Improved lung function and patient-reported outcomes with co-suspension delivery technology glycopyrrolate/formoterol fumarate metered dose inhaler in COPD: a randomized Phase III study conducted in Asia, Europe, and the USA

Figures & data

Table 1 Patient demographics and baseline characteristics (ITT population)

	GFF MDI 18/9.6 μg (n=551)	GP MDI 18 μg (n=474)	FF MDI 9.6 μg (n=480)	Placebo MDI (n=235)
Age (years), mean (SD)	64.7 (7.4)	64.0 (8.1)	64.1 (7.6)	63.9 (7.5)
Male, n (%)	408 (74.0)	346 (73.0)	365 (76.0)	171 (72.8)
Race, n (%)
White	315 (57.2)	275 (58.0)	260 (54.2)	137 (58.3)
Black/African American	12 (2.2)	18 (3.8)	16 (3.3)	6 (2.6)
Asian	223 (40.5)	181 (38.2)	204 (42.5)	92 (39.1)
American Indian or Alaska Native	1 (0.2)	0	0	0
BMI (kg/m^2), mean (SD)	26.3 (5.9)	26.5 (5.7)	26.3 (6.2)	26.2 (6.2)
Smoking status, n (%)
Current	252 (45.7)	209 (44.1)	208 (43.3)	113 (48.1)
Former	299 (54.3)	265 (55.9)	272 (56.7)	122 (51.9)
Number of pack-years smoked,a mean (SD)	45.9 (24.3)	44.8 (25.5)	46.9 (26.1)	45.7 (26.4)
COPD severity,b n (%)
Mildc	6 (1.1)	9 (1.9)	5 (1.0)	6 (2.6)
Moderate	330 (59.9)	283 (59.7)	290 (60.4)	137 (58.3)
Severe	192 (34.8)	168 (35.4)	171 (35.6)	86 (36.6)
Very severe	23 (4.2)	14 (3.0)	14 (2.9)	6 (2.6)
COPD duration (years), mean (SD)	(n=546) 6.2 (5.9)	(n=474) 6.2 (5.8)	(n=477) 6.1 (6.2)	(n=234) 6.1 (5.6)
Postbronchodilator FEV1 (% predicted), mean (SD)	(n=550) 53.96 (13.73)	(n=472) 54.82 (14.08)	(n=480) 53.92 (13.22)	(n=235) 54.40 (13.90)
Reversibility to albuterol
Reversible,d n (%)	249 (45.2)	207 (43.7)	207 (43.1)	108 (46.0)
Reversibility postbronchodilator for FEV1 (%), mean (SD)	17.5 (15.2)	16.9 (13.8)	17.3 (14.6)	18.1 (15.9)
Use of ICS,e n (%)	169 (30.7)	143 (30.2)	142 (29.6)	79 (33.6)
BDI focal score, mean (SD)	(n=532) 6.7 (2.2)	(n=457) 6.7 (2.3)	(n=458) 6.8 (2.2)	(n=217) 6.2 (2.2)
SGRQ total score, mean (SD)	(n=489) 40.8 (16.9)	(n=412) 39.4 (17.7)	(n=415) 38.7 (16.9)	(n=196) 41.7 (17.2)
CAT total score,f mean (SD)	(n=550) 14.9 (7.0)	(n=472) 15.2 (7.3)	(n=480) 14.9 (7.0)	(n=235) 15.2 (7.4)
Rescue medication useg (puffs/day), mean (SD)	(n=256) 4.3 (3.4)	(n=225) 4.0 (2.7)	(n=232) 4.1 (2.8)	(n=109) 4.1 (2.9)

Notes:

a Number of pack-years smoked = (number of cigarettes each day/20) × number of years smoked.

b Severity of COPD was based on the nonmissing postalbuterol assessment at screening.

c These patients were characterized as having mild COPD due to the application of an Asian correction factor to baseline lung function assessments at the time of analysis.

d Reversible is defined as improvement in FEV₁ postalbuterol administration compared to the prealbuterol of ≥12% or ≥200 mL.

e Defined as using ICS on the day of the first dose of study medication.

f CAT total score is the sum of eight CAT item scores (range: 0–40).

g Rescue medication use was analyzed in the rescue medication user population, defined as all patients in the ITT population with the mean baseline rescue albuterol sulfate use of ≥1 puff/day.

