Extrafine triple therapy delays COPD clinically important deterioration vs ICS/LABA, LAMA, or LABA/LAMA

Abstract

Background

Current pharmacological therapies for COPD improve quality of life and symptoms and reduce exacerbations. Given the progressive nature of COPD, it is arguably more important to understand whether the available therapies are able to delay clinical deterioration; the concept of “clinically important deterioration” (CID) has therefore been developed. We evaluated the efficacy of the single-inhaler triple combination beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G), using data from three large 1-year studies.

Methods

The studies compared BDP/FF/G to BDP/FF (TRILOGY), tiotropium (TRINITY), and indacaterol/glycopyrronium (IND/GLY; TRIBUTE). All studies recruited patients with symptomatic COPD, FEV₁ <50%, and an exacerbation history. We measured the time to first CID and to sustained CID, an endpoint combining FEV₁, St George’s Respiratory Questionnaire (SGRQ), moderate-to-severe exacerbations, and death. The time to first CID was based on the first occurrence of any of the following: a decrease of ≥100 mL from baseline in FEV₁, an increase of ≥4 units from baseline in SGRQ total score, the occurrence of a moderate/severe COPD exacerbation, or death. The time to sustained CID was defined as: a CID in FEV₁ and/or SGRQ total score maintained at all subsequent visits, an exacerbation, or death.

Results

Extrafine BDP/FF/G significantly extended the time to first CID vs BDP/FF (HR 0.61, P<0.001), tiotropium (0.72, P<0.001), and IND/GLY (0.82, P<0.001), and significantly extended the time to sustained CID vs BDP/FF (HR 0.64, P<0.001) and tiotropium (0.80, P<0.001), with a numerical extension vs IND/GLY.

Conclusion

In patients with symptomatic COPD, FEV₁ <50%, and an exacerbation history, extrafine BDP/FF/G delayed disease deterioration compared with BDP/FF, tiotropium, and IND/GLY.

Trial registration

The studies are registered in ClinicalTrials.gov: TRILOGY, NCT1917331; TRINITY, NCT1911364; TRIBUTE, NCT2579850.

Keywords:

• anticholinergics
• beta-2 agonists
• chronic obstructive pulmonary disease
• disease activity
• inhaled corticosteroids

Data availability

Chiesi commits to sharing with qualified scientific and medical researchers, conducting legitimate research, the anonymized patient-level data, the study-level data, the clinical protocol and the full CSR of Chiesi Farmaceutici SpA-sponsored interventional clinical trials in patients for medicines and indications approved by the European Medicines Agency and/or the US Food and Drug Administration after 1 January 2015.

Chiesi commits to sharing the clinical data of TRILOGY (NCT1917331) and TRINITY (NCT1911364) studies starting from 1 January 2019, following the approval of any received research proposal and the signature of a Data Sharing Agreement. Chiesi provides access to clinical trial information consistently with the principle of safeguarding commercially confidential information and patient privacy. To date, TRIBUTE (NCT2579850) is out of scope of the Chiesi policy on clinical data sharing.

Other information on Chiesi’s data sharing commitment, access, and research request’s approval process will be available from 1 January 2019 in the Clinical Trial Transparency section of this webpage page: http://www.chiesi.com/en/research-and-development/.

Supplementary materials

Figure S1 TRILOGY: Time to sustained CID (without TDI), alternative definition.

Notes: Time to sustained CID was defined as: a CID in FEV₁ and/or SGRQ total score maintained at all subsequent visits; a moderate/severe exacerbation followed by a CID in FEV₁ and/or SGRQ total score at all subsequent visits, or the exacerbation resulted in study discontinuation, or they had at least one further exacerbation; or death.

Abbreviations: CID, clinically important deterioration; BDP, beclometasone dipropionate; FF, formoterol fumarate; G, glycopyrronium; TDI, Transition Dyspnea Index; SGRQ, St George’s Respiratory Questionnaire.

Figure S2 TRILOGY: Time to sustained CID (with TDI), alternative definition.

Notes: Time to sustained CID was defined as: a CID in FEV₁ and/or SGRQ total score and/or TDI focal score maintained at all subsequent visits; a moderate/severe exacerbation followed by a CID in FEV₁ and/or SGRQ total score and/or TDI focal score at all subsequent visits, or the exacerbation resulted in study discontinuation, or they had at least one further exacerbation; or death.

Abbreviations: CID, clinically important deterioration; BDP, beclometasone dipropionate; FF, formoterol fumarate; G, glycopyrronium; TDI, Transition Dyspnea Index; SGRQ, St George’s Respiratory Questionnaire.

Figure S3 TRINITY: Time to sustained CID, alternative definition.

Notes: Time to sustained CID was defined as: a CID in FEV₁ and/or SGRQ total score maintained at all subsequent visits; a moderate/severe exacerbation followed by a CID in FEV₁ and/or SGRQ total score at all subsequent visits, or the exacerbation resulted in study discontinuation, or they had at least one further exacerbation; or death.

Abbreviations: CID, clinically important deterioration; BDP, beclometasone dipropionate; FF, formoterol fumarate; G, glycopyrronium; SGRQ, St George’s Respiratory Questionnaire.

Figure S4 TRIBUTE: Time to sustained CID, alternative definition.

Notes: Time to sustained CID was defined as: a CID in FEV₁ and/or SGRQ total score maintained at all subsequent visits; a moderate/severe exacerbation followed by a CID in FEV₁ and/or SGRQ total score at all subsequent visits, or the exacerbation resulted in study discontinuation, or they had at least one further exacerbation; or death.

Abbreviations: CID, clinically important deterioration; BDP, beclometasone dipropionate; FF, formoterol fumarate; G, glycopyrronium; IND/GLY, indacaterol/glycopyrronium; SGRQ, St George’s Respiratory Questionnaire.

Table S1 Number (%) of patients with a sustained CID overall and by individual component

Acknowledgments

The authors would like to thank the investigators and patients at the investigative sites for their support of these studies.

Writing support was provided by David Young of Young Medical Communications and Consulting Ltd. This writing support was funded by Chiesi Farmaceutici SpA. TRILOGY, TRINITY, and TRIBUTE were funded by Chiesi Farmaceu-tici SpA. Employees of Chiesi Farmaceutici were involved in the design and conduct and interpretation of the analyses reported in this article, and (as authors) in the development of the manuscript.

Disclosure

DS is supported by the National Institute for Health Research (NIHR) Manchester Biomedical Research Centre (BRC). DS received personal fees from Chiesi during the conduct of these studies. Outside the submitted work, DS reports grants and personal fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Glenmark, Johnson and Johnson, Merck, NAPP, Novartis, Pfizer, Takeda, Teva, Theravance, and Verona, and personal fees from Genentech and Skyepharma. LMF reports grants, personal fees, and non-financial support from Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Merck Sharp & Dohme, Takeda, AstraZeneca, Novartis, Menarini, Laboratori Guidotti, and Almirall; personal fees and non-financial support from Pearl Therapeutics, Mundipharma, and Boston Scientific; personal fees from Kyorin, Bayer, and Zambon; and grants from Pfizer, Dompè, Malesci, Alfasigma, and Vree Health Italia, all outside the submitted work. SV and SP are employed by Chiesi, the sponsor of the studies. AP reports grants, personal fees, non-financial support, and advisory board membership from Chiesi, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Mundipharma, and TEVA; personal fees and non-financial support from Menarini, Novartis, and Zambon; and grants from Sanofi, all outside the submitted work. The authors report no other conflicts of interest in this work.