Introduction

Chronic Obstructive Pulmonary Disease (COPD) is a significant global health issue affecting an estimated 328 million people worldwide and is projected to be the leading cause of death by 2030 1,2,3. COPD refers to a larger group of chronic lung diseases that cause limitations in lung airflow, and is primarily caused by smoking tobacco, indoor air pollution, outdoor air pollution, and occupational dusts and chemicals 2. These factors can contribute to cause two of the most common conditions classified under COPD: emphysema, in which the alveoli at the end of the bronchioles are destroyed, and chronic bronchitis, which is characterized by inflammation of the lining of the bronchial tubes, which are responsible for transporting air to and from the alveoli 4. They lead to the most common symptoms of COPD, namely breathlessness, excessive sputum production, and chronic cough, as well as an increased risk of cardiovascular disease, lung cancer, depression, and premature death 2,4. COPD also carries a substantial economic burden, through both healthcare costs and productivity loss, and is also associated with a reduced quality of life 5,6.

COPD consists of four stages: mild, moderate, severe, and very severe. Each stage is calculated according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Staging System. The forced expiratory volume in one second (FEV1) measurement, derived from a pulmonary function test, is used to categorize the severity 7. The forced vital capacity (FVC) test which measures the amount of air an individual can forcefully and quickly exhale after taking a deep breath, is also an important in diagnosis. FEV1 shows the amount of air a person can forcefully exhale in one second of the FVC test. Generally, lower FEV1 signals more severe COPD 8. The breakdown of COPD stages and FEV1 cut-offs is presented in Table 1.

Stage

FEV1

GOLD

Severity

I

≥ 80%

1

Mild

II

50% - 80%

2

Moderate

III

30% - 40%

3

Severe

IV

≤ 30%

4

Very Severe

Table 1. COPD Stages

Clinical consultation is usually sought once COPD progresses to the moderate stage, and it is in this stage that physicians usually begin to prescribe bronchodilators for treatment 8. A recent study found a prevalence of 10.1% in moderate-to-severe COPD worldwide – equivalent to GOLD 2 or higher 9. COPD cannot be cured, however, treatment and effective management can provide symptom relief, improved quality of life, and reduce the risk mortality 2. Long-acting muscarinic antagonists (LAMAs), a class of bronchodilator, have been shown to be an efficacious treatment option for patients with moderate to severe COPD. These are recommended as a maintenance therapy by the GOLD, but until recently, haven’t been available in a once-daily nebulized form, easing their administration for patients.

Revefenacin, a novel LAMA produced by Theravance Biopharma, has recently been approved by the Food and Drug Administration (FDA) in the US due to its efficacy, safety, and tolerability profile 10,11. It acts as a long-acting muscarinic antagonist (LAMA) and only needs to be administered once-daily via a nebulizer 12. Revefenacin prevents bronchoconstriction and allows bronchodilation by inhibiting muscarinic M3 receptors in airway smooth muscles 13. There are five muscarinic receptors – M1 to M5 – which are all expressed in the lungs. Muscarinic antagonists that target M1 to M3 are used to treat lung diseases 14. The drug, being a competitive antagonist of M3 receptors, which mediate the contraction of the airway smooth muscle, suppresses the acetylcholine-evoked calcium mobilization and contractile responses in the airway tissue in order to regulate tone and patency 14,15. Despite the current variety of bronchodilators, Revefenacin becomes innovative in that it is the first approved once-daily sprayable LAMA compatible with common nebulizers 12.

The FDA approved Revefenacin on 8th November 2018 under the drug name YulperiTM 16. The agency, moreover, approved Theravane Biopharma Inc. and Mylan N.V.’s ‘New Drug Application’, making these the main companies behind the inhalation solution 17. However, this recent approval prompts the need for summative information on the effectiveness of revefenacin and serves as motivation for a systematic review and meta-analysis of the data regarding its efficacy for the treatment of patients with moderate to very severe COPD.