Abbreviations: BDI, Baseline Dyspnea Index; BMI, body mass index; CAT, COPD assessment test; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; ICS, inhaled corticosteroid; ITT, intent-to-treat; MDI, metered dose inhaler; SGRQ, St George’s Respiratory Questionnaire.

Figure 1 Patient disposition.

Note: ^aOne patient in the GP MDI group completed Week 24 but did not complete the follow-up call (14 days after last study drug dosing), so was categorized as having discontinued the study but was not classed as withdrawing from the study.
Abbreviations: FF, formoterol fumarate; GFF, GP/FF; GP, glycopyrrolate; MDI, metered dose inhaler.

Table 2 Primary and secondary lung function endpoints (ITT population)

	GFF MDI 18/9.6 μg	GP MDI 18 μg	FF MDI 9.6 μg	Placebo MDI
Primary endpoint
Change from baseline in morning predose trough FEV1 at Week 24 (mL)
n	488	412	413	196
LSM	120	60	47	−45
SE	9.1	9.9	9.9	14.3
Treatment difference for GFF MDI vs monocomponents and placebo MDI
LSM (95% CI)	NA	59 (33, 86)	72 (46, 99)	165 (132, 198)
P-value	NA	<0.0001a	<0.0001a	<0.0001a
Secondary endpoints
Change from baseline in morning predose trough FEV1 over 24 weeksb (mL)
n	541	465	467	225
LSM	135	80	63	−20
SE	7.0	7.6	7.6	10.9
Treatment difference for GFF MDI vs monocomponents and placebo MDI
LSM (95% CI)	NA	55 (35, 76)	72 (52, 92)	155 (129, 180)
P-value	NA	<0.0001a	<0.0001a	<0.0001a
Peak change from baseline in FEV1 within 2 hours postdosing at Week 24 (mL)
n	490	412	413	196
LSM	358	214	247	55
SE	10.2	11.1	11.1	16.0
Treatment difference for GFF MDI vs monocomponents and placebo MDI
LSM (95% CI)	NA	145 (115, 174)	111 (81, 140)	303 (266, 340)
P-value	NA	<0.0001a	<0.0001a	<0.0001a

Notes:

a Statistically significant/superior.

b Morning predose trough FEV₁ over 24 weeks was based on assessments at Weeks 2, 4, 8, 12, 16, 20, and 24.

Abbreviations: FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; ITT, intent-to-treat; LSM, least squares mean; MDI, metered dose inhaler; NA, not applicable; SE, standard error.

Figure 2 LSM change (±SE) from baseline in morning predose trough FEV₁ over 24 weeks (ITT population).

Abbreviations: FF, formoterol fumarate; GFF, GP/FF; GP, glycopyrrolate; ITT, intent-to-treat; LSM, least squares mean; MDI, metered dose inhaler; SE, standard error.

Table 3 Secondary patient-reported outcome endpoints (ITT population, unless stated otherwise)

	GFF MDI 18/9.6 μg	GP MDI 18 μg	FF MDI 9.6 μg	Placebo MDI
TDI focal score over 24 weeksa
n	532	457	458	217
LSM	1.6	1.3	1.5	0.8
SE	0.09	0.10	0.10	0.14
Treatment difference for GFF MDI vs monocomponents and placebo MDI
LSM (95% CI)	NA	0.33 (0.07, 0.59)	0.15 (−0.11, 0.41)	0.80 (0.47, 1.13)
P-value	NA	0.0125b	0.2530	<0.0001b
TDI focal score over 24 weeksa (symptomatic population)c
n	244	228	217	108
LSM	1.5	1.1	1.3	0.7
SE	0.14	0.15	0.15	0.22
Treatment difference for GFF MDI vs monocomponents and placebo MDI
LSM (95% CI)	NA	0.41 (0.01, 0.81)	0.20 (−0.21, 0.60)	0.73 (0.22, 1.23)
P-value	NA	0.0425b,c	0.3379	0.0048b,c
Change from baseline in SGRQ total score at Week 24
n	489	412	415	196
LSM	−5.3	−3.7	−5.6	−0.9
SE	0.54	0.59	0.59	0.86
Treatment difference for GFF MDI vs monocomponents and placebo MDI
LSM (95% CI)	NA	−1.62 (−3.19, −0.05)	0.30 (−1.27, 1.87)	−4.40 (−6.39, −2.41)
P-value	NA	0.0427b	0.7084	<0.0001b
Change from baseline in SGRQ total score at Week 24 (symptomatic population)c
n	220	202	189	92
LSM	−6.9	−3.8	−7.8	−1.6
SE	0.88	0.91	0.95	1.37
Treatment difference for GFF MDI vs monocomponents and placebo MDI
LSM (95% CI)	NA	−3.10 (−5.59, −0.61)	0.89 (−1.65, 3.44)	−5.33 (−8.52, −2.14)
P-value	NA	0.0148b	0.4908	0.0011b
Change from baseline in mean daily rescue medication use over 24 weeksd (puffs/day) (rescue medication user population)
n	256	225	232	109
LSM	−1.4	−0.6	−1.0	−0.4
SE	0.13	0.14	0.14	0.21
Treatment difference for GFF MDI vs monocomponents and placebo MDI
LSM (95% CI)	NA	−0.77 (−1.16, −0.38)	−0.41 (−0.80, −0.03)	−0.98 (−1.47, −0.49)
P-value	NA	0.0001b	0.0345e	<0.0001b

