A Phase IIb, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Safety, and Pharmacokinetics of Glycopyrrolate Inhalation Solution Over 1 Week in Subjects With COPD
Phase: PHASE2
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Verona Pharma plc

 
 
 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Phase IIb, randomized, double-blind, placebo-
controlled study to assess the efficacy, safety, and 
pharmacokinetics of glycopyrrolate inhalation solution 
over 1 week in subjects with COPD 
Protocol Number: 
RPL554-CO-211 
Version: 
3.0 
Investigational Product: 
glycopyrrolate 
Short Title: 
A Phase IIb study of glycopyrrolate inhalation solution 
over 1 week in subjects with COPD 
Study Phase: 
IIb 
Sponsor Name: 
Verona Pharma plc 
 
Legal Registered Address: 3 More London Riverside 
London, SE1 2RE 
UK 
Regulatory Agency 
Identifying Number(s): 
US IND Number: 170330 
Date of Protocol: 
14 October 2024  
 
 

Protocol RPL554-CO-211 
 
 
Version 3.0; 14 October 2024 
Verona Pharma plc 
CONFIDENTIAL 
Page 2 of 110 
 
Sponsor Signatory: 
 
I have read this protocol in its entirety and agree with the content: 
 
 
 
 
 
 
Date 
 
 
 
Medical Monitor name and contact information can be found in Appendix 2. 

Protocol RPL554-CO-211 
 
 
Version 3.0; 14 October 2024 
Verona Pharma plc 
CONFIDENTIAL 
Page 3 of 110 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document History 
Protocol 
Version 
Amendment 
Date 
Substantial – Timing 
Region 
Version 1.0 
Original Protocol 
12 March 2024 
Original Protocol 
Global 
Version 2.0 
Amendment 1.0 
6 June 2024 
Yes – prior to initial regulatory 
submission 
Global 
Version 3.0 
Amendment 2.0 
14 October 2024 
No 
Global 
 
Protocol Version 3.0, Amendment 2.0: 14 October 2024 Overall 
Rationale for the Amendment 
The protocol is amended to address: 
1. Minor administrative items (spelling, punctuation, spaces, and table numbering). 
2. Clarifications. 
3. Clarify procedures to address public emergencies and natural disasters. 

Protocol RPL554-CO-211 
 
 
Version 3.0; 14 October 2024 
Verona Pharma plc 
CONFIDENTIAL 
Page 4 of 110 
Section 
Number 
Change 
Brief 
Rationale 
Synopsis: 
Overall Design 
& Sec. 4.1 
Each subject is expected to complete all 4 Treatment Periods. 
Subjects who do not complete at least 2 Treatment Periods may be 
replaced.  
 
Clarifying 
plan to 
replace 
subjects who 
do not 
complete at 
least 2 
Treatment 
Periods. 
Synopsis: 
Overall Design 
During the treatment period, subjects will complete all assessments 
and procedures as outlined in the Schedule of Activities (Section 1.3) 
for approximately 24 10 weeks for each subject.  
 
Corrected 
study 
duration.  
Synopsis: 
Number of 
Investigators 
and Study 
Sites 
Approximately 67 Investigators and study centers are expected to 
participate in this study. 
 
Increased 
estimated site 
number.  
SoA Sec. 1.3 
 
 
 
Updates for 
consistency 
and clarity.  
Added line to 
clarify timing 
of 
registration in 
IRT versus 
randomizatio
n in IRT.  
Removed 
collection of 
FSH for 
consistency 
with 
Appendix 3 
and 
Appendix 7.  

Protocol RPL554-CO-211 
 
 
Version 3.0; 14 October 2024 
Verona Pharma plc 
CONFIDENTIAL 
Page 5 of 110 
Study 
Treatment Sec. 
6.0 
Subjects will receive double-blind study medication (either 
glycopyrrolate or placebo) in the proposed FDC formulation 
administered by inhalation via a standard jet nebulizer (Section 6.2.2) 
supplied by the Sponsor. To account for visit windows, sufficient 
drug supply will be dispensed for up to 11 days of treatment for each 
treatment period. 
Added 
language to 
clarify 
amount of 
drug 
dispensed.  
Subject 
Discontinuation 
Sec. 7.3 
Subjects who require an extended washout period > 28 days will be 
withdrawn from the study. 
Added 
language to 
clarify 
withdrawal 
criteria. 
Study 
Assessments 
Sec. 8.0 
Adherence to the study design requirements, including those specified 
in the SoA, is essential and required for study conduct. In the event a 
public emergency or natural disaster impacts a subject’s ability to 
complete study requirements, refer to Section 8.9.  
 
