10 Feb 2022 A systematic review of TRELEGY ELLIPTA single inhaler triple therapy for treatment of adult patients with moderate-to-severe chronic obstructive pulmonary disease (COPD)
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Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by airway inflammation and airflow limitation that is not fully reversible. The goal of COPD treatment is to prevent acute moderate to severe exacerbations, improve quality of life and reduce symptoms such as dyspnea. The main treatment options belong to a number of pharmacological classes: bronchodilators (short-acting beta2 agonists [SABA], long-acting beta2 agonists [LABA], short-acting muscarinic antagonists [SAMA], and long-acting muscarinic antagonists [LAMA]), inhaled corticosteroids [ICS], and inhibitors of the enzyme phosphodiesterase-4 [PDE4 inhibitors]. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) report recommends stepwise intensification to triple therapy in those patients (classified as “group D”) with persisting symptoms and who still have frequent exacerbations despite maximal dual therapy with either LAMA/LABA or LABA/ICS drug therapy. Trelegy Ellipta is a new triple fixed-dose combination of umeclidinium 62.5 mcg (LAMA), fluticasone furoate 100 mcg (ICS), and vilanterol 25 mcg (LABA) that is indicated for the long-term, once daily, maintenance treatment of COPD, including chronic bronchitis and/or emphysema in patients who are not adequately treated by a combination of an ICS/LABA. It is not indicated to treat acute bronchospasm or asthma. This is the only triple therapy inhaler licensed in Canada.
- Requested Research Question
In double blind active controlled parallel group RCTs of at least 24 weeks duration, does triple therapy with fluticasone furoate 100mcg/umeclidinium 62.5 mcg/vilanterol 25 mcg (FF/UMEC/VI) prevent acute moderate to severe exacerbations, improve quality of life and reduce dyspnea symptoms as compared to combination therapy with 2 drugs (UMEC 62.5 mcg/VI 25 mcg or FF 100 mcg/VI 25 mcg or UMEC 62.5 mcg/FF 100 mcg), all administered once daily as a single inhaler or multiple inhalers, in adult patients with symptomatic COPD (diagnosed FEV1/FVC <0.70) who are not adequately treated by a combination of an ICS/LABA (i.e. classified as Group D in the GOLD report)?
Ovid MEDLINE, MEDLINE In-Process, MEDLINE Ahead of Print, Ovid Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and EBSCO CINAHL were searched from dates of inception until June 2018. We also searched clinicaltrials.gov, Drugs@FDA, European Medicines Agency public assessment reports and the manufacturer’s website for all relevant RCT reports. Reports prepared by independent groups such as FDA, Health Canada, European Medicines Agency (EMA), Prescrire, NICE, AHRQ and Drug Therapy Bulletin (DTB) were retrieved and summarized. Outcomes were analyzed in order of clinical importance (i.e. a health outcome hierarchy) recognizing that not all outcomes are of equivalent value and not all evidence has uniform protection against bias. Meta-analysis was carried out whenever possible. Risk of bias was assessed according to the Cochrane risk of bias tool and helped to inform conclusions.
- Summary of Available Evidence
Only IMPACT 2018, a double blind RCT in 10,355 patients with symptomatic COPD and a history of exacerbation within a year before enrolment met the inclusion criteria for this review. This 1-year study compared triple therapy with FF/UMEC/VI (n=4151) with UMEC/VI (n=4134) and FF/VI (n=2070), all administered once daily as a single inhaler, in patients who were classified as Group D, using the GOLD criteria. The same drugs and doses of ICS, LABA and LAMA were used in the triple-therapy and comparator groups. No studies were identified that compared FF/UMEC/VI with FF/UMEC.
The mean age of study participants was 65.3 (± 8.3) years, 66% male, and 65% former smokers. Post-bronchodilator FEV1 was 45.5% of predicted normal value and a mean CAT score of 20.1 (± 6.1) at screening. Fourty-seven percent and 26% had a history of ≥2 moderate COPD exacerbations and ≥1 severe COPD exacerbation, respectively. Patients with a history of asthma were included in the study. Nearly 40% of the patients were receiving triple therapy, and more than 70% were receiving ICS at baseline.
9087 patients (88%) completed the trial and 7991 (77%) completed the trial while receiving randomized therapy. This study used intention to treat to analyze safety and efficacy. Patients who permanently discontinued study treatment did not receive further evaluation but were encouraged to continue in the study by participating in telephone contacts in order to assess exacerbations, SAEs and concomitant medications post-treatment. The proportion of patients successfully contacted was not reported. The accuracy and completeness of phone call information was not reported. Vital status was available for 9781 (94.4%) of the total study population at Week 52.
Given that nearly 40% of the patients were receiving triple therapy and more than 70% were receiving a COPD regimen that included ICS at randomization, a major confounder in IMPACT 2018 is “stepping down” of therapy in patients randomized to either dual therapy group. In particular, ICS was abruptly withdrawn at randomization in those patients assigned to the dual bronchodilator (UMEC/VI) group, which included patients with a history of asthma. Evidence from at least 2 double blind, placebo controlled, parallel group RCTs in moderate to severe COPD patients with a history of exacerbations report that abrupt withdrawal of ICS increased the risk of moderate or severe exacerbations [RR 1.6 (95% CI 1.2,2.2); HR 1.5 (95% CI 1.1,2.1)].