Notes:

a TDI focal score over 24 weeks was based on assessments at Weeks 4, 8, 12, 16, 20, and 24.

b Statistically significant/superior.

c The symptomatic population was defined as patients in the ITT population with a COPD assessment test score ≥15 at baseline (screening).

d The rescue medication user population was defined as all patients in the ITT population with the mean baseline rescue albuterol sulfate use of ≥1 puff/day.

e Nominally significant (ie, P<0.05 but not statistically significant due to procedure to control Type I error).

Abbreviations: FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; ITT, intent-to-treat; LSM, least squares mean; MDI, metered dose inhaler; NA, not applicable; SE, standard error; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

Table 4 Responder analyses for MCID of secondary, patient-reported outcome endpoints (ITT population)

	GFF MDI 18/9.6 μg	GP MDI 18 μg	FF MDI 9.6 μg	Placebo MDI
Proportion of patients achieving the MCID thresholda
≥1 unit improvement in TDI focal score over 24 weeks
n	548	474	477	235
Responders, n (%)	313 (57.11)	223 (47.14)	256 (53.73)	88 (37.19)
Treatment comparison for GFF MDI vs monocomponents and placebo MDI
OR (95% CI)	NA	1.49 (1.17, 1.91)	1.15 (0.90, 1.47)	2.25 (1.64, 3.08)
P-value	NA	0.0015b	0.2785	<0.0001b
≥1 unit improvement in TDI focal score over 24 weeks (symptomatic population)c
n	255	239	228	117
Responders, n (%)	137 (53.80)	92 (38.49)	115 (50.38)	43 (36.70)
Treatment comparison for GFF MDI vs monocomponents and placebo MDI
OR (95% CI)	NA	1.86 (1.30, 2.66)	1.15 (0.80, 1.64)	2.01 (1.28, 3.15)
P-value	NA	0.0007b	0.4540	0.0024b
≥4 unit improvement from baseline in SGRQ total score at Week 24
n	549	474	480	235
Responders, n (%)	256 (46.31)	193 (40.51)	219 (46.19)	81 (33.06)
Treatment comparison for GFF MDI vs monocomponents and placebo MDI
OR (95% CI)	NA	1.27 (0.98, 1.63)	1.00 (0.78, 1.29)	1.75 (1.27, 2.41)
P-value	NA	0.0669	0.9696	0.0007b
≥4 unit improvement from baseline in SGRQ total score at Week 24 (symptomatic population)c
n	255	239	229	117
Responders, n (%)	125 (48.78)	100 (41.78)	112 (49.50)	35 (28.80)
Treatment comparison for GFF MDI vs monocomponents and placebo MDI
OR (95% CI)	NA	1.33 (0.93, 1.90)	0.97 (0.68, 1.39)	2.35 (1.47, 3.77)
P-value	NA	0.1229	0.8757	0.0004b

Notes: Percentages are based on a logistic regression model with TDI or SGRQ response as a binary response (response/no response). Relevant baseline value (BDI or SGRQ) and reversibility to albuterol sulfate were continuous covariates, and treatment was a categorical covariate.

a Validated thresholds for the MCID for each endpoint were used.³⁴

b Statistically significant/superior.

c The symptomatic population was defined as patients in the ITT population with a COPD assessment test score of ≥15 at baseline (screening).