Added 
reference to 
new section 
for 
emergencies.  
Emergency 
Procedures 
Sec. 8.9 
Sufficient study drug is provided to enable up to 11 days of dosing in 
a given treatment period. In the event of a public emergency or 
natural disaster, the dosing interval may be extended up to 11 days to 
allow at least 6 consecutive days of dosing prior to the End of 
Treatment Period Visit (nominal Day 7 Visit) which may occur 
between Day 7 and Day 11. If a public emergency or natural disaster 
results in a subject being unable to complete at least 6 consecutive 
days of dosing prior to the End of Treatment Period Visit (nominal 
Day 7 visit which may occur between Days 7 and 11), the treatment 
period should be repeated with the repeat Day 1 visit occurring at 
least 7 days after the last administered dose of blinded study 
medication. In the event of a public emergency or natural disaster, the 
7-day washout period may be extended up to 28 days. Subjects 
requiring a washout period > 28 days will be withdrawn from the 
study.  
New section 
to address 
public health 
emergencies 
and natural 
disasters. 
 
Protocol Version 2.0, Amendment 1.0: 06 June 2024 Overall Rational 
for the Amendment 
The protocol is amended to address: 
1. Minor administrative items (spelling, punctuation, spaces, and Table numbering). 
2. Clarifications. 
3. Allow use of LABA ± ICS BID as background therapy during the study. 

Protocol RPL554-CO-211 
 
 
Version 3.0; 14 October 2024 
Verona Pharma plc 
CONFIDENTIAL 
Page 6 of 110 
4. Remove requirement to discontinue any COPD medications for study entry. 
5. Remove the interim analysis. 
6. Remove the inclusion criteria around FEV1 responsiveness requirements. 
7. Add a cap to the proportion of subjects with low responsiveness to albuterol. 
8. Change timeframe for the exclusion criteria around COPD symptoms. 
9. Add COPD withdrawal criteria. 

Protocol RPL554-CO-211 
 
 
Version 3.0; 14 October 2024 
Verona Pharma plc 
CONFIDENTIAL 
Page 7 of 110 
Section 
Number 
Change 
Brief Rationale 
Synopsis: 
Rationale 
& 
Sec 2.2.3 
It has similar affinity to the subtypes of muscarinic receptors M1 to M5, 
and higher affinity for M3 over M2. 
Clarifying data 
on 
glycopyrrolate 
Synopsis: 
Objectives 
& 
Sec 3.1.2 
& 
multiple 
other 
locations 
• To evaluate the bronchodilator effect of BID inhaled 
glycopyrrolate solution in the proposed FDC 
formulation on Day 7 peak FEV1, average FEV1 
area under the curve versus time from time 0 to 4 
hours (AUC0-4h), average FEV1 AUC0-12h, and 
evening trough FEV1. 
Clarification 
Synopsis: 
Overall 
Design & 
4.1 
Dose Level 
Blinded Study Medication 
A 
Glycopyrrolate 85 µg BID  
B 
Glycopyrrolate 42.5 µg BID 
C 
Glycopyrrolate 14 µg BID 
D 
Placebo BID 
Dose Arm A: glycopyrrolate (85 µg) BID 
Dose Arm B: glycopyrrolate (42.5 µg) BID 
Dose Arm C: glycopyrrolate (14 µg) BID 
Dose Arm D: placebo BID 
Clarification 
putting text in 
table 
Synopsis: 
Overall 
Design & 
4.1 
Subjects will be randomly assigned to Treatment Sequences 1 to 4 in a 
1:1:1:1 ratio to receive the 4 dose levels in the following sequences: 
Treatment 
Sequence 
Dose Levels Administered in Each Treatment 
Period 
Treatment 
Period 1  
(N = 40) 
Treatment 
Period 2  
(N = 40) 
Treatment 
Period 3  
(N = 40) 
Treatment 
Period 4  
(N = 40) 
Sequence 
1 
(N = ~10) 
A 
D 
B 
C 
Sequence 
2 
(N = ~10) 
B 
A 
C 
D 
Sequence 
3 
(N = ~10) 
C 
B 
D 
A 
Sequence 
4 
(N = ~10) 
D 
C 
A 
B 
receive the 4 dose levels in 1 of 4 dosing sequences: 
Sequence 1: A:D:B:C 
Sequence 2: B:A:C:D 
Sequence 3: C:B:D:A 
Sequence 4: D:C:A:B 
Clarifying text 