Objective

The objective of this systematic review and meta-analysis is to determine the clinical efficacy of Revefenacin, a novel nebulized LAMA, in the treatment of patients with moderate to very severe COPD (GOLD Stages 2 through 4), and any comparator. Eligible studies can have participants of any age, gender, and in any location. The primary outcome of interest is trough change in FEV1 from baseline to study endpoint, so studies were evaluated and excluded in full text review if this outcome was not present.

Methods

Protocol and Registration

The protocol for this systematic review and meta-analysis is registered on the PROSPERO international prospective register of systematic reviews, registration identification: CRD42019131334.

Inclusion Criteria – PICOS Framework

Population: Studies involving patients with moderate to very severe COPD of all ages were included as clinical diagnosis and prescription of bronchodilators usually occurs at the moderate stage 8.

Intervention: All studies including treatment with Revefenacin alone (of any dosage or dosing regimen) were included. Revefenacin is a novel, nebulized, once-daily LAMA used in the treatment of moderate to very severe COPD. All dosage levels were included in the meta-analysis.

Comparator: Any study with Revefenacin and comparator was included in the study, but placebo was the primary comparator for analysis, as it is the standard comparator for efficacy studies 18,19.

Outcome: The primary outcome of interest was Trough FEV1 change from baseline to study endpoint in mL. Outcomes do not determine eligibility in the initial screening, yet will be considered in the full text analysis in order to determine whether the study has sufficient information for final inclusion.

Study type: Randomised controlled trials (RCTs). RCTs are the most effective and least biased study design in evaluating the efficacy of a new treatment, as they use random allocation and comparison to a control in order to account for any confounders on the outcome of interest 18. Completed studies with results in English from any year were included.

Exclusion Criteria

Studies involving treatment with Revefenacin in patients with specific comorbidities in addition to, or in place of, COPD were excluded as the results of these studies could bias efficacy measures. Studies that included patients with unspecified stages of COPD were also excluded because of possible bias, along with studies that failed to measure FEV1, due to a lack of implication in the meta-analysis.

Information Sources and Search Strategy

We searched for eligible studies up to the 24th of February 2019, using MEDLINE (OVID), EMBASE, and CINAHL databases because of their breadth covering clinical research. Search strategies for the different databases using medical subject headings (MeSH) and free text keywords including ‘Revefenacin’, ‘chronic obstructive pulmonary disease’, ‘randomised control trial’ and more, were developed and are reproduced in Appendix A. We also searched the grey literature using ClinicalTrials.Gov and the International Clinical Trials Registry Portal for relevant clinical trials. Our search was restricted to studies with results in English.

Study Selection

Records from the search were stored using Mendeley Reference Management Software throughout the review. Titles and abstracts were initially screened by two independent reviewers to assess eligibility. Ineligible studies were then excluded, and those deemed eligible underwent full text review by two independent reviewers to determine final eligibility. Any discrepancies in eligibility determination were assessed by a third independent reviewer and discussion took place until consensus was achieved. Ineligible studies were removed and included studies entered the data collection process.

Data Collection and Items

Relevant study data was then extracted and compiled in a Microsoft Excel spreadsheet by five study team reviewers, with cross check for consensus. The form for data extraction included: authors, title, publication year, trial ID, study design, study duration, follow up duration, trial start year, country, number of participants, number of males, number of females, mean age, COPD stage (mean FEV1%), number of participants in intervention group, dosage, regimen, number of participants in control group, trough FEV1 change from baseline for placebo with standard deviation, trough FEV1 change from baseline for Revefenacin with standard deviation, and placebo-adjusted trough FEV1 change from baseline (if available) with standard deviation (Table 3). As all of the trials were multi-armed for different dosages of intervention, each dosage arm was treated as its own study and its standard error later adjusted for the unit-of analysis error and correlation between the shared placebo group using the exact adjustment method (Method 4) in Rucker et al., 2017 (See Appendix B) 20. Adjustment was performed in R statistical software, and the code can be found in Appendix C.