Abbreviations: BDI, Baseline Dyspnea Index; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; ITT, intent-to-treat; MCID, minimum clinically important difference; MDI, metered dose inhaler; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

Table 5 Summary of AEs (safety population)

	GFF MDI 18/9.6 μg (n=551)	GP MDI 18 μg (n=474)	FF MDI 9.6 μg (n=480)	Placebo MDI (n=235)
TEAEs, n (%)
Patients with ≥1 TEAE	306 (55.5)	250 (52.7)	256 (53.3)	131 (55.7)
Patients with TEAEs relateda to study treatment	55 (10.0)	51 (10.8)	46 (9.6)	23 (9.8)
Patients with serious TEAEs	53 (9.6)	34 (7.2)	40 (8.3)	19 (8.1)
Patients with serious TEAEs relateda to study treatment	3 (0.5)	4 (0.8)	4 (0.8)	2 (0.9)
Patients with TEAEs leading to early discontinuation	27 (4.9)	25 (5.3)	24 (5.0)	10 (4.3)
Deaths (all cause) during treatment period	1 (0.2)	1 (0.2)	1 (0.2)	1 (0.4)
Deaths (all cause) during treatment period +14 days	1 (0.2)	1 (0.2)	1 (0.2)	1 (0.4)
AEs occurring in ≥2% of patients in any treatment arm (preferred term), n (%)
Viral upper respiratory tract infection	50 (9.1)	44 (9.3)	46 (9.6)	16 (6.8)
Upper respiratory tract infection	37 (6.7)	33 (7.0)	29 (6.0)	20 (8.5)
COPDb	16 (2.9)	12 (2.5)	13 (2.7)	7 (3.0)
Headache	15 (2.7)	11 (2.3)	10 (2.1)	3 (1.3)
Hypertension	16 (2.9)	6 (1.3)	3 (0.6)	8 (3.4)
Cough	13 (2.4)	10 (2.1)	8 (1.7)	2 (0.9)
Dyspnea	11 (2.0)	6 (1.3)	7 (1.5)	7 (3.0)
Back pain	15 (2.7)	7 (1.5)	5 (1.0)	1 (0.4)
Dizziness	8 (1.5)	12 (2.5)	4 (0.8)	1 (0.4)
Pneumonia	9 (1.6)	5 (1.1)	5 (1.0)	6 (2.6)
Bronchitis	4 (0.7)	8 (1.7)	6 (1.3)	5 (2.1)
Pharyngitis	11 (2.0)	3 (0.6)	4 (0.8)	0

Notes:

a Related = possibly, probably, or definitely related in the opinion of the investigator.

b Worsening of COPD defined as a COPD exacerbation since the patient’s last visit. COPD exacerbations were only recorded as an AE if they were considered to be a serious TEAE.

Abbreviations: AE, adverse event; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; MDI, metered dose inhaler; TEAE, treatment-emergent AE.

