Efficacy and safety of dupilumab for the treatment of uncontrolled asthma: a meta-analysis of randomized clinical trials

Background Several recent clinical trials have assessed the effects of dupilumab in uncontrolled asthma, but reached no definite conclusion. We therefore conducted this meta-analysis to evaluate the overall efficacy and safety of dupilumab for the treatment of uncontrolled asthma. Methods All randomized controlled trials were included. Standard mean differences (SMD) or relative risks (RR) were calculated using Fixed-or random-effects models. Results Five studies involving 3369 patients were identified. Pooled analysis showed significant improvements in the first-second forced expiratory volume (FEV1) (SMD = 4.29, 95% CI: 2.78–5.81) and Asthma Quality of Life Questionnaire scores (SMD = 4.39, 95% CI: 1.44–7.34). Dupilumab treatments were also associated with significantly decreased 5-item Asthma Control Questionnaire scores (SMD = − 4.95, 95% CI: − 7.30 to − 2.60), AM and PM asthma symptom scores (SMD = − 5.09, 95% CI: − 6.40 to − 3.77; SMD = − 4.92, 95% CI: − 5.98 to − 3.86, respectively), and severe exacerbation risk (RR = 0.73; 95% CI: 0.67–0.79) compared with placebo, with similar incidence of adverse events (RR = 1.0; 95% CI: 0.96–1.04). Conclusion Dupilumab treatment is relatively well-tolerated and could significantly improve FEV1, symptoms, asthma control, and quality of life, and reduced severe exacerbation risk in patients with uncontrolled asthma.


Introduction
Asthma is one of the most common chronic diseases and affects around 334 million people worldwide [1], of whom approximately 20-25% have uncontrolled disease [2]. Many of these patients have substantially reduced lung function and a higher risk of disease exacerbation, despite maximum treatment, and require the use of a considerable proportion of health care resources [3,4]. Immunologically, type 2 cytokines (specifically interleukin [IL]-4, IL-5, and IL-13) are recognized as playing a substantial pathobiological role in asthma [5][6][7]. These cytokines link to a type-2/ T-helper-2-cell (Th2)-high molecular asthma phenotype in up to 50% of asthmatic patients, across all levels of severity [8][9][10].
Dupilumab, a fully human monoclonal antibody, is directed against the alpha subunit of the IL-4 receptor, thereby blocking both IL-4 and IL-13 signaling, and hence type 2 inflammation [11]. It has been approved for the treatment of moderate-to-severe atopic dermatitis [12]. Several randomized, placebo-controlled studies (RCTs) have shown efficacy of dupilumab in patients with uncontrolled asthma. However, because the sample sizes of these studies were varied and results were less consistent, the evidence is insufficient for drawing robust conclusions. Therefore, we conducted a meta-analysis to assess the overall efficacy and safety of dupilumab treatment for uncontrolled asthma.

Data sources and searches
We searched PubMed, Embase, the Cochrane Library and Chinese Biological Medicine (CBM) databases for articles published up to June 30, 2018, to identify all trials assessing dupilumab therapy for patients with uncontrolled asthma, using the search terms: "asthma" and "dupilumab". Publication species was limited to humans. In addition, relevant review articles and their reference lists were checked manually.

Study selection
Studies were considered eligible if they met the following criteria: 1) trials recruited adults/adolescents (≥ 12 years old) diagnosed with uncontrolled asthma, 2) participants received dupilumab therapy at any dose, 3) RCTs, and 4) RCTs reporting the following outcomes: lung function (FEV 1 ), he 5-item Asthma Control Questionnaire (ACQ-5) score, fractional exhaled nitric oxide (FE NO ), AM and PM asthma symptom scores, quality of life (AQLQ), severe exacerbation rate, or adverse events. Two investigators (XFX and MZ) independently screened all references according to the selection criteria. Disagreements were resolved through discussion.
The patients were diagnosed with asthma persisting for 1 year or more, according to the Global Initiative for Asthma 2009 or 2014 guidelines [13,14]. Uncontrolled asthma was defined based on current treatment with a medium-to-high-dose inhaled glucocorticoid (fluticasone propionate at a total daily dose of ≥500 μg or equipotent equivalent), plus up to 2 additional controllers (e.g., a long-acting β2-agonist or leukotriene receptor antagonist); a forced expiratory volume in 1 s (FEV 1 ) ≤ 80% of the predicted normal value before bronchodilator use (or ≤ 90% of the predicted normal value in those 12-17 years of age); FEV 1 reversibility of at least 12% and 200 ml [15]; the 5-item Asthma Control Questionnaire (ACQ-5) score ≥ 1.5 (on a scale from 0 [no impairment] to 6 [maximum impairment]; the minimal clinically important difference is 0.5) [16]; and a worsening of asthma in the previous year that led to hospitalization, emergency medical care, or treatment with systemic glucocorticoids ≥3 days [15]. Asthma symptom scores are patient-reported measures of asthma symptoms, taken upon waking and in the evening. Their effects on activities (PM) and sleep (AM) were noted. These symptom scores range from 0 to 4, with higher scores indicating greater disruption [15]. A severe exacerbation was defined as a deterioration of asthma that required the use of systemic corticosteroids for at least 3 days, or hospital admission, or an emergency department visit because of asthma, treated with systemic corticosteroids [17]. The AQLQ is a patient-reported measure of the effect of asthma on quality of life; higher scores indicate a better quality of life; a global score is calculated and ranges from 0 to 7 [15].

