Methods
Study design and objectives
Between April 2017 and October 2018, we conducted a phase II study in 64 centers in 9 countries (GSK protocol 205,724;
ClinicalTrials.gov identifier NCT03034967). The study protocol, any amendments, the informed consent, and other information that required pre-approval were reviewed and approved by a national, regional, or investigational center ethics committee or institutional review board. The study was conducted in accordance with the revised Declaration of Helsinki (2008), International Council for Harmonisation guidelines for Good Clinical Practice, and all applicable regulatory requirements. Full written informed consent was obtained from all participants before the performance of any study-specific procedures.
Consenting males or females, aged 40–80 years of age with a current diagnosis of COPD based on American Thoracic Society/European Respiratory Society guidelines [
8] (postbronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC] ratio < 0.7 and FEV1% predicted ≥40% [
9]) and with a smoking history of ≥10 pack years were eligible to participate in the study. Eligible participants were required to have a history of respiratory symptoms including chronic cough, mucus hypersecretion, and dyspnea on most days for at least the previous 3 months prior to screening, and a documented history of COPD exacerbations in the 12 months prior to study participation (≥2 moderate-severe exacerbations or 1 moderate-severe exacerbation plus a screening plasma fibrinogen concentration of ≥3 g/L [
10‐
12]). Full inclusion and exclusion criteria are described in the online supplement.
The study was a randomised, double-blind, placebo-controlled, parallel-group study. Following a screening visit and completion of the run-in period assessments, participants were randomised (1:1:1:1:1:1) using an interactive voice response system to receive oral danirixin hydrobromide salt tablets (5, 10, 25, 35 or 50 mg) or placebo tablets for 24 weeks (in addition to COPD standard-of-care). The dose range used was based on a relative bioavailability study comparing two formulations of danirixin, which demonstrated that the danirixin hydrobromide salt has approximately twice the bioavailability of danirixin free base (used in the previous Phase 2a study) [
13]. The dose range tested would allow estimation of the danirixin dose-response curve; the top dose of 50 mg was chosen to avoid exposures that could exceed the safety margin required based on non-clinical safety assessment studies.
The primary endpoints were safety (adverse events (AEs), vital signs, 12-lead electrocardiogram, clinical laboratory and hematological evaluations) and the change from baseline in respiratory symptoms measured by the E-RS: COPD daily diary at month 6, both total score and subscales (i.e., breathlessness, cough and sputum, and chest symptoms). Secondary endpoints included HCRU-defined COPD exacerbations, time to first HCRU-defined COPD exacerbation, number of EXAcerbations of Chronic Pulmonary Disease Tool (EXACT) tool defined events, change from baseline in the St. George’s Respiratory Questionnaire (SGRQ) total score (derived from St. George’s Respiratory Questionnaire – COPD specific [SGRQ-C]), change from baseline of the COPD Assessment Tool (CAT) total score, lung function (FEV1, FEV1% predicted, FVC, FEV1/FVC ratio), rescue medication use, participant experience of physical activity (subset of participants) measured using Clinic Visit PROactive Physical Activity in COPD (CPPAC), and pharmacokinetics. Biomarker assessments included measurements of systemic inflammation (i.e., C-reactive protein [CRP] and fibrinogen), and markers of extracellular matrix turnover.
Assessment methodology
Respiratory symptoms were evaluated using the E-RS: COPD, an 11-item, patient-reported outcome instrument completed each evening using an electronic diary (eResearch Technology, Inc. [Philadelphia, PA, USA]) as part of the 14-item EXACT [
14,
15], which was also measured as part of the study. The E-RS: COPD yields a total score, quantifying respiratory symptom severity overall, with a score range of 0–40 and higher scores indicating more severe symptoms. It has been suggested that score changes ≥2 are clinically meaningful [
14,
15]. Three domain or subscale scores assess breathlessness (scores 0–17, meaningful change 1.0 point), cough and sputum (0–11; meaningful change 0.7) and chest symptoms (0–12; meaningful change 0.7). Monthly weighted mean scores for E-RS: COPD total and domain scores were calculated. Baseline scores were defined as the average score over days 1–7 of the run-in period. Responders were defined as those with a change from baseline equal to or greater than the minimal clinically important difference (MCID).
Symptom-defined exacerbations were identified using the EXACT [
16]. This instrument assesses the severity of respiratory and systemic manifestations of a COPD exacerbation as reported by the patient to capture the occurrence, frequency, severity, and duration of symptom-defined events. The EXACT total score ranges from 0 to 100; higher scores indicate more severe symptoms, with sustained worsening > 9 points for 3 days or 12 or more points for 2 days constituting the onset of a symptom-defined event.