Protocol RPL554-CO-211 
 
 
Version 3.0; 14 October 2024 
Verona Pharma plc 
CONFIDENTIAL 
Page 8 of 110 
Synopsis: 
Overall 
Design & 
4.1 
Screening for eligibility will include a reversibility responsiveness test 
(spirometry both pre- and post - 4 puffs of albuterol) performed 
between 7 and 14 days before the first dose of blinded study 
medication. The proportion of the study population who have a 
post-albuterol FEV1 increase of < 12% or < 200 mL will be capped at 
approximately 50%.To be eligible, subjects must have a ≥ 150 mL 
increase in FEV1 with albuterol. Rescreening is allowed once for a 
screen failure due to Inclusion Criterion #6: ≥ 150 mL increase from 
pre bronchodilator FEV1, if the subject that screen failed was within 
10% (15 mL) of this threshold. 
Remove the 
inclusion criteria 
around FEV1 
responsiveness 
requirements & 
add a cap to the 
proportion of 
subjects with 
low 
responsiveness 
to albuterol 
Synopsis: 
Overall 
Design & 
4.1 
Eligible subjects will have discontinued long-acting SomeProhibited  
COPD medications are prohibited for the time periodsprior to and 
during the study are described in Table 8 prior to Visit 2. It is not 
recommended that subjects discontinue  
Discontinuation of any maintenance COPD therapies for the sole 
purpose of entering this studystudy eligibility is not recommended. 
Remove 
requirement to 
discontinue any 
COPD 
medications for 
study entry 
Synopsis: 
Overall 
Design & 
4.1 
UStable use of BID LABA ± inhaled corticosteroids (ICS) at a 
maintenance dose is allowed under certain condpermitted during the 
studyitions (Table 7). 
Allow use of 
LABA ± ICS 
BID as 
background 
therapy during 
the study 
Synopsis: 
Overall 
Design & 
4.1 
At the Screening (Visit 1), all subjects will be dispensed albuterol as 
rescue medication to be used as needed during the screening, treatment, 
and washout periods.   Subjects who are required to withhold 
medications prior to Screening (Visit 1) for a washout period will be 
dispensed albuterol as rescue medication upon signing of the Informed 
Consent Form (ICF) for use prior to Visit 1.  
Remove 
requirement to 
discontinue any 
COPD 
medications for 
study entry 
Synopsis: 
Overall 
Design & 
4.1 
Subjects will should withhold rescue medication use for ≥ 4 hours and, 
if applicable, BID LABA ± ICS use for approximately 24≥ 12 hours 
prior to spirometry at all required visits. If If the rescue medication this 
withholding period is not met,  or if BID LABA ± ICS medications are 
taken the morning of a clinic visit where spirometry is conducted, the 
subject will be rescheduled for a repeat visit within 7 or 3 days of Day 1 
or Day 7, respectively. 
Add withholding 
requirement for 
background 
LABA/ICS prior 
to spirometry. 
Synopsis: 
Overall 
Design & 
4.1 
Subjects will be screened for eligibility during a screening period of 7 
to 14 days. Prohibited medications and the prohibited time intervals 
prior to Screening are described in Section . 
Remove 
redundant 
language 
Synopsis: 
Overall 
Design & 
4.1 
Subjects will complete all assessments and procedures as outlined in the 
Schedule of Activities (SoA; ).  
During the treatment period, subjects will complete all assessments and 
procedures as outlined in the Schedule of Activities (Section 1.3) for 24 
weeks.  
Subjects completing treatment will complete a Follow-Up Phone Call 
7 ± 1 days after the last scheduled study visit.  
Clarification 
Synopsis: 
Overall 
Design 
Subjects who experience ≥ 1 moderate or severe COPD exacerbations 
during the study will discontinue study medication and be withdrawn 
from the study. 
Addition of 
COPD 
withdrawal 
criteria 