Table S1 Institutional review boards and approval numbers

Institutional review board	Approval numbera
Schulman Associate Institutional Review Board, Inc., 4445 Lake Forrest Drive, Suite 300, Cincinnati, OH 45242, USA	201500174
Fakultni Nemocnice Kralovske Vinohrady, The University Hospital Kralovske Vinohrady, Srobarova 50, 100 34 Praha 10, Czech Republic	Reference number MEK/08/0/2015
Ethik-Kommission bei der Landesarztekammer Hessen, Im Vogelsgesang 3, 60488 Frankfurt, Germany	Registration number FF 23/2015
NRES Committee London-Bloomsbury, HRA NRES Centre Manchester, Barlow House 3rd Floor, 4 Minshull Street, Manchester M1 3DZ, UK	REC reference 15/LO/0523 IRAS project 167822
Egyeszegugyi Tudomanyos Tanacs, Klinikai Farmakologiai Etikai Bizottsaga, Arany Janos u 6-8, 1051 Budapest, Hungary	Reference number OGYI/32844-2/2015
Korea University Anam Hospital, 73, Inchon-ro, Seongbuk-gu, Seoul 136-705, Korea	IRB number ED14345 Review number AN14345-001
Institutional Review Board of Yeungnam University Hospital, 170, Hyeonchung-ro, Nam-gu, Deagu 705-703, Korea	IRB file number YUMC 2015-02-008
Institutional Review Board of The Catholic University of Korea St Paul’s Hospital, 180, Wangsan-ro, Dongdaemun-gu, Seoul 130-709, Korea	Document number PIRB-00131-003 Study number PC15MGGT0002
Institutional Review Board of KyungHee University Hospital, 23, Kyungheedae-ro, Dongdaemun-gu, Seoul 130-872, Korea	IRB file number KHUH 2015-02-102-005
Institutional Review Board of Korea University Guro Hospital, 148, Gurodong-ro, Guro-gu, Seoul 152-703, Korea	Approval number KUGH14324-001
Dong-A University Hospital Institutional Review Board, 26 Daesingongwon-ro, Seo-gu, Busan 602-715, Korea	Study number15-022
Institution Review Board of Yonsei University Wonju Severance Christian Hospital, 20, IIsan-Ro, Wonju-Si, Gangwon-Do 220-701, Korea	Approval number CR115030
Institution Review Board of Inje University Seoul Paik Hospital, 31, Supyo-ro, Jung-gu, Seoul 100-032, Korea	Study number SIT-2015-003
Komisja Bioetyczna, Okregowej Izby Lekarskiej w Bialymstoku, UI Swietojanska 7, 15-082 Bialystok, Poland	5/2015/VI
Independent Interdisciplinary Committee on Ethics Evaluation of Clinical Trials (Central IRB), 51, Leningradsky Prospect, Moscow 125468, Russia	489298-20-1
Ethics Committee at Federal State Governmental Establishment “Burdenko Main Military Clinical Hospital” of Russian Federation Défense Ministry, 3, Hospital sq, Moscow 105229, Russia	489298-20-1
Local Ethics Committee of Saint Petersburg State Budgetary Healthcare Institution, “Consulting and Diagnostic Center # 85”, pr Veteranov, 89, bld 3, Saint Petersberg 198260, Russia	489298-20-1
Local Ethics Committee of State Budgetary Healthcare Institutions of Leningrad Region (SBHI LR), “Gatchina Clinical Interdistrict Hospital”, Roshchinskaya Str. 15a, Gatchina, Leningard Region, Russia	489298-20-1
Local Ethics Committee Of SBHI LR “Occupational Pathology Center”, 27, liter O, Mechnikova pr, Saint Petersburg 195271, Russia	Protocol number 22/2015
Local Ethics Committee of SBEI HPE “Pavlov First Saint Petersburg State Medical University”, of the Ministry of Healthcare of the Russian Federation, 10, Rentgena Str, Saint Petersburg 197101, Russia	489298-20-1
Independent Ethics Committee of Federal State Budgetary Institution “Central Scientific and Research Institute of Tuberculosis” of Russian Academy of Medical Science, 2, Yauzskaya Alleya, Moscow 107564, Russia	489298-20-1
Local Ethics Committee, The Ministry of Healthcare of the Russian Federation State Budgetary Educational Institution of Higher Professional Education, IM Sechenov First Moscow State Medical University, 8-2 Trubetskaya Str, Moscow 119991, Russia	NA
Local Ethics Committee of State Budgetary Education Institution of Higher Professional Education, Pavlov First Saint Petersburg State Medical University, 10, Rentgena Str, Saint Petersburg 197101, Russia	489298-20-1
Local Ethics Committee Of State Budgetary Healthcare Institution of Stavropol Region (SBHI SR), City Hospital #2 of Pyatigorsk, 6, Admiralskogo Str, 357538 Pyatigorsk, Stavropol Region, Russia	493403-20-1
Chang Gung Medical Foundation Institutional Review Board, No 5, Fusing St, Gueishan Township, Taoyuan City, Taiwan, ROC	NA
China Medical University & Hospital Research Ethics Committee, No 2, Yude Rd, North Dist, Taichung City 40447, Taiwan, ROC	NA
The Institutional Review Board of Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect 4, Taichung 40705, Taiwan, ROC	IRB TCVGH number SC15104A
Research Ethic Committee C of National Taiwan University Hospital Members, No 1, Changde Street, Taipei City 100, Taiwan, ROC	NTUH-Rec number 201504046MSC
