Role of nebulized glycopyrrolate in the treatment of chronic obstructive pulmonary disease

Figures & data

Table 1 Advantages and disadvantages of inhalation devices

Device type	Advantages	Disadvantages
pMDI	– Portable	– Needs coordination between inspiration and dose actuation
	– Does not require preparation	– High oropharyngeal deposition
	– No drug contamination risk	– Does not always indicate the number of doses left
	– High reproducibility for each actuation	– Contain propellants
	– Multidose	– Need to be re-primed after no use
	– High number of drugs to choose
Ultrafine pMDI	– Portable	– Few drugs to choose
	– Does not require preparation	– Needs coordination between inspiration and dose actuation
	– No drug contamination risk	– Does not always indicate the number of doses left
	– High reproducibility for each actuation	– Fast expiration if containing formoterol
	– Multidose	– Needs to be re-primed after no use
	– High lung deposition and minor oropharyngeal deposition
Breath-actuated pMDI	– Useful when coordination is lacking	– Needs adequate inhalation effort
	– Useful in older age
	– Does not require spacers
DPI	– No coordination required	– Usually requires more steps to prepare the drug prior to inhalation
	– No propellant needed	– Some are single-dose
	– Remaining dose counters	– Needs adequate inhalation effort
	– Portable	– Higher oropharyngeal deposition
	– Usually multidose	– Usually more expensive than pMDIs
	– Short administration time	– Humidity can reduce the released dose
		– Device declivity for a correct loading dose
SMI	– Easy to use	– Needs careful preparation at the first use
	– Portable	– Multiple steps involved
	– Multidose	– Needs to be re-primed after no use
	– No propellant needed
	– Higher actuation duration limiting the effects of poor coordination activation/inhalation
Jet nebulizer	– Easy to use	– Cumbersome
	– No need for coordination	– Noisy
	– Adapt for every age (even <4 years)	– High treatment time
	– Available for oxygen enrichment	– Possibility of microbial contamination
	– Contemporaneous use of different drugs	– Needs cleaning and periodic maintenance
	– No propellant needed	– Needs electricity
	– Can be used by bedridden patients	– Uncertainty of effective dose delivered to the lung
Ultrasonic wave nebulizer	– Easy to use Requires minimal cognitive ability	– Possible drug heat degradation
	– Lightweight	– Too much liquid waste
	– Silent	– High treatment time
	– No need for coordination	– Possibility of microbial contamination
	– Adapt for every age (even <4 years)	– Needs cleaning and periodic maintenance
	– Available for oxygen enrichment	– Needs electricity
	– Contemporaneous use of different drugs	– Uncertainty of effective dose delivered to the lung
	– No propellant needed
	– Can be used by bedridden patients
Ultrasonic VMT	Same advantages as ultrasonic nebulizers	– Higher price
	– Shorter treatment time	– Needs cleaning after every use
	– High efficiency and less waste	– Not available for contemporaneous use of different drugs
	– No drug degradation	– May not readily aerosolize drug suspensions
	– Battery powered
	– Easy to clean, disinfect and autoclave
	– Display delivers feedback during inhalation

Abbreviations: DPI, dry powder inhaler; pMDI, pressurized metered dose inhaler; SMI, soft mist inhaler; VMT, vibrating mesh technology.

Figure 1 Simplified structure of the eFlow^® (PARI Pharma GmbH, Starnberg, Germany) nebulizer.

Figure 2 Chemical structure of glycopyrronium bromide (left) and its plasma metabolite M9 (right).

Note: M9 is formed through nonenzymatic hydrolysis of glycopyrronium bromide.