Protocol RPL554-CO-211 
 
 
Version 3.0; 14 October 2024 
Verona Pharma plc 
CONFIDENTIAL 
Page 9 of 110 
Synopsis: 
Overall 
Design & 
4.1 
Subjects who permanently discontinue double-blind study medication 
will be withdrawn from the study. 
Subjects meeting the withdrawal criteria during the study or who 
withdraw from the study for other reasons will be discontinued and 
requested to complete the Early Termination/Withdrawal Procedures 
and complete a Follow-Up Phone Call 7 ± 1 days after the Early 
Termination/Withdrawal Visit.Subjects completing treatment will 
complete a Termination Visit 7 ± 1 days after the last dose of blinded 
study medication. Subjects who discontinue blinded study medication, 
meet the withdrawal criteria during the study, or who withdraw from 
the study for other reasons will be discontinued from the study and 
requested to complete Early Withdrawal Visit 7 ± 1 days after the last 
dose of blinded study medication. 
Subjects who permanently discontinue double blind study medication 
will be withdrawn from the study. 
Clarification 
Synopsis: 
Inclusion 
Criteria & 
Sec 5.1 
6.    Post-bronchodilator (4 puffs of albuterol) spirometry at Screening 
demonstrating the following: 
• 
FEV1/forced vital capacity (FVC) ratio of < 0.70 
• 
FEV1 ≥ 40 30 % and ≤ 8070% of predicted normal (Quanjer et 
al. 2012) 
≥ 150 mL increase from pre-bronchodilator FEV1Note: The 
proportion of the study population who have a post-
albuterol FEV1 increase of < 12% or < 200 mL will be 
capped at approximately 50%. 
Remove FEV1 
responsiveness 
criterion, change 
severity 
criterion, and 
add cap on low-
responsive 
subjects. 
Synopsis: 
Inclusion 
Criteria & 
Sec 5.1 
8.0 
Capable of withdrawing from long-acting bronchodilators for 
the duration of the study and short-acting bronchodilators for 4 
hours prior to spirometry testing and from BID LABA ± ICS 
therapy for 24 hours prior to spirometry.. 
Remove 
withdrawal of 
COPD meds and 
add requirement 
to withhold 
LABA/ICS prior 
to spirometry. 
Synopsis: 
Exclusion 
Criteria & 
Sec 5.2 
2.0 
Within 3 6 months prior to Screening: 
a. 
COPD exacerbation requiring hospitalization. 
b. Use of therapies for COPD exacerbation (e.g., oral, 
intravenous, or intramuscular glucocorticoids). 
Change 
timeframe for 
the exclusion 
criteria around 
COPD 
symptoms. 
Synopsis: 
Exclusion 
Criteria & 
Sec 5.2 
1.18. Severe comorbidities including unstable cardiac, (e.g., 
myocardial infarction within 1 year prior to screening, unstable 
angina within 6 months prior to screening, or unstable or life-
threatening arrhythmia requiring intervention within 3 months prior 
to screening, diagnosis of NYHA class III or IV heart disease) or 
any other clinically significant medical conditions including 
uncontrolled diseases (e.g., endocrine, neurological, hepatic, 
gastrointestinal, renal, hematological, urological, immunological, 
psychiatric or ophthalmic diseases) that would, in the opinion of 
the Investigator, preclude the subject from safely completing the 
required tests or the study, or is likely to result in disease 
progression that would require withdrawal of the subject. 
Change the 
order of the 
Exclusion 
Criteria for 
clarity. 
Synopsis: 
Treatment 
Groups 
and 
Duration 
All blinded study medications will be double-blind and administered 
using the inhaled route via a standard jet nebulizer supplied by the 
Sponsor. Nebulization time should be approximately 5 to 10 minutes. 
Subjects taking maintenance BID LABA ± ICS medications should 
take the LABA ± ICS medication prior to taking blinded study 
medication when taking the blinded study medication at home. 
Provide 
guidance on 
when to dose 
LABA/ICS 

Protocol RPL554-CO-211 
 
 
Version 3.0; 14 October 2024 
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CONFIDENTIAL 
Page 10 of 110 
Synopsis: 
Statistical 
Methods 
& Sec 9.6 
A Data Assessment Committee (DAC) will perform an unblinded 
interim analysis either when approximately 18 subjects have completed 
Visit 9 (Day 7 of Treatment Period 4) OR when approximately 
36 subjects have completed Visit 5 (Day 7 of Treatment Period 2), 
whichever occurs earliest. This interim analysis will analyze available 
FEV1, PK, and safety data to inform glycopyrrolate dose selection for a 
subsequent fixed dose combination study of glycopyrrolate and 
ensifentrine (Study CO 212). The interim analysis will not impact study 
integrity, completion, change subject recruitment, or lead to design 
changes for this study. Unblinded data and interim results will not be 
shared outside the DACNo interim analysis is planned. 
Remove interim 
analysis 
Sec 1.3 
 