Data extraction and quality assessment
The Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) statement was followed. Two authors (XFX and MZ) performed data extracted and recorded desirable information of each enrolled study in a standard form as recommended by Cochrane [18]. Any disagreement was resolved through discussion or adjudicated by a third author (HXW). In addition, we evaluated the risk of bias using the Cochrane Collaboration's domains [19].

Statistical analyses
Intervention effects were presented using risk ratios (RR) and 95% confidence intervals (CIs) for dichotomous data and using mean differences (MD) and 95% CIs for continuous data. If a trial presented more than 2 intervention groups, we combined 2 or 3 groups into a single group according to the Cochrane handbook [19]. Heterogeneity was quantified by I 2 statistic and the χ 2 test. Random-effects model was performed in the presence of high heterogeneity (I 2 > 50%); otherwise, fixed-effects model was applied [20]. Meta-regression was used to explore potential sources of heterogeneity. Funnel plots with the Begg's and Egger's tests were used to test publication bias [21]. All statistical analysis was accomplished by an independent statistician using Review Manager (Version 5.3, The Cochrane Collaboration, Copenhagen) and Stata (Version 12.0, Stata Corporation, USA), and rendered statistical significance as P-value < 0·05. Meta-analyses may cause type I errors because of sparse data and repetitive testing of accumulating data [22]. We performed trial sequential analysis (TSA) to assess the risk of type I errors, which can identify whether the evidence in a meta-analysis is reliable and authentic. If the cumulative z curve crosses the trial, the boundaries, and the required information size, the evidence is sufficient to reach a conclusion, and no further studies are needed. We calculated the required information size for FEV 1 using α = 0.05 (2-sided) and β = 0.20 (power of 80%). TSA version 0.9 beta (http://www.ctu.dk/tsa) was applied for the analyses [23].

Study identification
The initial database search resulted in 419 articles. After reviewing the titles and abstracts, 43 were found to be relevant for further detailed evaluation. Of these 38 were excluded as the population was wrong (n = 24), there  Trial sequential analysis of 7 groups (two trial contains two groups) illustrating that the cumulative z curve crossed both the conventional boundary and the trial sequential monitoring boundary, establishing sufficient and conclusive evidence and suggesting that further trials are not required. Using α = 0.05 (two-sided) and β = 0.20 (power of 80%) calculate that the optimal sample size was 1882 patients was no placebo control (n = 4), or data were unavailable (n = 10). Thus, 5 RCTs were included in the meta-analysis [15,[24][25][26][27] (Fig. 1).
Trial sequential analysis TSA found that the optimal sample size required for reliable detection of a reasonable effect of dupilumab treatment on FEV 1 of asthma was 1882 participants; the number of patients included in our study far exceeded this number. TSA presented that the cumulative z curve crossed both the conventional boundary and the sequential monitoring boundary, which indicated that the cumulative evidence is reliable and authentic. Therefore, further studies were not needed (Fig. 2).

Quality of the individual studies and subgroup analyses
All trials had a low risk of bias in terms of the 6 domains (Fig. 11). The publication bias of trials was estimated by visual inspection of the funnel plot and Egger's test, and there was no publication bias ( Fig. 12, P = 1.00). According to the funding source, subgroup analyses were performed to assess sponsorship biases. Unfortunately, all studies were funded by a pharmaceutical company (Sanofi or Regeneron Pharmaceuticals). Thus, the results should be expounded with caution. In order to examine the source of heterogeneity, subgroup analyses were conducted for FEV 1 and ACQ-5 scores. The studies were stratified in terms of the effects model, region of trial, sample size, treatment duration, blood eosinophil count, and sources of funding, but no significant difference was found between groups in terms of FEV 1 and ACQ-5 scores (Table 3).

