Effects of baseline symptom burden on treatment response in COPD

Abstract

Rationale

In symptomatic patients with COPD, the decision whether to initiate maintenance treatment with a single agent or a combination of long-acting bronchodilators remains unclear.

Objective

To investigate whether baseline symptomatic status influences response to tiotropium/olodaterol treatment.

Materials and methods

Post hoc analysis of the randomized OTEMTO^® studies (NCT1964352; NCT2006732), in which patients with moderate-to-severe COPD received placebo, tiotropium 5 µg, tiotropium/olodaterol 2.5/5 µg, or tiotropium/olodaterol 5/5 µg once daily for 12 weeks via the Respimat^® inhaler (Boehringer Ingelheim, Ingelheim am Rhein, Germany). Impact of baseline symptomatic status (modified Medical Research Council [mMRC] score) on response to treatment with tiotropium/olodaterol 5/5 µg, tiotropium 5 µg, or placebo at Week 12 was assessed by St George’s Respiratory Questionnaire (SGRQ) total score and response rate, transition dyspnea index (TDI) focal score and response rate, and trough forced expiratory volume in 1 second response.

Results

Tiotropium/olodaterol improved SGRQ total scores and response rates compared with placebo and tiotropium for patients with baseline mMRC scores 0–1 and ≥2. For tiotropium/olodaterol vs tiotropium, greater improvements were observed for patients with mMRC ≥2 (SGRQ score adjusted mean treatment difference −3.44 [95% CI: −5.43, −1.46]; P=0.0007; SGRQ response rate ORs 2.09 [95% CI: 1.41, 3.10]; P=0.0002). Dyspnea, measured by TDI score, was consistently improved with tiotropium/olodaterol vs placebo for patients with mMRC scores 0–1 and ≥2 (adjusted mean treatment difference 1.63 [95% CI: 1.06, 2.20]; P<0.0001 and 1.60 [95% CI: 1.09, 2.10]; P<0.0001, respectively). In patients with mMRC scores 0–1 and ≥2, tiotropium/olodaterol consistently improved TDI response rate and lung function vs placebo and tiotropium.

Conclusions

Patients with COPD with more severe baseline dyspnea appear to derive greater health status benefit with tiotropium/olodaterol compared with tiotropium alone.

Keywords:

• tiotropium
• olodaterol
• COPD

Supplementary materials

Supplementary S1

Details of ethics committees for participating centres

UZ Brussel, Commissie voor Medische Ethiek, Laarbeeklaan 101, 1090 Brussel, Belgium

IRB Services, 372 Holland Trail, Suite 300, Aurora, Ontario, L4G 0A5, Canada

Health Research Ethics Board of Alberta Clinical Trials Committee, 1500, 10104 – 103 Avenue NW, Edmonton, Alberta, T5J 4A7, Canada

Etiska komise pro multicentricka klinicka hodnoceni, Fakultni nemocnice v, Motole V Uvalu 84, 15006, Praha 5, Czech Republic

De Videnskabsetiske Komitéer for Region Syddan-mark Sundhedssekretariatet, Damhaven 12, 7100 Vejle, Denmark

Varsinais-Suomen sairaanhoitopiirin kuntayhtymän eettinen toimikunta, Kiinamyllynkatu 4-8, 20521 Turku, Finland

Ethikkommission der Ärztekammer Schleswig-Holstein, Bismarckallee 8-12, 23795 Bad Segeberg, Germany

NRES Committee North West – Greater Manchester Central, 3rd Floor, Barlow House, 4 Minshull Street, Manchester, M1 3DZ, UK

Comité Ético de Investigación Clínica del Hospital Universitario Puerta de Hierro Majadahonda, C/Joaquín Rodrigo, 2, 28222-Majadahonda, (Madrid) Spain

UCT Ethics Faculty of Health Sciences, Room E52-23, Groote Schuur Hospital, Old Main Building, Observatory, 7925, South Africa

Ste llenbosch Ethics, Health Research Ethics Committee Division of Research and Support, PO Box 19063, Tygerberg 7505, 021 938 9677, South Africa

Pharma Ethics, 123 Amcor Road, Lyttelton Manor, Pretoria, South Africa

Chesapeake IRB, 6940 Columbia, Gateway Drive Suite 110, Columbia, MD 21046-3403, USA

Mercy St Vincent, Medical Center Adult IRB, 2213 Cherry Street, Toledo, OH 43608, USA

Sir Charles Gairdner, Human Research Ethics Committee, A Block, Hospital Avenue, Nedlands, Perth, Australia

Southern Adelaide Clinical Human Research Ethics Committee, Bedford Park 5042, Adelaide, Australia

Bellberry Human Research Ethics Committee, 129 Glen Osmond Road, Eastwood, Adelaide, Australia

