Efficacy and safety of coadministration of once-daily indacaterol and glycopyrronium versus indacaterol alone in COPD patients: the GLOW6 study

Figures & data

Figure 1 GLOW6 study design.

Abbreviation: od, once-daily.

Figure 2 Patient disposition, n (%).

Table 1 Baseline demographics, background characteristics, and spirometry (safety population)

	IND + GLY (N=226)	IND + PBO (N=221)
Mean (SD) age, years	63.4 (8.44)	64.1 (7.67)
Male, n (%)	180 (79.6)	186 (84.2)
Ethnicity, n (%)
Caucasian	224 (99.1)	217 (98.2)
Native American	0	1 (0.5)
Other	2 (0.9)	3 (1.4)
Severity of airflow limitation (GOLD 2013), n (%)
Moderate	139 (61.5)	148 (67.0)
Severe	87 (38.5)	73 (33.0)
Mean (SD) duration of COPD, years	7.1 (5.65)	7.2 (5.35)
Baseline COPD exacerbation history,* n (%)
0 exacerbations	158 (69.9)	156 (70.6)
1 exacerbation	57 (25.2)	46 (20.8)
≥2 exacerbations	11 (4.9)	19 (8.6)
ICS use at baseline, n (%)	138 (61.1)	142 (64.3)
Smoking history, n (%)
≥Ex-smoker	130 (57.5)	129 (58.4)
≥Current smoker	96 (42.5)	92 (41.6)
Mean (SD) duration of smoking, pack-years	44.5 (23.40)	44.4 (22.24)
Mean (SD) FEV1 postbronchodilator, L	1.5 (0.46)	1.6 (0.46)
Mean (SD) postbronchodilator FEV1 % predicted	54.2 (12.90)	55.5 (12.62)
Mean (SD) postbronchodilator FEV1 reversibility, %	19.4 (14.82)	19.6 (14.71)
Mean (SD) postbronchodilator FEV1/FVC, %	48.8 (9.83)	48.1 (10.21)

Notes:

* In the year prior to screening; duration of COPD calculated from the date first diagnosed with COPD until visit 1; pack-years = total years of smoking multiplied by cigarette packs smoked per day.

Abbreviations: COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GLY, glycopyrronium; GOLD, Global initiative for chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; IND, indacaterol; PBO, placebo; SD, standard deviation.

Table 2 Differences between treatments for primary and secondary efficacy outcomes on day 1 and at week 12 (FAS)

Variable	LSM (95% CI) treatment difference (IND + GLY vs IND + PBO)	P-value
Day 1
Trough FEV1, L	0.074 (0.046–0.101)	<0.001
Peak FEV1, L	0.108 (0.079–0.137)	<0.001
FEV1 AUC30min–4h, L	0.106 (0.080–0.132)	<0.001
Trough FVC, L	0.111 (0.054–0.167)	<0.001
IC at 30 min postdose, L	0.059 (−0.001–0.118)	0.054
IC at 2 h postdose, L	0.109 (0.039–0.179)	0.003
IC at 4 h postdose, L	0.083 (0.014–0.152)	0.019
Week 12
Trough FEV1, L (primary end point)	0.064 (0.028–0.099)	<0.001
Trough FEV1 in the PPS, L	0.064 (0.028–0.101)	<0.001
Peak FEV1, L	0.106 (0.070–0.143)	<0.001
FEV1 AUC30min–4h, L	0.111 (0.076–0.145)	<0.001
Trough FVC, L	0.093 (0.027–0.160)	0.006
IC at 25 min predose, L	0.081 (0.002–0.160)	0.043
IC at 30 min postdose, L	0.159 (0.073–0.246)	<0.001
IC at 2 h postdose, L	0.122 (0.037–0.207)	0.005
IC at 4 h postdose, L	0.138 (0.051–0.225)	0.002
IC at 24 h postdose, L	0.068 (−0.014–0.150)	0.105
TDI focal score	0.494 (0.030–0.958)	0.037
SGRQ-C total score	−1.47 (−3.42–0.48)	0.140
Over 12 weeks
Rescue-medication use
Change from baseline in mean daily number of puffs	−0.1 (−0.5–0.2)	0.471
Percentage of days with no rescue-medication use	0.2 (−6.0–6.5)	0.945
Change from baseline in mean daily total symptom score	0.0 (−0.3–0.3)	0.810
Change from baseline in mean daytime respiratory symptom score	−0.1 (−0.1–0.0)	0.025
Percentage of days able to perform usual activities	6.2 (1.2–11.3)	0.016