Ino Hospital Institutional Review Board, 1-27 Shiosaki Oshio-cho, Himeji-shi, Hyogo 671-0102, Japan	NA
Nihon University Hospital’s Joint Institutional Review Board, 30-1 Oyaguchi kamicho, Itabashi-ku, Tokyo 173-8610, Japan	File number 2706-1430
Nagata Hospital Institutional Review Board, 523-1 Shimomiyanagagamachi, Yanagawa-shi, Fukuoka 832-0059, Japan	NA
Institutional Review Board of National Hospital Organization Tenryu Hospital, 4201-2 Oro, Hamakita-ku, Hamamatsu-shi, Shizuoka 434-8511, Japan	NA
Dokkyo Medical University Hospital Institutional Review Board, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi 321-0293, Japan	File number S-288
Institutional Review Board of Kishiwada City Hospital, 1001 Gakuhara-cho, Kishiwada-shi, Osaka 596-8501, Japan	NA
Takamatsu Municipal Hospital Institutional Review Board, 2-36-1 Miyawakicho, Takamatsu, Kagawa 760-8538, Japan	NA
National Hospital Organization Fukuoka Hospital Institutional Review Board, 4-39-1 Yakatabaru, Minami-ku, Fukuoka-shi, Fukuoka 811-1394, Japan	File number 2015C1
Review Board of Human Rights and Ethics for Clinical Studies Institutional Review Board, 13-2 Ichiban-cho, Chiyoda-ku, Tokyo 102-0082, Japan	NA
Tohoku Rosai Hospital Institutional Review Board, 4-3-2-1, Dainohara, Aoba-ku, Sendai-city, Miyagi 981-8563, Japan	File number 15A003a
Institutional Review Board of Ishikawa Prefectural Central Hospital, 2-1 Kuratsukihgashi, Kanazawa, Ishikawa 920-8530, Japan	NA
Institution Review Board of National Hospital Organization, Ibarakihigashi National Hospital, 825 Terunuma, Tokai-mura, Naka-gun, Ibaraki 319-1113, Japan	NA
Review Board of Human Rights and Ethics for Clinical Studies Institutional Review Board, 13-2 Ichiban-cho, Chiyoda-ku, Tokyo 102-0082, Japan	NA
Institutional Review Board of Nagaoka Red Cross Hospital, 2-297-1 Sensyu, Nagaoka-shi, Niigata 940-2085, Japan	NA
National Hospital Organization Fukuoka Higashi Medical Center Institutional Review Board, 1-1-1 Chidori, Koga-shi, Fukuoka 811-3195, Japan	NA
The IRB of Tosei General Hospital, 160 Nishioiwake-cho, Seto, Aichi 489-8642, Japan Kobe City Medical Center General Hospital Institutional Review Board, 2-1-1 Minatojima- minamimachi, Chuo-ku, Kobe-shi, Hyogo 650-0047, Japan	File number H270501PT File number Chi 15-08
The IRB of healthcare corporation Tesshokai, 1344, Higashi-cho, Kamogawa City, Chiba 296-0041, Japan	NA
Institutional Review Board of Shinshu University Hospital, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan	File number 1482
Sendai Open Hospital Institutional Review Board, 5-22-1 Tsurugaya Miyagino-ku, Sendai, Miyagi 983-0824	NA
The Institution Review Board of Japan Community Healthcare Organization Chukyo Hospital, 1-1-10 Sanjo, Minami-ku, Nagoya-shi, Aichi 457-8510, Japan	File number 15-003
The Institution Review Board of National Hospital Organization Ehime Medical Center, 366 Yokogawara, Toon-shi, Ehime 791-0281, Japan	File number 2015-B-03
The Institution Review Board of Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki-shi, Kanagawa 216-8511, Japan	File number A219
The Institution Review Board of National Hospital Organization Asahikawa Medical Center, 7-4048, Hanasaki-cho, Asahikawa-shi, Hokkaido 070-0901, Japan	File number 15-a-7
Adachi Kyosai Hospital Institutional Review Board, 1-36-8 Yanagihara, Adachi-ku, Tokyo 120-0022, Japan	NA
Institutional Review Board of Shintokai Yokohama Minoru Clinic, 1-13-8, Bessho, Minami-ku, Yokohama-shi, Kanagawa 232-0064, Japan	NA
Japan Conference of Clinical Research Institutional Review Board, 2F, Ichigo Minami Ikebukuro Building, 2-27-17, Mianami Ikebururo, Toshima-ku, Tokyo 171-0022, Japan	File number 3-175
Tokyo-Eki Center-building Clinic Institutional Review Board, 3-3-14, Nihonbashi, Churo-ku, Tokyo 103-0027, Japan	File number 3-173
Nanfang Hospital Southern Medical University, No 1838, North of Guangzhou Avenue, Guangzhou, Guangdong Province 510515, China	Approval number NFEC-2016-006
Ethics Committee of The Second Xiangya Hospital of Central South University, No 139, Middle Renmin Road, Changsha, Hunan Province 410011, China	CFDA approval 2015L03321
Medical Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University, 151, Yan Jiang Xi Road, Guangzhou (Canton) 510120, China	EC review (2015) number 26 CFDA approval 2015L03321
Medical Ethics Committee of Guangdong General Hospital, No 106, Zhongshan Second Road, Guangzhou, Guangdong Province 510080, China	CFDA approval 20l5L03321
Ethics Committee of Hebei General Hospital, No 348, Hepingxi Road, Shijazhuang, Hebei, China	Study number Y-2015-22 CFDA approval 2015L03321