COPD-related health status was assessed during clinic visits at days 1, 84 and 168 and follow-up using the 8-item CAT questionnaire [
17]. Patients rated their experience on a 6-point scale, where 0 = no impairment and 5 = maximal impairment, summed to yield a total score range of 0–40. Higher scores indicate greater disease impact. Responders were defined as patients with health status improvement indicated by a decrease from baseline in CAT score of ≥2 [
18].
The SGRQ-C is an FDA-qualified, COPD disease-specific questionnaire derived from the SGRQ, designed to measure the impact of respiratory disease and its treatment on a COPD patient’s HRQoL [
19]. The SGRQ-C comprises of 40 questions, and total score and MCID are equivalent to the SGRQ instrument [
20]. Responders were defined as those with a decrease from baseline equal to or greater than the MCID, defined as a 4-point improvement (decrease) [
21].
Actigraph GT9X activity monitors were provided by Actigraph (Pensacola, FL, US), and issued to a subset of consenting participants for physical activity monitoring. Methods for assessment of PK concentrations and biomarkers were as previously described [
22‐
24].
Statistical analyses
The sample size estimations were based on the primary efficacy endpoint of change from baseline in respiratory symptoms measured by E-RS: COPD daily diary at month 6. Based on simulations, a sample size of at least 600 participants (100 in each of the 6 study treatment groups) was used to allow for adequate precision in estimation of the 35 mg DNX dose as well as a sufficient proportion with 90% confidence interval (CI) difference from placebo excluding 0, and a sufficient proportion with 90% CI of dose estimate excluding 0.
Three interim analyses were planned and performed for this study: 1) The first interim analysis was an evaluation of DNX PK conducted after 10 participants in each treatment group had participated in the PK sub-study; 2) an interim analysis for futility based on the E-RS: COPD endpoint was conducted after approximately 150 participants had completed 3 months of study treatment; and 3) a third interim analysis was conducted after 450 participants had completed 6 months of study treatment. The interim analyses were performed for the purpose of internal decision making and no changes were made to the study conduct based on the results of the interim analyses.
The modified Intent-to-Treat (mITT) Population comprised all randomized participants apart from those who were randomized in error (i.e. were also recorded as screen or run-in failures and did not receive a dose of study treatment). Randomized participants were assumed to have received study medication unless definitive evidence to the contrary exists. All data summaries and analyses for this population were based on the actual treatment received, if it was different to the randomized treatment. This population constituted the primary population for all study population and safety analyses. The per protocol (PP) population comprised all participants from the mITT population who did not have a protocol deviation considered to impact efficacy.
A Bayesian dose response model of maximum observed efficacy (Emax) was used to determine the dose-response curve for the primary efficacy endpoint of this study, the change from baseline in respiratory symptoms by ERS: COPD at month 6. The dose-response model was fitted to the data using Bayesian techniques using functional uniform priors for the ED50 (dose that yields 50% of the maximal response) and m (dose-response slope) parameters and non-informative priors for E0 and Emax. The log-linear, 3-parameter Emax and 4-parameter Emax models were fitted and the best fitting model was presented. Where possible, covariates (i.e., baseline, smoking status, country) were included in the E0 and Emax terms of the selected model. This endpoint was assessed in the PP Population. Posterior mean change, standard deviation (SD), posterior median and 90% credible intervals were presented for the change from baseline for all treatment arms and all pairwise differences between each DNX dose and placebo. The posterior probability of a difference from placebo of < 0, − 0.5, − 1, − 1.5 and − 2 was presented for each DNX dose.
For secondary efficacy analyses, a Bayesian generalized linear model assuming a negative binomial distribution for the underlying exacerbation rate with a log link function was used to determine the annual rate of on-treatment moderate/severe HCRU exacerbations and EXACT events. A Bayesian proportional hazards model was used to determine time to first on-treatment moderate/severe HCRU exacerbation, time to first on-treatment severe HCRU exacerbation and time to first on-treatment EXACT event. A generalized linear mixed model was used to determine response according to E-RS:COPD total score, subscale scores, CAT score and SGRQ total score.
A frequentist mixed model repeated measures was used to analyze change from baseline post-bronchodilator FEV1 and FVC. PK parameters were calculated by standard non-compartmental analysis using Phoenix WinNonlin Version 7.0. All calculations of non-compartmental parameters were based on actual sampling times and were performed for the sub-set of participants providing serial blood samples for PK.