Note: Results of analysis in the FAS, unless otherwise stated.

Abbreviations: AUC, area under the curve; CI, confidence interval; FAS, full analysis set; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GLY, glycopyrronium 50 μg; IC, inspiratory capacity; IND, indacaterol 150 μg; LSM, least squares mean; PBO, placebo; PPS, per protocol set; SGRQ-C, St George’s Respiratory Questionnaire – COPD; TDI, transition dyspnea index; vs, versus; COPD, chronic obstructive pulmonary disease.

Figure 3 Trough FEV₁ after first dose (end of day 1) and week 12 (FAS).

Notes: *P<0.001. Data are least squares means ± standard error.
Abbreviations: FAS, full analysis set; FEV₁, forced expiratory volume in 1 second.

Figure 4 FEV₁ from 30 minutes to 4 hours postdose and 24 hours postdose (A) on day 1 and (B) at week 12 (FAS).

Notes: P<0.001 at all time points from 30 minutes to 4 hours and at 24 hours, except at 24 hours on week 12 where P<0.01. Data are least-squares means ± standard error.
Abbreviations: FEV₁, forced expiratory volume in 1 second; FAS, full analysis set.

Figure 5 Subgroup analyses of treatment differences in trough FEV₁ at week 12 (FAS).

Note: Data are least squares mean ± 95% CI.
Abbreviations: BMI, body mass index; CI, confidence interval; FAS, full analysis set; FEV₁, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LSM, least squares mean; N1, number of patients analyzed in the indacaterol + glycopyrronium treatment group; N2, number of patients analyzed in the indacaterol + placebo treatment group.

Figure 6 TDI focal score at week 12 (FAS).

Note: Data are least squares means ± standard error.
Abbreviations: FAS, full analysis set; TDI, transition dyspnea index.

Table 3 Most frequent AEs (at least three patients in either treatment group) and discontinuations due to AEs (safety population), n (%)

Preferred term	IND + GLY (N=226), n (%)	IND + PBO (N=221), n (%)
Any AE(s)	85 (37.6)	75 (33.9)
COPD worsening*	33 (14.6)	28 (12.7)
Nasopharyngitis	10 (4.4)	11 (5.0)
Lower respiratory tract infection	7 (3.1)	2 (0.9)
Cough	6 (2.7)	10 (4.5)
Back pain	4 (1.8)	3 (1.4)
Upper respiratory tract infection	4 (1.8)	5 (2.3)
Bacterial infection	3 (1.3)	0
Headache	3 (1.3)	2 (0.9)
Influenza	3 (1.3)	1 (0.5)
Pain in extremity	3 (1.3)	1 (0.5)
Upper respiratory tract infection, bacterial	3 (1.3)	4 (1.8)
Viral upper respiratory tract infection	3 (1.3)	5 (2.3)
Oropharyngeal pain	0	5 (2.3)
Discontinuation from study drug due to AE(s)	3 (1.3)	4 (1.8)

Note:

* Including COPD exacerbations.

Abbreviations: AE, adverse event; GLY, glycopyrronium 50 μg; IND, indacaterol 150 μg; PBO, placebo; COPD, chronic obstructive pulmonary disease.