Ethics Committee of First Hospital of Shanxi Medical University, No 85, JieFang Road, Taiyuan, Shanxi Province 030001, China	(2016) EC review number 01 SFDA approval 2015L03321
Ethics Committee of the First Affiliated Hospital of Soochow University, No 188 Shinzi Street, Suzhou, Jiangsu Province 215006, China	EC number 2015100 SFDA approval 2015L03321
Ethics Committee of Hainan General Hospital, F3, Information Building, No 19, Xiuhua Road, Xiuying District, Haikou, Hainan 570311, China	CFDA approval number 2015L03321
Ethics Committee of Wuxi people’s Hospital, No 299, Qingyang Road, Wuxi Jiangsu Province 214023, China	Approval number 2015LLPJ-III-18
Ethics Committee of the Second Affiliated Hospital of Nanchang University, No 1, Minde Road, Donghu District, Nanchang, Jiangxi 330006, China	CFDA approval number 2015L03321
IEC for Clinical Research of Zhongda Hospital, Affiliated to Southeast University, No 87, Dingjaqiao Road, Gulou District, Nanjing, Jiangsu Province 210009, China	Approval number 2015ZDSYLL083.0
Clinical Trial Ethics Committee of West China Hospital, Sichuan University, No 37, Guoxue Lane, Wuhou District, Chengdu, Sichuan 610041, China	CFDA approval number 2015L03321
Medical Ethic Committee of The General Hospital of Shenyang Military Command, No 83, Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, China	CFDA approval number 2015L03321
The Clinical Research Ethics Committee of Anhui Provincial Hospital, No 17, Lunjiang Road, Hefei City, Anhui Province, China	SFDA approval number 2015L03321 Approval number 2016 EC number 03
The first Hospital of Jilin University Ethics Committee, No 71 Xinmin Main Street, Changchun, Jilin Province, China	CFDA approval number 2015L03321 Trial review number 160225-013
Ethics Committee of the People’s Hospital of Guangxi Zhuang Autonomous Region, No 6, Taoyuan Road, Nanning, Guangxi 530021, China	CFDA approval number 2015L03321
Inner Mongolia People’s Hospital clinical trial Ethics Committee, No 20, Zhaowuda Rd, Hohhot, Inner Mongolia 010017, China	Clinical trial protocol identify number YWLCSYLL2015-11 CFDA approval number 2015L03321
Ethics Committee of Beijing Friendship Hospital, Capital Medical Hospital, No 95, Yongan Road, Xicheng District, Beijing, China	CFDA approval number 2015L03321
Ethics Committee of Peking University Shou Gang Hospital, No 9, Jinyuanzhuang Road, Shijingshan District, Beijing, China	EC review approval IRB-AF-27-04
The drug clinical trial Ethics Committee of Chengdu Military General Hospital, No 2, Gonghe Road, Chengdong district, Xining, China	Project number CDA2015Y032 Issue number 20150015
Ethics Committee of Shanghai Pulmonary Hospital, No 507, Zhengmin Road, Shanghai 200433, China	Approval number 15136HX CFDA approval number 2015L03321
Ethics Committee of the Second Hospital of Hebei Medical University, No 215, Hepingxi Road, Shijazhuang, Hebei, China	Study number 2016EC02-05-1 CFDA approval number 2015L03321
Ethics Committee of Beijing Anzhen Hospital, Capital Medical University, No 2, Anzhen Road, Chaoyang District, Beijing, China	Accepted number 2015-63D Approval number 2016 number 2 CFDA approval number 2015L03321
Ethics Committee of Guizhou Provincial People’s Hospital, No 83, East Zhongshan Rd, Guiyang, Guizhou 55002, China	SFDA approval number 2015L03321
Medical Ethic Committee of Shengjing Hospital of China Medical University, No 36, Sanhao Street, Heping District, Shenyang, Liaoning 110004, China	EC review number 2015PS32 CFDA approval number 2015L03321
Ethics Committee of Huadong Hospital Affiliated to Fudan University, No 221, West Yan’an Road, Jing’an District, Shanghai 200040, China	Approval number 20150238 Protocol number in the Ethics Committee document 2015L041
Ethics Committee of Zhongshan Hospital Xiamen University, No 201-209, South Hubin Road, Xiamen, Fujian 361004, China	Approval number 2016 EC number 11 Accepted number 20160001 CFDA approval number 2015L03321
Qinghai Provincial People’s Hospital Clinical Trial Ethics Committee, No 2, Gonghe Road, Chengdong District, Xining, China	Approval number PJ2016-001-001
Drug Ethics Committee of Tianjin Medical University General Hospital, No 154 An Shan Ave, Heping District, Tianjin 300052, China	Approval number IRB2016-018-01 ZYY-IRB-SOP-016 (F)-002-03
Ethics Committee of Shanghai East Hospital, No 150, Jimo Road, Pudong District, Shanghai 200120, China	Approval number (2016) number 007 Clinical review
Ethics Committee of Yiyang Central Hospital, No 118, Kangfu North Road, Yiyang, Hunan, China	CFDA approval number 2015L03321