IMPACT 2018 was judged to have a high risk of bias according to the Cochrane Risk of Bias Tool with respect to attrition, selective reporting and source of funding. There are also other biases with respect to study design and presence of confounding that misrepresent the treatment effect.
- Results and Interpretation
IMPACT 2018 randomized patients with symptomatic COPD and a history of exacerbations despite being on triple therapy (38%) and combination therapy with ICS/LABA (29%) or LAMA/LABA (9%) at baseline.
The published study reports on total mortality during treatment, whereas the Supplementary Appendix provides data on all-cause mortality that occurred on- and off-treatment for 94.4% of randomized patients. Time-to-first-event analysis found that the reduction in total mortality with triple therapy was statistically significant [HR 0.71(95% CI 0.51,0.99); p=0.043] as compared to UMEC/VI. There was no difference in the time-to-event analysis of mortality between triple therapy and FF/VI group. Our independent analysis of mortality events (not time-to-event) during the 1-year study found the differences in total mortality between triple therapy with FF/UMEC/VI were not statistically significant: FF/UMEC/VI versus FF/VI = 89 (2.1%) vs 97 (2.4%) RR 0.91 (0.69,1.21) and FF/UMEC/VI versus UMEC/VI = 89 (2.1%) vs 60 (2.9%) RR 0.74 (0.54,1.02) The discrepancy between the time-to-event analysis performed by the study authors and our analysis cannot be explained by available data.
Total SAEs (which includes all cause hospitalization and hospitalization due to severe exacerbation), total adverse events and withdrawal due to adverse events were not reduced with triple therapy as compared to either dual therapy combination. The risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with UMEC/VI but not with FF/VI. However, this event rate is not reported on the total patient population.
The study reports a reduction in the annual rate of moderate or severe exacerbations with triple therapy [rate ratio 0.75 (95% CI 0.70,0.81); 25% difference; P<0.001 versus UMEC/VI; rate ratio 0.85 (95% CI 0.80,0.90); 15% difference; P<0.001 versus FF/VI]. However, these rates do not include full reporting of about 25% of the study sample (18, 25 and 27% in UMEC/FF/VI, FF/VI and UMEC/VI, respectively). Also, the number of patients with one or more moderate or severe exacerbation was not reported. Instead, the paper reports the average number of exacerbations in a group. Patients with 2-3 exacerbations in a year are very different than people with 0 to 1 in the study period, but their differences are hidden in an ‘average’ annual rate. The number of patients with one or more exacerbations could, in fact, be similar in the two groups, which changes the clinical relevance of this finding.
The annual rate of severe exacerbations was significantly lower with UMEC/FF/VI as compared to UMEC/VI [rate ratio 0.66 (95% CI 0.56,0.78); P<0.001] but was not significantly lower compared with FF/VI. The number of patients hospitalized due to severe exacerbation is not reported. Only presenting the average number of severe exacerbations is similar to only reporting total exacerbations, noted above.
Total SAEs, which includes hospitalizations for reasons other than exacerbations of COPD were not significantly reduced with triple therapy. Total SAEs provides the best summary statistic of therapeutic impact accounting for all known and unknown serious impact (benefit and harm) from therapy.
Time-to-first-event analysis found that triple therapy was associated with a lower risk of moderate or severe exacerbations during treatment than either dual therapy [HR 0.85 (95% CI 0.80 to 0.91; 15% difference; P<0.001 versus FF/VI; HR 0.84 (95% CI 0.78 to 0.91; 16% difference; P<0.001 versus UMEC/VI]. However, time-to-first-event analysis cannot be interpreted correctly without knowing how many patients had more than one exacerbation during the study period. In addition, time-to-first-event analysis is biased by an increase in exacerbations following abrupt withdrawal of ICS and LAMA in the UMEC/VI group and FF/VI groups, respectively.
Quality of life (SGRQ) and dyspnea symptoms (TDI) were evaluated in 49 and 76% of randomized patients, respectively. Triple therapy improved SGRQ and TDI scores, in these subgroups, but the results are not considered valid due to missing data.
Use of rescue salbutamol, a protocol-defined endpoint, was not reported in the published study. This is a key outcome measure that needs to be reported to corroborate any claim regarding symptomatic improvement in patients.
COPD related health care utilization, which includes physician visits/ER visits and hospitalizations, is another protocol-defined endpoint that was not reported in the published material. These findings would corroborate the findings of decreased rate of acute moderate to severe exacerbation.
In a subset of 7916 (76%) patients evaluated, triple therapy improved trough FEV1 more than dual therapy comparators. The finding of improved FEV1 with triple therapy is unreliable, because the FEV1 values are unreliable and because data for 24% of randomized patients are missing.
There is insufficient evidence that triple therapy with FF/UMEC/VI provides therapeutic advantage versus dual therapy (FF/VI or UMEC/VI) in terms mortality, total serious adverse events (which includes all cause hospitalization and hospitalization due to severe exacerbation), moderate exacerbations, total adverse events or withdrawal due to adverse events, COPD symptoms or quality of life.
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