Early bronchodilator action of glycopyrronium versus tiotropium in moderate-to-severe COPD patients: a cross-over blinded randomized study (Symptoms and Pulmonary function in the moRnING)

Figures & data

Figure 1 SPRING study design.

Notes: *50 μg refers to the quantity of glycopyrronium moiety present in the capsule, which corresponds to a delivered dose of 44 μg. ^#Patients on parenteral or oral corticosteroids therapy who may enter the study after 28-day wash-out period.
Abbreviations: od, once-daily; SPRING, Symptoms and Pulmonary function in the moRnING.

Figure 2 Disposition of patients during the study.

Notes: Values are n (%) unless otherwise stated. *Two randomized patients did not receive at least one dose of any study medication, thus resulting in 124 (98.4%) patients in the ITT and the safety follow-up population.
Abbreviation: ITT, intention-to-treat.

Table 1 Baseline characteristics (ITT population)

	n=124
Mean (SD) age (years)	65.7 (8.1)
Male, n (%)	87 (70.2)
Race, n (%)
Caucasian	124 (100.0)
Mean BMI (SD) (kg/m^2)	27.9 (5.1)
Smoking history, n (%)
Ex-smoker	64 (51.6)
Current smoker	60 (48.4)
Mean (SD) duration of smoking, pack-years	47.7 (23.6)
Mean (SD) duration of COPD, years	7.6 (5.9)
Severity of COPD (GOLD 2013), n (%)
Moderate	88 (71.0)
Severe	19 (15.3)
Unknown*	17 (13.7)
Number of COPD exacerbations in the previous year, n (%)
0	88 (71.0)
1	24 (19.4)
≥2	12 (9.7)
ICS use at baseline, n (%)**	52 (44.4)
Prior COPD medication use, n (%)	117 (94.4)
Mean (SD) post-bronchodilator FEV1 (L)	1.7 (0.5)
Mean (SD) post-bronchodilator FEV1 (% predicted)	60.6 (10.6)
Mean (SD) post-bronchodilator FEV1 reversibility (%)	13.9 (12.7)
Mean (SD) post-bronchodilator FEV1/FVC (%)	50.4 (8.9)

Notes:

* Patients with unacceptable forced spirometry measurement;

** n=117 patients (patients who received at least one prior COPD medication).

Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; ICS, inhaled corticosteroid; ITT, intention-to-treat; SD, standard deviation.

Figure 3 FEV₁ AUC_0-4h treatment differences between glycopyrronium and tiotropium post-first treatment dose on Day 1 (ITT and PP population).

Notes: *P<0.05; data are least squares means; Δ, treatment difference between glycopyrronium and tiotropium.
Abbreviations: FEV₁, forced expiratory volume in 1 second; AUC_0-4h, area under the curve from 0 to 4 hours; CI, confidence interval; ITT, intention-to-treat; od, once-daily; PP, per protocol.

Figure 4 FEV₁ AUC_0-4h treatment differences between glycopyrronium and tiotropium by time point post-first treatment dose on Day 1 (ITT population).

Note: *P<0.05 versus tiotropium at the relative time points.
Abbreviations: FEV₁, forced expiratory volume in 1 second; AUC_0-4h, area under the curve from 0 to 4 hours; ITT, intention-to-treat; od, once-daily.

Table 2 PRO-Morning COPD Symptoms Questionnaire total score comparison between Day 1 versus Day 28 for each treatment, separately (ITT population)

	Glycopyrronium (n=124)	Tiotropium (n=124)
PRO-Morning COPD Symptoms Questionnaire score on Day 1 (pre-dose)	16.7 (11.1)	16.6 (10.0)
PRO-Morning COPD Symptoms Questionnaire score on Day 28 (pre-dose)	14.5 (10.7)	15.2 (11.6)
Improvement in PRO-Morning COPD Symptoms Questionnaire score from Day 1 versus Day 28 (pre-dose)	1.9 (7.8)	1.2 (7.9)
P-value	0.002	0.063

Note: Values are least squares mean (SD).