Risk of Bias in Individual Studies

Risk of bias in individual studies was measured at the study level by two independent reviewers with The Cochrane Collaboration’s tool for assessing risk of bias in randomised controlled trials 21. This tool measures a range of sources of bias within individual studies, including: selection bias, through random sequence generation and allocation concealment; performance bias, through blinding of participants and personnel; detection bias, through blinding of outcome assessment; attrition bias, through incomplete outcome data; and reporting bias, through selective reporting (Table 2) 21. Each item in the tool was designated as low, unclear, or high risk of bias. Studies determined to have a high risk of bias will be excluded for sensitivity analysis. The risk of bias assessment within studies was created in Review Manager 5.3 29.

Table 2: Possible biases
Table 2: Possible biases

Principal Summary Measures

For our study, difference in means is the principal summary measure used, as measured by the change in trough FEV1 from baseline to study endpoint in mL, as this is the standard in evaluating efficacy of treatments in COPD interventions 22. Difference in means is used because of the same outcome and unit being measured in each of the included studies, as per the Cochrane Handbook 23.

Synthesis of Results

A random-effects pairwise meta-analysis was performed using Stata statistical software for a difference in means of change in trough FEV1 from baseline to study endpoint in mL between the Revefenacin intervention group and the placebo group. A random effects model was used because of the variation in dosages, study duration, and study design across the studies 24. As mentioned, adjusted standard errors were used in the pairwise meta-analysis in order to include information from multi-armed studies 20. The meta-analysis results were presented in difference in means (or mean difference) with the 95% confidence interval, and I2 was calculated as a measure of heterogeneity 25.

Risk of Bias Across Studies

The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) tool was used to evaluate risk of bias, imprecision, inconsistency, indirectness, publication bias and confidence in cumulative evidence (Table 3) 26. Funnel plots with mean difference and standard error were used to assess possible bias across studies, as well as publication bias.

Table 3: GRADE Factors
Table 3: GRADE Factors

Additional Analyses

Subgroup analysis was performed for study duration and drug dosage, which were both pre-specified, as well as study design (parallel or nonparallel), and study source (as results from the same trial are split into the different arms for analysis). Meta-regressions for drug dosage and study duration were performed for robustness. Sensitivity analysis was performed excluding studies with potential high risk of bias 27.

Results

Study Selection

We initially screened 1571 records from EMBASE, MEDLINE, and CINAHL databases, as well as 161 from the grey literature, and then removed 13 duplicates for a total of 1719 records. 27 records were assessed in full-text review, and eventually 13 full text articles containing information for 7 randomised controlled trials were included in the qualitative synthesis and meta-analysis (Figure 1). See Appendix C for full-text exclusions with reasons. Table 4 displays the authors and titles of the selected trials.

Study identification and selection flow diagram
Figure 1: Study identification and selection flow diagram 28

Author

Title

Pudi et al. 2017

A 28-day, randomized, double-blind, placebo-controlled, parallel group study of nebulized Revefenacin in patients with chronic obstructive pulmonary disease.

Nicholis et al. 2014

A Randomized, Crossover, 7-Day Study Of Once-Daily TD 4208, A Long-Acting Muscarinic Antagonist, In Subjects With COPD

Potgieter et al. 2012

A randomized, crossover study to examine the pharmacodynamics and safety of a new antimuscarinic (TD-4208) in COPD

Theravance Biopharma 2017

A 7-Day Cross-over Study of QD (Once Daily) and BID (Twice Daily) TD-4208 in Chronic Obstructive Pulmonary Disease (COPD)

Ferguson et al. 2017

Efficacy of Revefenacin , a Novel Once-Daily Nebulized Long-Acting Muscarinic Antagonist: Results of Two Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 3 Trials in Participants with Moderate to Very Severe Chronic Obstructive Pulmonary Disease

Pudi et al. 2016

Trials in Progress: Two 12-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 3 Trials of a Nebulized Long-Acting Muscarinic Antagonist (Revefenacin ) in Study Participants With Moderate to Very Severe COPD