Sydney Local Health District Human Research Ethics Committee – Concord Repatriation General Hospital, Sydney, Australia

CEC Ethikkommission des Landes Oberösterreich Wagner-Jauregg-Weg 15, 4020 Linz, Austria

LEC 43004, Ethikkommission des Landes Steiermark, Abt 8, FAGPSanitätsdirektion Amt der Steiermärkischen, Landesregierung, Friedrichgasse 9/E/28, 8010 Graz, Austria

EED Leoforos Mesogion, 284, P.C: 15562, Cholargos, Athens

Northern A Health and Disability Ethics Committee, Ministry of Health, 1–3 The Terrace, PO Box 5013, Wellington 6011, New Zealand

Regional komité for medisinsk og helsefaglig forskningsetikk (REK sør-øst), Sweden

CEC (LEC 42104 site): Eticka komisia Presovskeho, samospravneho kraja, Urad Presovskeho, samospravneho kraja, Namestie mieru 208001 Presov, Slovakia

LEC: Eticka komisia Narodny ustav tuberkulozy, plucnych, chorob a hrudnikovej chirurgie 059 84 Vysne Hagy, Slovakia

LEC: Eticka komisia Urad Kosickeho, samospravneho kraja, Namestie Maratonu, Mieru 1, 042 66 Kosice, Slovakia

LEC: Eticka komisia, Nemocnica s, poliklinikou sv. Jakuba, Bardejov, ul. Sv. Jakuba 21, 085 01 01 Bardejov, Slovakia

Regionala Etikprövningsnämnden, i Lund, Box 133, 221 00 Lund, Sweden.

Figure S1 Study design of OTEMTO^® 1 and 2.

Abbreviation: R, randomization.

Figure S2 Forest plot of SGRQ response after 12 weeks versus baseline variables for (A) all treatment groups and (B) T/O 5/5 µg treatment group.

Abbreviations: GOLD, Global Initiative for Chronic Obstructive Lung Disease; mMRC, modified Medical Research Council; O, olodaterol; SGRQ, St George’s Respiratory Questionnaire; T, tiotropium.

Acknowledgments

Medical writing assistance was provided by Gail Rickard, PhD, of Complete HealthVizion, which was contracted and compensated by Boehringer Ingelheim Pharma GmbH & Co. KG. The study was sponsored by Boehringer Ingelheim Pharma GmbH & Co. KG.

Author contributions

FJM contributed to the design and conduct of the study, and wrote the first draft of the manuscript. RA, GTF, LB, and DS contributed to the design and conduct of the study. LG was involved in all aspects of the design, conduct, and data analysis of the study. FV provided statistical support and was involved in the data analysis of this post hoc study. All authors contributed to data analysis, drafting and revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

FJM reports grants from NHLBI during the conduct of the study, grants from National Institutes of Health, personal fees from Continuing Education, Forest Laboratories, GlaxoSmithKline, Nycomed/Takeda, AstraZeneca, Boehringer Ingelheim, Bellerophon Therapeutics (formerly Ikaria), Genentech, Novartis, Pearl, Roche, Sunovion, Theravance, CME Incite, Annenberg Center for Health Sciences at Eisenhower, Integritas, InThought, National Association for Continuing Education, Paradigm Medical Communications, LLC, PeerVoice, UpToDate, Haymarket Communications, Western Society of Allergy and Immunology, ProterixBio (formerly Bioscale), Unity Biotechnology, Concert Pharmaceuticals, Lucid, Methodist Hospital, Columbia University, Prime Healthcare Ltd, WebMD, PeerView Network, California Society of Allergy and Immunology, Chiesi, and Puerto Rico Thoracic Society, and advisory board participation for Janssen. RA reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline, and grants from Pearl Therapeutics. GTF reports consulting and advisory board fees from Boehringer Ingelheim, AstraZeneca, Pearl Therapeutics, Novartis, Forest, Sunovion, and Verona, consulting fees from Receptos, speaker fees from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Pearl Therapeutics, Forest, and Sunovion, and research grants from Boehringer Ingelheim, AstraZeneca, Pearl Therapeutics, Sunovion, Novartis, Theravance, Sanofi, Forest, and GlaxoSmithKline. LB reports advisory board participation or personal fees for lectures from ALK, Airsonett, AstraZeneca, Boehringer Ingelheim, Chiesi, Glaxo SmithKline, Novartis, Takeda, and Teva. FV is an employee of Boehringer Ingelheim. LG was an employee at the time of the conduct of the study, and is currently employed by CSL Behring. DS reports personal fees from Apellis, Cipla, Genentech, Peptinnovate, and Vectura (formerly Skyepharma), and grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Glenmark, Merck, Mundipharma, Novartis, Pfizer, Pulmatrix, Teva, Theravance, and Verona. The authors report no other conflicts of interest in this work.