Abbreviations: PRO, patient reported outcomes; ITT, intention-to-treat; SD, standard deviation.

Table 3 Summary of safety findings (safety population)

	Glycopyrronium n=124	Tiotropium n=124
Number of patients with at least one TEAE	18 (14.5)	13 (10.5)
Discontinuations due to TEAE	2 (1.6)	1 (0.8)
Lower respiratory tract infection	0 (0.0)	1 (0.8)
Pneumonia	1 (0.8)	0 (0.0)
Dyspnea	1 (0.8)*	0 (0.0)
Serious TEAE(s)	2 (1.6)	2 (1.6)
Dyspnea	1 (0.8)*	0 (0.0)
Pleurisy	0 (0.0)	1 (0.8)
Pneumonia	1 (0.8)	0 (0.0)
Lumbar vertebral fracture	0 (0.0)	1 (0.8)

Notes: Values are n (%);

* viral infection.

Abbreviation: TEAE, treatment emergent adverse event.

Figure S1 FEV₁ AUC_0-4h treatment differences between glycopyrronium and tiotropium post-first treatment dose on Day 28 (ITT).

Notes: P=0.7293; data are least squares means; Δ, treatment difference between glycopyrronium and tiotropium.

Abbreviations: AUC_0-4h, area under the curve from 0 to 4 hours; CI, confidence interval; FEV₁, forced expiratory volume in 1 second; ITT, intention-to-treat; od, once-daily.

Figure S2 FEV₁ AUC_0-4h treatment differences between glycopyrronium and tiotropium by time point post-first treatment dose on Day 28 (ITT population).

Abbreviations: AUC_0-4h, area under the curve from 0 to 4 hours; FEV₁, forced expiratory volume in 1 second; ITT, intention-to-treat; od, once-daily.

Table S1 PRO-Morning COPD Symptoms Questionnaire

PRO-Morning COPD Symptoms Questionnaire: pre-morning dose assessment
Please rate the severity of your shortness of breath when you woke up today	0–10 Numeric Rating Scale (0= no shortness of breath to 10= shortness of breath as bad as you can imagine)
Please rate the difficulty you had clearing the phlegm/mucus from your lungs when you woke up today	0–10 Numeric Rating Scale (0= no phlegm/mucus to 10= as difficult as you can imagine)
Please rate the severity of your chest tightness when you woke up today	0–10 Numeric Rating Scale (0= no chest tightness to 10= chest tightness as bad as you can imagine)
Please rate the severity of your wheezing when you woke up today	0–10 Numeric Rating Scale (0= no wheezing to 10= wheezing as bad as you can imagine)
Please rate the severity of your coughing when you woke up today	0–10 Numeric Rating Scale (0= no coughing to 10= coughing as bad as you can imagine)
Please rate how bothered you were by your COPD symptoms when you woke up today	0–10 Numeric Rating Scale (0= no bother to 10= bothered as bad as you can imagine)
PRO-Morning COPD Symptoms Questionnaire: post-morning dose assessment: to be answered approximately 3 hours after morning medication
Please rate the severity of your shortness of breath as you feel now	0–10 Numeric Rating Scale (0= no shortness of breath to 10= shortness of breath as bad as you can imagine)
Please rate the difficulty you had clearing the phlegm/mucus as you feel now	0–10 Numeric Rating Scale (0= no phlegm/mucus to 10= as difficult as you can imagine)
Please rate the severity of your chest tightness as you feel now	0–10 Numeric Rating Scale (0= no chest tightness to 10= chest tightness as bad as you can imagine)
Please rate the severity of your wheezing as you feel now	0–10 Numeric Rating Scale (0= no wheezing to 10= wheezing as bad as you can imagine)
Please rate the severity of your coughing as you feel now	0–10 Numeric Rating Scale (0= no coughing to 10= coughing as bad as you can imagine)
Please rate how bothered you feel now by your COPD symptoms	0–10 Numeric Rating Scale (0= no bother to 10= bothered as bad as you can imagine)

Abbreviations: COPD, chronic obstructive pulmonary disease; PRO, patient reported outcome.