Table 2 Available studies on nebulized GB for COPD treatment

Name (ID)	Study design	Drugs	Population	Primary endpoints	Main secondary endpoints	Main results
Leaker et al^Citation41	Phase II, two-center, randomized, placebo-controlled, double-blind, dose ranging, single dose, six way cross-over	GBn via eFlow^® nebulizer, single dose (12.5, 25, 50, 100, and 200 μg)	42 (40–75 years of age with moderate-to-severe COPD)	– Dose ranging	– AE, vital signs, ECG and clinical laboratory tests – Plasma pharmacokinetic of GBn	– Dose–response relationship for time normalized FEV1 (0–24 hours) and placebo-adjusted mean ΔFEV1 (P<0.05 with GBn 50 μg) – Clinically meaningful improvements (>100 mL) for 100 and 200 μg doses – Comparable AE profile to placebo – Peak plasma concentration at 15–30 min – Dose-proportional increase in Cmax – t1/2 0–1 hours: 1.10–1.15 hours – t1/2 0–12 hours: 2.30–7.45 hours for GBn 50–400 μg
GOLDEN-1,^Citation42 NCT01426009	Phase II, multicenter, randomized, double-blind, placebo-controlled, seven arm, four-period cross-over, incomplete block design, 1 week	– GBn via eFlow^® nebulizer OD – Tiotropium bromide via HandiHaler^® OD – Ipratropium bromide via general purpose nebulizer 500 μg TID	105 (40–75 years of age with moderate-to-severe COPD)	– Trough FEV1 – Mean change in 24-h postdose trough FEV1 on days 1 and 7 – FEV1 AUC – Standardized change in FEV1 AUC (0–12 and 12–24 hours) on days 1 and 7	– Proportion of subjects reaching MCID in trough FEV1 on days 1 and 7 – Safety and tolerability of GBn – AEs, vital signs, ECG, and clinical laboratory tests – Rescue medication use	– No difference in AEs between dosages – No dose relationship for AEs – Vital signs and ECG comparable between treatment groups – Significant dose-related improvements in FEV1 (AUC 0–24) vs placebo (110–169 mL)
GOLDEN-2,^Citation43,Citation86 NCT01706536	Phase II, randomized, double-blind, placebo-controlled, parallel arm, 4 weeks	– GBn via eFlow^® nebulizer BID (12.5, 25, 50, and 100 μg) – Aclidinium bromide via Pressair^® 400 μg	282 (35–75 years of age, with moderate-to-severe COPD)	– Morning trough FEV1 on 29th day	– FEV1 AUC (0–12) – FEV1 AUC (12–24) – Peak FEV1 – TEAE leading or not to discontinuation – Treatment-emergent SAE	GOLDEN-2 + GOLDEN-6 pooled (N=378): – Clinical important improvements vs placebo at days 7 and 28 (82 mL for GBn 6.25 BID and 177 mL for 100 μg BID) – Corresponding FEV1 AUC (0–12): from 84 to 183 mL
GOLDEN-6,^Citation47,Citation86 NCT02038829	Phase II, randomized, double-blind, placebo and active-controlled, cross-over, 1 week	– GBn via eFlow^® nebulizer BID (3, 6.25, 12.5, 25, and 50 μg) – Aclidinium bromide via Pressair^® 400 μg BID	96 (40–75 years of age with moderate-to-severe COPD)	– Change in trough FEV1 day 7	– FEV1 AUC (0–12 hours) – TEAE (overall and by treatment)	– GBn doses of 25 and 50 μg comparable to aclidinium – GBn 3 μg dose = no effect dose
GOLDEN-3,^Citation44,Citation88,Citation92 NCT02347761	Phase III, randomized, double-blind, placebo-controlled, parallel-group, multicenter, 12 weeks	– GBn via eFlow^® nebulizer BID (25 and 50 μg)	653 (40–75 years of age with moderate-to-severe COPD)	– Trough FEV1 at week 12	– FEV1 AUC (0–12) at 12 weeks in the sub-study population – Trough FVC at week 12 – SGRQ at week 12 – Rescue medication use – TEAE leading or not to discontinuation – N treatment emergent SAE – MACE	GOLDEN-3 and GOLDEN-4 pooled analysis: Trough FEV1 vs placebo at week 12 for GBn 25 and 50 μg (all P<0.0001): – GOLDEN-3: 0.105 and 0.126 L; – GOLDEN-4: 0.084 and 0.082 L; No difference in efficacy depending on previous chronic treatment Trough FVC1 vs placebo at week 12 for GBn 25 and 50 μg (all P<0.0001):
GOLDEN-4,^Citation45,Citation88,Citation92 NCT02347774	Phase III, randomized, double-blind, placebo-controlled, parallel-group, multicenter, 12 weeks	– GBn via eFlow^® nebulizer BID (25 and 50 μg)	640 (40–75 years of age with moderate-to-severe COPD)	– Trough FEV1 at week 12	– Trough FVC – SGRQ – Rescue medication use – TEAE leading or not to discontinuation – Treatment emergent SAE – MACE	– GOLDEN-3: 0.149 and 0.167 L – GOLDEN-4: 0.130 and 0.113 L SGRQ week 12: Placebo-adjusted LS mean (SD) – GBn 25 μg: −3.35 (0.79) – GBn 50 μg: −2.71 (0.80) Adjusted LS mean (SD) symptoms domain: – GBn 25 μg: −3.61 (1.16) – GBn 50 μg: −3.92 (1.16) SGRQ responders: – 46.8, 41.7, and 34.5% for 25 and 50 μg and placebo (P<0.05) Most frequent TEAEs: COPD worsening and cough. No difference in exacerbation rates vs placebo TEAEs leading to discontinuation more frequent for placebo (9% in both studies) GOLDEN-3: 3 MACE (GBn 50 μg) GOLDEN-4: 2 MACE (placebo) No difference in ECG parameters
GOLDEN-5,^Citation46,Citation89 NCT02276222	Phase III, randomized, open-label, active-controlled, parallel-group, multicenter, long-term, 48 weeks	– GBn via eFlow^® nebulizer 50 μg BID – Tiotropium bromide via Handihaler^® 18 μg OD	1,086 (GBn n=620, tiotropium n=466) (40–75 years of age with moderate-to-severe COPD)	– TEAEs – Treatment-emergent SAEs – TEAEs leading to discontinuation	– MACE, including cardiovascular death, ischemia/infarction, and stroke – Trough FEV1 at 48 weeks	SGRQ responders were similar for tiotropium (48.6%) and GBn (51.2%) at week 24 TEAEs similar for GBn (69%) vs TIO (67%) Most frequent TEAEs: COPD and cough TEAEs leading to discontinuation: 10% for GBn and 2.8% for TIO Most frequent for GBn: cough (2.3%); dyspnea (1.5%); and COPD (1.9%) MACE incidence rate: 6.4/1,000 persons per year for GBn and 20.3/1,000 per year for TIO Three deaths in GBn group and four deaths in TIO No deaths treatment related

Note: ID, ClinicalTrials.gov identifier.

Abbreviations: AEs, adverse events; BID, bis in die; COPD, chronic obstructive pulmonary disease; ECG, electrocardiogram; FEV₁, forced expiratory volume in the first second; FVC, forced vital capacity; GBn, nebulized glycopyrronium bromide; GOLDEN, Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer; LS, least squares; MACE, major adverse cardiovascular events; OD, once daily; MCID, minimal clinical importance difference; QTc, corrected QT interval; SAE, serious adverse event; SGRQ, St George’s Respiratory Questionnaire; TEAE, treatment-emergent adverse event; TID, ter in die.

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