Acknowledgements
The authors thank the patients and their families, as well as the following principal investigators and their institutions for their contributions to the study:
Australia: Philip Bardin (Monash Medical Centre, Clayton, Victoria), Peter Bremner (TrialsWest, Murdoch, Western Australia), David Langton (Frankston Hospital, Frankston, Victoria), Anne-Marie Southcott (Footscray Hospital, Footscray, Victoria), Paul S. Thomas (Prince of Wales Hospital, Randwick, New South Wales), John Wheatley (Westmead Hospital, Westmead, New South Wales). Canada: Kenneth R. Chapman (Inspiration Research Limited, Toronto, ON), Murdo Ferguson (Colchester Research Group, Truro, NS), Lawrence A. Homik (Concordia Hospital, Winnipeg, MB), Francois Maltais (Institut universitaire de Cardiologie et de Pneumologie de Quebec, Quebec, QC), Bonavuth Pek (Clinique de Pneumologie et du Sommeil de Lanaudiere, Borromee, QC), Eric St-Amour (Q&T Research Qutaouais Inc., Gatineau, QC). Germany: Tamara Eckermann (Praxisgemeinschaft Heimeranplatz, Muenchen, BY), Andreas Eich (IKF Pneumologie GmbH & Co. KG, Frankfurt, HE), Guido Ern (Praxis Dr. med. Ludger Lindemann, Gelsenkirchen, NW), Karin Foerster (Gem. Praxis Drs. Karin und Andreas Foerster, Berlin, BE), Andreas Forster (Pneumostudien Darmstadt, Darmstadt, HE), Martin Hoffmann (Pneumologicum im Suedstadtforum, Hannover, NI), Claus Keller (Praxis Dr. med. Claus Keller, Frankfurt, HE), Anneliese Linnhoff (Research Centre for Medical Studies (RCMS), Berlin, BE), Ruth Nischik (medamed GmbH, Leipzig, SN), Isabelle Schenkenberger (KFB- Klinsche Forschung Berlin, Berlin, BE), Olaf Schmidt (Studienzentrum KPPK, Koblenz, RP). Republic of Korea: Joong Hyun Ahn (The Catholic University of Korea, Incheon Saint Mary’s hospital, Bupyeong-gu, Incheon), Hee Soon Chung (Seoul National University Boramae Medical center, Dongjak-gu, Seoul), Do-Jin Kim (Soonchunhyang Univ. Bucheon Hospital, Wonmi-gu, Bucheon-si), Jae Yeol Kim (Chung-Ang University Hospital, Dongjak-gu, Seoul), Sang Haak Lee (Catholic University of Korea - St.Paul’s Hospital, Dongdaemun-gu, Seoul), Yeon-Mok Oh (Asan Medical Center, Songpagu, Seoul), Myung Jae Park (Kyung Hee University Medical Center, Dongdaemun-gu, Seoul), Suk Joong Yong (Yonsai University, Wonju Severance Christian Hospital, Wonju Si, Gangwon-Do). Netherlands: Willem G. Boersma (Noordwest Ziekenhuisgroep, Alkmaar), Simone Van der Sar (Amphia Ziekenhuis, Breda), Hendrik Timmer (Ziekenhuisgroep Twente, Hengelo), (Pascal L.M.L. Wielders (Catharina Ziekenhuis, Eindhoven). Poland: Anna Olech-Cudzik (Ostrowieckie Centrum Medyczne, Ostrowiec Swietokrzyski), Krzysztof Wytrychowski (NZOZ Lekarze Specjalisci J.Malolepszy i Partnerzy, Wroclaw). Romania: Ghiulten Apti (Spitalului Clinic de Pneumoftiziologie Constanta, Constanta), Andreia Madalina Balta and Doru Didita (Spitalul de Urgenta Slobozia, Slobozia), Livia Filip (Spitalului Clinic de Pneumoftiziologie “Leon Daniello” Cluj, Cluj Napoca), Bogdan Mihai Mincu (Cabinet Medical de Pneumologie Dr. Mincu Bogdan, Cluj Napoca), Viorica Mincu (Cabinet Medical Individual Pneumologie Dr. Mincu Viorica, Ramnicu Valcea), Tatiana I. Montia (County General Emergency Hospital "Sf. Ioan Cel Nou" Suceava, Suceava), Roxana Maria Nemes (Institutului de Pneumoftiziologie “Marius Nasta”, Bucuresti), Maria Elena Scridon (Spitalul Clinic de Pneumoftiziologie Sibiu, Sibiu), Antigona Carmen Trofor (Spitatul Clinic De Pneumoftiziologie Iasi, Iasi), Dragos G. Ungurean (Spitalul de Pneumoftiziologie Bacau, Bacau). Spain: Ramon Agüero Balbín (Hospital Marques de Valdecilla, Santander), Miguel Barrueco Ferrero (Hospital Universitario de Salamanca, Salamanca), José Maria Echave-Sustaeta (Hospital Quirón Madrid, Madrid), José María Marín Trigo (Hospital Universitario Miguel Servet, Zaragoza), Eduardo Monso Mola (Corporacio Sanitaria Parc Tauli, Barcelona), Sergi Pascual Guardia (Hospital del Mar, Barcelona), Germán Peces-Barba Romero (Fundación Jiménez Díaz, Madrid). United States: Roger A. Abrahams (Morgantown Pulmonary Clinical Research, Morgantown, WV), Thomas M. Hyers (CARE Clinical Research, LLC, Saint Louis, MO), Edward M. Kerwin (Crisor, LLC c/o Clinical Research Institute of Southern Oregon Inc., PC, Medford, OR), Shawn M. Magee (Cotton O’Neil Clinical Research Center, Topeka, KS), Murali Ramaswamy (Pulmonix LLC, Greensboro, NC), Richard Elliot Sterling (Carolina Research, Orangeburg, SC), James Michael Wells (UAB Lung Health Center, Birmingham, AL).
The authors also acknowledge the contributions of the following GSK employees: Faye Jamali, Rosalida Leone, Elliza Naseem, Poonam Kocharekar and Jackie Bloomer.
Ethics approval and consent to participate
After institutional review board approval was provided at each institution, written informed consent was obtained from each patient or the patient’s legally authorized surrogate prior to conduct of study-specific procedures.
Australia: Monash Medical Centre, 246 Clayton Road, Clayton, 3168; Bellberry Limited, 129 Glen Osmond Road, Eastwood, South Australia,
Canada: Institutional Review Board Services, Suite 300, 372 Hollandview Trail, Aurora, Ontario, L4G 0A5; Concordia Hospital Ethics Committee, 1095 Concordia Avenue, Winnipeg, Manitoba, R2K 3S8; Comité d’éthique de la recherche de l’Institut universitaire de cardiologie et de pneumologie de Qué, 2725 Chemin Ste-Foy, Quebec, Québec, G1V 4G5.
Germany: Ethikkommission Schleswig-Holstein, Bismarckallee 8–12, Bad Segeberg, 23795.
Republic of Korea: Incheon Saint Mary’s Hospital, 56, Dongsu-ro, Bupyeong-gu, Incheon, 021431; Seoul National University Boramae Medical center, 20, Boramae-ro 5-gil, Dongjak-gu, Seoul, 156–707; Soon Chun Hyang University Bucheon Hospital, 170 Jomaru-ro, Wonmi-Gu, Bucheon-Si, Gyeonggi-Do, 420–767; Chung-Ang University Hospital, 102, Heukseok-ro, Dongjak-gu, Seoul, 06973; St. Paul’s Hospital, 180, Wangsan-ro, Dongdaemun-gu, Seoul, 02559; Asan Mecial Center, Institutional Review Board, #388–1 Pungnap 2-dong, Songpa-gu, Seoul, 138–736; Kyung Hee University Medical Center, #1 Hoegi-dong, Dondaemeun-gu, Seoul, 130–702; Yonsei University, Wonju Severance Christian Hospital, 20, Ilsan-ro, Wonju, Gangwon-do, 26426.
Netherlands: St. Antonius Ziekenhuis, Koekoekslaan 1, Nieuwegein, 3435 CM, Netherlands.
Poland: Komisja Bioetyczna, ulica Sklodowskiej-Curie 11, Szczecin, 71–332.
Romania: Comisia Nationala de Bioetica a medicamentelor si a Dispozitivelor Medicale, Pavilion K, Spitalul Clinic Colentina, Sos. Stefan cel Mare nr. 19–21, Bucuresti, 20125.
Spain: Fundación Jiménez Díaz, Avenue Reyes Católicos, 2, Madrid, 28040.
United States: Advarra Institutional Review Board, Suite 110, 6940 Columbia Gateway Drive, Columbia, Maryland, 21046–3431; Western Institutional Review Board, 1019 39th Avenue South East, Suite 120, Puyallup, Washington, 98374–2115.