Table 4 SAEs (safety population), n (%)

Primary system organ class Preferred term	IND + GLY (N=226), n (%)	IND + PBO (N=221), n (%)
Patients with any SAE(s)	5 (2.2)	5 (2.3)
Respiratory, thoracic and mediastinal disorders	2 (0.9)	2 (0.9)
COPD worsening*	1 (0.4)	2 (0.9)
Hemoptysis	1 (0.4)	0
Gastrointestinal disorders	1 (0.4)	0
Inguinal hernia	1 (0.4)	0
Immune system disorders	1 (0.4)	0
Hypersensitivity	1 (0.4)	0
Infections and infestations	1 (0.4)	1 (0.5)
Bacterial infection	1 (0.4)	0
Urinary tract infection	0	1 (0.5)
Musculoskeletal and connective tissue disorders	1 (0.4)	0
Osteitis	1 (0.4)	0
Cardiac disorders	0	1 (0.5)
Angina pectoris	0	1 (0.5)
Injury, poisoning, and procedural complications	0	1 (0.5)
Rib fracture	0	1 (0.5)
Renal and urinary disorders	0	1 (0.5)
Renal failure, acute	0	1 (0.5)

Notes:

* Including COPD exacerbations; a patient with multiple occurrences of an SAE was counted only once in the SAE category.

Abbreviations: COPD, chronic obstructive pulmonary disease; GLY, glycopyrronium 50 μg; IND, indacaterol 150 μg; PBO, placebo; SAE, serious adverse event.

Table S1 List of study centers

Belgium: UZ Brussel, 101 Avenue de Laerbeek, Brussels 1090; Longartsenpraktijk, 5 Winterslagstraat, Genk 3600; UCL Mont-Godinne, 1 Avenue Terasse, Yvoir 5530; Saint-Joseph, Sainte-Thérèse, and IMTR, 6 Rue de la Duchère, Gilly 6060; AZ Sint-Elisabeth, 133 Nederrij, Herentals 2200; Hôpital Erasme, 808 Route de Lennik, Brussels 1070; Centre Hospitalier du Luxembourg, 4 Rue Barblé, Luxembourg 1210; private practice – Dr Martinot, 93 Boulevard de la Meuse, Jambes 5100; private practice – Dr Aumann, 36/2A Prins Bisschopssingel, Hasselt 3500; private practice – Dr Delobbe, 6A Chemin des quartiers, Malmedy 4960; Centre Hospitalière Universitaire André Vésale, 706 Rue de Gozée, Montigny-le-Tilleul 6100; Centre Hospitalière Universitaire Sart Tilman, Bâtiment B 35 Sart Tilman, Liège 4000; Clinique Notre-Dame De Grâce, 212 Chee de Nivelles, Gosselies 6041; Sint-Elisabeth Ziekenhuis, 166 Rubensstraat, Turnhout 2300

Bulgaria: Medical Centre of Pneumophthisiatric Diseases EOOD, 78 Kiril i Metodii Street, Sofia 1000; MHAT Stara Zagora, 11 Armeiska Street, 6000 Stara Zagora; SHAT for Pneumophthisiatric Diseases, 1 Aleya Lilia Street, Ruse 7002; UMHAT Sveti Georgi, 66 Peshtersko Shose Boulevard, Plovdiv 4002; Military Medical Academy – MHAT, 3 Georgi Sofiiski Street, Sofia 1606; UMHAT Dr Georgi Stranski, EAD, 81 Vladimir Vazov Street, Pleven 5800; Multiprofile Hospital for Active Treatment Sveta Marina, 1 Hristo Smirnenski Street, Varna 9010; SHATPD St Sofia, 19 Ivan Geshov Boulevard, Sofia 1431

Greece: SOTIRIA General Hospital, 152 Mesogeion Avenue, Athens 11527; Papageorgiou General Hospital of Thessaloniki, Periferiaki odos Thessaloniki-Neas Efkarpias, Thessaloniki 56403; General Hospital of Athens Evangelismos, 45–47 Ipsilantou, Athens 10676