Note:

a Approval numbers are shown where available (some IRBs provided reference or file numbers and some did not assign approval numbers).

Abbreviations: IRBs, institutional review boards; NA, not available; REC, Research Ethic Committee; IRAS, Integrated Research Approval System; TCVGH, Taichung Veterans General Hospital; NTUH-Rec, National Taiwan University Hospital Research Ethic Committee; CFDA, China Food and Drug Administration; EC, ethics committee; SFDA, State Food and Drug Administration.

Table S2 Additional patient-reported outcome endpoints (ITT population, unless stated otherwise)

	GFF MDI 18/9.6 μg	GP MDI 18 μg	FF MDI 9.6 μg	Placebo MDI
TDI focal score at Week 24
n	487	410	413	196
LSM	1.8	1.4	1.6	0.9
SE	0.12	0.13	0.13	0.19
Treatment difference for GFF MDI vs monocomponents and placebo MDI
LSM (95% CI)	NA	0.41 (0.06, 0.75)	0.20 (−0.15, 0.55)	0.90 (0.46, 1.34)
P-value	NA	0.0229	0.2659	<0.0001
TDI focal score at Week 24 (symptomatic population)a
n	219	201	188	91
LSM	1.7	1.1	1.6	0.8
SE	0.19	0.20	0.20	0.29
Treatment difference for GFF MDI vs monocomponents and placebo MDI
LSM (95% CI)	NA	0.63 (0.10, 1.17)	0.11 (−0.43, 0.66)	0.87 (0.19, 1.55)
P-value	NA	0.0202	0.6879	0.0122
Change from baseline in SGRQ total score over 12–24 weeksb
n	516	436	436	205
LSM	−5.2	−3.6	−5.0	−1.7
SE	0.46	0.50	0.50	0.72
Treatment difference for GFF MDI vs monocomponents and placebo MDI
LSM (95% CI)	NA	−1.62 (−2.94, −0.30)	−0.27 (−1.59, 1.05)	−3.50 (−5.18, −1.82)
P-value	NA	0.0165	0.6908	<0.0001
Change from baseline in SGRQ total score over 12–24 weeksb(symptomatic population)a
n	237	218	200	97
LSM	−6.9	−3.9	−7.3	−3.1
SE	0.76	0.79	0.83	1.19
Treatment difference for GFF MDI vs monocomponents and placebo MDI
LSM (95% CI)	NA	−2.99 (−5.15, −0.84)	0.32 (−1.89, 2.53)	−3.83 (−6.60, −1.06)
P-value	NA	0.0066	0.7787	0.0068

Notes:

a The symptomatic population was defined as patients in the ITT population with a COPD assessment test score ≥15 at baseline (screening).

b SGRQ score over 12–24 weeks was based on assessments at Weeks 12, 16, 20, and 24.

Abbreviations: FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; ITT, intent to treat; LSM, least squares mean; MDI, metered dose inhaler; NA, not applicable; SE, standard error; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

JonesPWBeehKMChapmanKRDecramerMMahlerDAWedzichaJAMinimal clinically important differences in pharmacological trialsAm J Respir Crit Care Med2014189325025524383418

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