and the 50 µg BID mometasone furoate demonstrated the sub-maximal efficacy. Mometasone furoate 200 µg BID showed no further improvement over the mometasone furoate 100 µg BID, but was even associated with numerically slightly lower efficacy than mometasone furoate 100 µg BID [23]. This revealed the effect of various doses of mometasone furoate on treatment efficacy, and 100 µg BID may be the ideal dose of mometasone furoate for the treatment of paediatric asthma.
Similar incidences of pharyngitis, upper respiratory tract infections and total adverse events were observed in mometasone furoate and placebo groups based on the results of this meta-analysis. There are several potential limitations. Firstly, our analysis is based on four RCTs, and more RCTs with a large sample size should be conducted to explore this issue. Next, different doses of mometasone furoate and treatment duration may have some influence on the pooling results. Finally, some unpublished and missing data may lead to some bias for the pooled effect.