Hungary: Ujpesti Egeszsegugyi Szolgaltato, 30 Gorgey Artur Street, Budapest 1046; Csongrad Megye Mellkasi Betegsegek Szakkorhaza, 36 Alkotmany Street, Deszk 6772; Dr Romics Laszlo Egeszsegugyi Intezmeny – Tudogondozo, 40 Hivatalnok Street, Erd H-2030; Tormay Karoly Eu Kozpont Tudobeteg-Gondozo Intezete, 62 Ady Endre Setany, Godollo 2100; Orszagos Koranyi TBC es Pulmonologiai Intezet, 1 Piheno Street, Budapest 1121

Ireland: Department of Rheumatology, Clinical Investigation Unit, Cork University Hospital, Wilton, Cork

Russia: NA Semashko Regional Clinical Hospital, 190 Rodionova Street, N Novgorod 603126; Hospital 13 of Avtozavodsky Region, 51 Patriotov Street, N Novogorod 603018; RMA of Postgraduate Education of Roszdrav, 5/2-d Botkinsky Drive, Moscow 125315; Saratov State Medical University of Roszdrav, 112 Bolshaya Kazachya Street, Saratov 410012

Slovakia: Respiro – Medical, 8 Nemocnicna Street, Kralovsky Chlmec 077 01; JURMED, Ambulancia Pneumologie a Ftizeologie, 2 Smetanova Street, Kosice 040 01; NsP Jakuba, 21 Jakuba Street, Bardejov 085 01; DAMIZA, 62/30 Cerveneho Kriza Street, Námestovo 02901; Sukromna Ambulancia PaF, 1737 Pri Zeleznici Street, Liptovsky Hradok 033 01; Pulmo-Medik, 41/1656 Janka Krala Street, Bojnice 972 01; Klinika Funkcnej Diagnostiky, FNsP, 6 Ruzinovska, Bratislava 826 06

Spain: Hospital Virgen de la Victoria, Campus Universitario Teatinos, Malaga, Andalusia 29010; CAP Centelles, 7 Plaza del Mestre, Centelles, Catalonia 08540; Hospital Santa Caterina, Parc Hospitalari Martí i Julia, Dr Castany, Salt, Catalonia 17190; Hospital de Sierrallana, Barrio Ganzo, Torrelavega, Cantabria 39300; Fundacion Hospital Jove, Avenida Eduardo de Castro, Gijon, Asturias 33290; Hospital de Merida, Polígono Nueva Ciudad, Mérida, Badajoz 06800; Hospital del Bierzo, 7 Medicos Sin Fronteras, Ponferrada, Castilla y Leon 24400; Hospital de Sant Boi, 13 Bonaventura Calopa, Sant Boi de Llobregat, Catalonia 08830; Hospital de la Santa Creu i Sant Pau, 167 Avenida de Sant Antoni Ma Claret, Barcelona, Catalonia 08025

Turkey: Sibel A Nayci, Mersin University Medical Faculty, Mersin 33079; Serir A Ozkan, Dr Suat Seren Chest Disease and Surgery, Education and Research Hospital, P1 Block, 331 Gaziler Caddesi, Yenisehir/Izmir 35110; Sule M Akcay, Baskent University Medical Faculty, Sokak 45, 10 Fevzi Cakmak Caddesi, Bahcelievler, Ankara 06490; Hatice Turker, Sureyya Pasa Chest Diseases and Thoracic Surgery Training Hospital, Istanbul 34854; Emel Caglar, Yedikule Gogus Hastaliklari Egitim ve Arastirma Hastanesi, Istanbul 34020; Ahmet H Ilgazli, Kocaeli University Medical Faculty, Kocaeli 41380