Quinn et al. 2018

Pharmacodynamics, pharmacokinetics and safety of Revefenacin (TD- 4208), a long-acting muscarinic antagonist, in patients with chronic obstructive pulmonary disease (COPD): Results of two randomized, double-blind, phase 2 studies

 Table 4. Selected Trials

Study Characteristics

Study characteristics in the format of the Excel spreadsheet used for data extraction are presented in Table 5. The articles which were merged for singular trials are presented in the leftmost column and only represent

Risk of bias within studies

Details of risk of bias within studies are presented in Figure 2, with a summary in Figure 3. Studies could be measured as Low risk, unclear risk, or high risk. Pudi et al. presented the only section with a high risk of bias, in random sequence generation. This was due to a lack of information detailing how patients were randomised.

Table 5. Characteristics of Individual Studies (30–43)
Table 5. Characteristics of Individual Studies 30–43

Figure 2. Risk of bias within studies
Figure 2. Risk of bias within studies

Figure 3. Summary of risk of bias within studies
Figure 3. Summary of risk of bias within studies

Risk of Bias Across Studies

The GRADE tool was used to evaluate risk of bias, imprecision, inconsistency, indirectness, publication bias and confidence in cumulative evidence 26. The results are reproduced in the GRADE Summary of Findings (Figure 4). Funnel plots assessing possible bias across studies (Appendix E) and publication bias (Figure 5) demonstrate asymmetry and possible risk of publication bias, respectively. The possible risk of publication bias is due to all of the measured outcomes demonstrating statistical significance, as well the sponsorship by the manufacturer for all studies.

Figure 4. GRADE Summary of Findings
Figure 4. GRADE Summary of Findings

Figure 5. Contour-Enhanced Funnel Plot of Random-Effects Meta-Analysis
Figure 5. Contour-Enhanced Funnel Plot of Random-Effects Meta-Analysis

Results of Individual Studies

Results of individual studies and the random-effects meta-analysis are presented in Figure 6, along with the accompanying forest plot in Figure 7. For the pairwise, random-effects meta-analysis, 1472 patients were analysed, and the overall difference in means was an increase of 119.073 mL in change in trough FEV1 from baseline to study endpoint for the Revefenacin group compared to the placebo. This result was statistically significant, with a 95% confidence interval of 102.254 mL to 135.893 mL. The heterogeneity between studies was significant with a p value of 0.000, and the I2 measure of consistency was equal to 98.9%, which means that 98.9% of variation in the difference in means is attributable to heterogeneity, which can be interpreted as a high level of statistical heterogeneity.

Figure 6. Results of Individual Studies and Overall Random-Effects Meta-Analysis
Figure 6. Results of Individual Studies and Overall Random-Effects Meta-Analysis

Figure 7. Forest plot of random-effects meta-analysis (Note that for Ferguson 2017 dosage was different per site)
Figure 7. Forest plot of random-effects meta-analysis (Note that for Ferguson 2017 dosage was different per site)

Additional Analysis

Subgroup analysis

Subgroup analysis was performed for study duration (Figure 8), demonstrating significant difference for difference in means for 1 day versus 7 days only, as the 95% confidence interval for 1 day was higher and did not overlap with that of 7 days. There were non-significant differences amongst the rest of the groups by study duration. Subgroup analysis was also performed for dosage (Figure 9), yielding the highest overall difference in change in trough FEV1 from baseline to study endpoint for 175 µg, significantly higher than that of 22 and 44 µg. A dosage of 22 µg yielded a significantly lower difference than all but a dosage of 44 µg, with non-significant differences amongst the groupings of 44, 88, 350, and 700 µg, as well as 88, 175, 350, and 700 µg. Subgroup analysis of study design yielded no significant difference between parallel and nonparallel studies. Overall study is included to demonstrate the additive study effects if results were pooled, as the arms of each different study were split for analysis (Appendix F).