Discussion
To our knowledge, this is the first meta-analysis and comparison of all published data of RCTs on the use of dupilumab for the treatment of uncontrolled asthma. Our study indicated that dupilumab treatment was relatively tolerated and could significantly improve FEV 1 and quality of life, and reduced the disease symptom score and severe exacerbations risk in patients with uncontrolled asthma. Fig. 6 The effect of dupilumab versus placebo on AM asthma symptom score Fig. 7 The effect of dupilumab versus placebo on PM asthma symptom score. SD = standard derivation, IV = Inverse Variance, CI = confidence interval, Std. Mean Difference = standardized mean difference Asthma is a heterogeneous disease [1]. Previous studies have indicated that the Th2 cytokines IL-4 and IL-13 play a part in asthma [28,29]. Dupilumab is an IL-4R antagonist that inhibits the IL-4 and IL-13 signaling pathway. Several clinical trials have been performed evaluating the effect of dupilumab in uncontrolled asthma. However, the evidence was insufficient to allow sound conclusions to be drawn, because the sample sizes varied; therefore, further analyses were necessary.
Based on pooled analyses, we found that dupilumab could significantly improve FEV 1 in patients with uncontrolled asthma. The clinical relevance of this finding may be clinically important, suggesting a potential effect of dupilumab on airway remodeling. However, a previous study [24] failed to show a significant effect on lung function as compared with placebo, which may be attributed to the small sample size and unselected population of patients with asthma. Compared to the previous study, we identified a selected population of patients with uncontrolled asthma. Moreover, we performed TSA to estimate the required information size for analysis, which can decrease the risk of random errors. Thus, our results may be more plausible. In addition, the different outcomes between our study and the previous trial suggested that dupilumab may be valid only in a targeted subgroup with uncontrolled asthma.
Three trails [15,26,27] showed that dupilumab could significantly reduce ACQ-5 scores and asthma symptom scores, which was consistent with our findings. AQLQ is a disease-specific health-related quality of life instrument that contains 32 items has been proven to be responsive in before-after studies and in clinical trials [30]. In our study, we used the AQLQ score to assess the quality of life of patients. Dupilumab treatment significantly improved AQLQ score in patients with uncontrolled asthma, this result was consistent with those of previous reviews. However, the mean change in AQLQ was less than the minimally important clinical difference of 0.5 units [31]. Thus, the relation of this finding to patients may not be clinically significant.
Given that nitric oxide (NO)-synthase activity and NO production are promoted by IL-13, FE NO levels can be used as a biomarker of Th2 inflammation and of IL-13 Fig. 8 The effect of dupilumab versus placebo on AQLQ. AQLQ = Asthma Quality of Life Questionnaire, SD = standard derivation, IV = Inverse Variance, CI = confidence interval, Std. Mean Difference = standardized mean difference Fig. 9 Forest plot of the effect of dupilumab treatment on asthma severe exacerbations verse placebo. Fixed-effects model. RR = relative risk, CI = confidence interval levels in the bronchial mucosa [32]. Therefore, FE NO levels could decrease after treatment with anti-IL-4/13 therapy [33]. The current meta-analysis further confirmed this theory: our study showed a significantly decrease in FE NO levels after dupilumab treatment. Similarly, all previous trials of dupilumab treating uncontrolled asthma observed a reduction in the FE NO level, which is consistent with the mechanism of action of dupilumab.
Severe asthma exacerbations are related to substantial mortality [34]. Reducing asthma exacerbation risk is a key target of disease management. The part of Th2 inflammation is about 50% of asthmatic patients, in whom proinflammatory cytokines abnormally product, such as IL-4, IL-5, and IL-13, which induce IgE synthesis and eosinophilic inflammation [35]. Trials using specific inhibitors have indicated a relation between eosinophils and the pathogenesis of asthma exacerbations [36,37]. Therefore, it is hypothesized that anti-IL-4 and anti-IL-13 therapies could decrease asthma exacerbation by inhibiting eosinophilic and airway inflammation. In further sustain of this concept, our study showed a significant reduction in severe exacerbation rates with dupilumab treatment. The improvements in asthma-related quality of life with dupilumab treatment may contribute to preventing severe asthma exacerbations.
The whole safety profile of dupilumab was equivalent to that of placebo in all RCTs, and the common adverse events were injection-site reactions, upper respiratory tract infection, headache, nasopharyngitis, bronchitis, and sinusitis. Four trials [15,[25][26][27] showed that the rates of upper respiratory tract infection in the dupilumab-treated group were low and similar to placebo group. However, all RCTs included revealed that the incidence of injection-site reactions was slightly higher in the dupilumab regimens. Therefore, more data are required to support the safety profile of dupilumab in terms of injection-site reactions.
This meta-analysis has some shortcomings. First, the severity of uncontrolled asthma and baseline therapy varied among studies; thus, it is impossible to probe the impact of these factors on results. Second, significant heterogeneity existed among trials evaluating FEV1, ACQ-5 score, FE NO , and AQLQ, possible sources of heterogeneity might include different geographic regions and races. Third, we combined 2 or 3 intervention groups into a single group according to the Cochrane handbook, regardless of differences in intervention dosage, which made it hard to determine the optimal dose. Last, as all the RCTs involved the pharmaceutical industry, the positive outcomes should be expounded cautiously. Our study also had some strengths; for instance, our patient selection was highly consistent, and all trials were of high quality, such that the internal validity of our meta-analysis was high.

Conclusions
The current meta-analysis demonstrated that dupilumab treatment was relatively tolerated and significantly improved FEV 1 , symptoms, asthma control, and quality of life, and reduced severe exacerbation risk in patients with uncontrolled asthma. Thus, dupilumab may be effective and safe for the treatment of uncontrolled