United Kingdom: Jerome Kerrane, Layton Medical Centre, 200 Kingscote Drive, Layton, Blackpool FY3 7EN; Anthony Gunstone, Staploe Medical Centre, Brewhouse Lane Soham, Cambridge CB7 5JD; Christopher Strang, Mortimer Surgery, 72 Victoria Road, Mortimer, Reading, RG7 3SQ; Joanna Nash, Southbourne Surgery, 337 Main Road, Southbourne, Emsworth PO10 8JH; Raj Sharma, Sea Road Surgery, 39–41 Sea Road, Bexhill-on-Sea, East Sussex, TN40 1JJ; Trevor Gooding, Atherstone Surgery, 1 Ratcliffe Road, Atherstone, Warwickshire CV9 1EU; Ian Orpen, St James Surgery, Northampton Buildings, Bath BA1 2SR; Gavin Durrant, Rowden Medical Partnership, Rowden Hill, Chippenham, Wiltshire SN15 2SB; Anthony De Soyza, Freeman Hospital, Freeman Road, Newcastle upon Tyne NE7 7DN; Dinesh Saralaya, Bradford Royal Infirmary, Duckworth Lane, Bradford BD9 6RJ; Lindsey Crockett, Peninsula Practice Health Centre, Mill Hoo, Alderton, Suffolk IP12 3DA; Paul Ainsworth, Sherbourne Medical Centre, 40 Oxford Street, Leamington Spa, Warwickshire CV32 4RA; See Kwok, Barlow Medical Centre, 828 Wilmslow Road, Manchester M20 2RN; lan Jackson, Sheepcot Medical Centre, Sheepcot Lane, Garston, Watford WD25 0EA; Nicky Simler, Hinchingbrooke Hospital NHS Trust, Hinchingbrooke Park, Huntingdon PE29 6NT; Frances Adams, Strensall Medical Centre, Southfields Road, Strensall, Yorkshire YO32 5UA; Mark D Blagden, Avondale Surgery, 3–5 Avondale Road, Chesterfield S40 4TF; Harmesh Moudgil, Princess Royal Hospital, Apley Castle, Telford TF1 6TF; Johann Brandmair, Cobblers Hall Surgery, Carer’s Way Burn Lane, Newton Aycliffe DL5 4SE; Rina Miah, Haven Surgery, Burnhope, Durham DH7 0BD

Table S2 Medications allowed in the GLOW6 study under certain conditions

Class of medication	Condition under which medication is permitted
SSRIs	Stable dose for at least 30 days prior to the screening visit and during the study; screening ECG is normal, with no clinical evidence of prior ECG abnormalities
Inhaled corticosteroids	Stable dose for at least 30 days prior to the screening visit and during the study
Intranasal corticosteroids	Stable dose for at least 30 days prior to the screening visit
H1 antagonists	Stable dose for at least 5 days prior to the screening visit (except mizolastine or terfenadine)
Inactivated influenza, pneumococcal, or any other inactivated vaccine	Not administered within 48 hours prior to a study visit

Abbreviations: ECG, electrocardiogram; SSRIs, selective serotonin reuptake inhibitors.

Table S3 Procedure for handling missing data in the GLOW6 study

Spirometry

• FEV1, FVC, and IC measurements within 6 hours of rescue-medication use or within 7 days of systemic corticosteroid use were set to missing. Trough FEV1 was defined as the average of the postdose 23 hour 15 minute and the 23 hour 45 minute FEV1 values. The allowable window for these scheduled measurements was 22 hours 45 minutes to 24 hours 15 minutes. Values measured outside of this window were set to missing. If one of the 23 hour 15 minute or 23 hour 45 minute values was missing, the remaining nonmissing value was taken as trough FEV1. If both values were missing, trough FEV1 was regarded as missing

• For the primary analysis, if trough FEV1 was missing at visit 8 (week 12) the latest nonmissing predose trough FEV1 (the mean of 45 and 15 minute predose measurements) from visits 5, 6, or 7 (days 29, 57, 84) was carried forward (LOCF). These measurements were required to have been taken before the next dose of study medication.

• Missing values for the analysis of secondary spirometry variables were not imputed.

Rescue-medication use

• The total number of puffs of rescue medication per day over the 12 weeks was calculated and divided by the total number of days with nonmissing rescue-medication data to derive the mean daily number of puffs of rescue medication taken for the patient. If the number of puffs was missing for part of the day (either morning or evening), then a half day was used in the denominator.

Abbreviations: FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; IC, inspiratory capacity; LOCF, last observation carried forward.