Figure 8. Random Effects Model Meta-analysis by Days
Figure 8. Random Effects Model Meta-analysis by Days

Figure 9. Random Effects Model Meta-analysis by Dosage
Figure 9. Random Effects Model Meta-analysis by Dosage

Meta-Regression

Meta-regression was performed for both study duration and dosages, yielding no significant correlation for either. Whilst meta-regression analysis for < 10 trials is not recommended, the precedent was unclear as we split the 7 trials into 20 intervention arms. Hence meta-regression was chosen to be robust (results in Appendix G).

Sensitivity Analysis

Sensitivity analysis included removing Pudi et al. from the analysis because of the high risk of bias in sequence of randomisation, resulting in a non-significant difference in difference in means before and after removal. The results of the sensitivity analysis are presented in Appendix H.

Discussion

Overall, through a systematic review and random-effects meta-analysis, 1472 patients were analysed from 7 RCTs. The difference in means in change in trough FEV1 from baseline to study endpoint between the Revefenacin intervention and the placebo comparator was significant, at an increase of 119.07 mL (95% CI 102.25, 135.89) demonstrating that Revefenacin is significantly more efficacious in treatment for moderate to very severe COPD compared to placebo. Subgroup analysis demonstrated 175 µg to potentially be the most efficacious dosage, in line with recommendations from the FDA.44 Heterogeneity was detected across studies, but the I2 statistic must be interpreted cautiously as the seven individual studies were split into twenty intervention arms for analysis, inflating the heterogeneity between the arms as all studies used multiple dosages. The contour-enhanced funnel plot demonstrated high risk of publication bias, which could be due to industry sponsorship (funding bias), or comparison to placebo, so this must be taken into account with interpretation. It has been demonstrated that industry sponsored studies more frequently result in favourable efficacy outcomes, possibly hampering the validity of our own selected studies. 45 GRADE assessment concludes that Revefenacin results in a significant, large increase in change in trough FEV1 from baseline to study endpoint when compared to placebo, with moderate certainty of evidence. The results are also consistent with the ‘time lag bias’ in which simultaneous studies with negative results are published years after those with positive ones, which also must be taken into consideration.21

Implications of this meta-analysis include supporting evidence in approval of Revefenacin as a LAMA treatment for COPD, but further research into drug combinations with long-acting beta agonists and comparison to other LAMAs and COPD interventions is necessary to test its relative efficacy.46 This study also used a recently developed method for including multi-armed trials in pairwise meta-analysis, allowing for dosage-specific subgroup analysis within the meta-analysis itself, a technique that will be useful in future drug intervention meta-analyses.20 Some limitations of the study are that the main comparison was placebo, due to the lack of available studies with comparators. To address this, further research in clinical trials and a network meta-analysis of moderate to very severe COPD interventions including Revefenacin should be conducted. The study is also limited by a low number of RCTs 7, and an update as Revefenacin is compared to other interventions should occur sometime in the near future. Furthermore, the generalizability of the study is limited due to the nature of RCTs and their controlling for other factors affecting outcome, such as multimorbidities. Moreover, a geographical bias might be present with the majority of trials being performed in the US (n=4). This adds to the low number of studies which could severely impact the generalisability of results. Furthermore, despite proving that Revefenacin is efficacious against placebo, it is important to point out this systematic review and meta-analysis does not take into account safety and tolerability of the drug, which will need to be further assessed.

Conclusion

This paper’s aim was to determine the clinical efficacy of Revefenacin in patients with moderate to severe COPD. Revefenacin has been determined to be an efficacious treatment for moderate to very severe COPD in comparison to placebo. Further research into whether it is efficacious in comparison to the current standard of care, through RCTs or network meta-analysis for the network of interventions to treat moderate to very severe COPD, is needed. This systematic-review and meta-analysis was limited by a small number of RCTs (n=7), and a larger body of evidence could provide further information on dosage gradients and duration of use. Moreover, being all the selected studies funded by Revefenacin ’s manufacturer poses an important risk of publication bias which needs to be considered. There is also a need for further research into efficacy of Revefenacin in multi-morbid and other trial-excluded patient groups. However, this systematic review and meta-analysis provides a summary of the current evidence and demonstrates the efficacy of Revefenacin in comparison to placebo in its current setting.

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