Edits for Clarity 

Protocol RPL554-CO-211 
 
 
Version 3.0; 14 October 2024 
Verona Pharma plc 
CONFIDENTIAL 
Page 11 of 110 
Sec 1.3 
a. Check subject’s use of check concomitant medications, subject’s  foruse of 
prohibited medications, subject’s washout withholding compliance, and that 
there are no clinically relevant changes in health status that, in the opinion of the 
investigator, would prohibit the subject from completing the treatment 
Treatment pPeriod.  
b. Study rescue medication should be dispensed once the subject has signed the ICF 
for subjects that require a wash outwithholding period prior to Screening (Visit 
1). 
c. Demographics to include (date of birth, age, gender, race, ethnicity). 
d. A posterior-anterior CXR at Screening or within 12 months prior to Screening 
showing no clinically significant abnormalities unrelated to COPD is required. If 
a CXR within the past 12 months is not available but a CT scan within the same 
time period is available, the CT scan may be reviewed in place of a CXR. 
e. ECGs should be obtained before all other simultaneously scheduled procedures 
are completed. 
f. Complete physical exam at Screening and on Day 1 pre dose to include:include 
assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, 
lungs, cardiovascular, abdomen (spleen and liver), lymph nodes and extremities. 
Findings of the physical exam should be recorded in the subjects medical history. 
g. Vital signs: (pulse rate, blood pressure) will be at screeningScreening, pre-dose, 1 
hour and 4 hours post-dose on Days 1 and, Day 7,, and at Early 
Withdrawal/Termination Visit (pre dose). 
h. The laboratory test to be performed are specified in Table 11.Hematology: WBC 
with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), 
RBC, Hg, HCT, and platelet count. 
i. 
Chemistry: BUN, creatinine, glucose, GGT, AST, ALT, ALP, creatine kinase, 
magnesium, potassium, sodium, chloride, amylase, total, indirect and direct 
bilirubin, total protein, phosphate, carbon dioxide (bicarbonate), calcium, lactase 
dehydrogenase, albumin, uric acid, triglycerides, eGFR (CK/MB fraction and 
conjugated and unconjugated bilirubin (if clinically indicated). 
j. 
The serology test to be performed are specified in Table 11Hepatitis B serology 
(markers include HBsAg, anti HBs, anti HBc, and others) and hepatitis C virus 
antibody.. 
k. On Days 1 and 7 of each Treatment Period, pre dose spirometry will be to be 
cconducted pre dose at 2 separate time points within 40 min pre dose on and 
post dose spirometry at 30 min, 1 h, 1.5 h, 2 h, and 4 h post dose. On Day 7 of 
each Treatment Period, pre dose spirometry to be conducted pre dose at one pre
dose timepoint approximately 12 hours following the prior evening dose and 
post dose spirometry at 30 min, 1, 2, 4, 6, 8, and 12 hours post dose (as specified 
in Table 2).  
l. 
Responsiveness testing only conducted at the Screening Visit. 
m. In clinic dosing performed after pre-dose spirometry and pre-dose PK sampling in 
the morning,. and after completion of the 12 hour spirometry timepoint in the 
evening. 
n. PK sample collection times on Day 7 of Treatment Periods 1 and 2 only are as 
follows: pre dose (within 30 minutes prior to dosing) and post dose at 10 ± 4, 20 
± 4, and 40 ± 4 minutes post dose and at 1, 1.5, 2, 4, 8, and 12 hours (all later 
timepoints at ± 15 minutes) post doseare specified in  (Table 3). PK samples 
should be taken after all concomitantly scheduled assessments (e.g., ECG, 
FEV1). 
o. AEs will be collected Day 1 through the EOS. SAE’s related to study participation 
will be recorded from the time the subject consents until study discharge. 
p. Phone call reminder to subjects to remind them to take their evening dose 
approximately 12 hours prior to the anticipated arrival time to the clinic on 
Day 7, to note the time of the Day 6 evening dose was taken and to report that 
time to site staff at the Day 7 visit, to withhold the Day 7 morning dose until at 
the clinic, to withhold albuterol within 4 hours of their Day 7 visit, to withhold, if 
applicable,  BID LABA ± ICS use within approximately 24 hours of their Day 7 
visit, and to bring their unused study medication to the clinic visit the next day. 
Remove 
washout of 
COPD meds and 
clarify text. 
Sec 1.3 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; ALP = alkaline 
phosphatase; anti HBc = total hepatitis B core antibody; anti HBs = hepatitis B surface 
antibody; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CK = creatine 
kinase; COPD = Chronic Obstructive Pulmonary Disease; CT = Computed Tomography; 
CXR = Chest X-Ray; ECG = Electrocardiogram; eGFR = estimated glomerular filtration 
rate; EOS = End of Study; ET/W/T = Early Termination/Withdrawal/Termination; 
FEV1 = forced expiratory volume over 1 second; FSH = follicle-stimulating hormone; 
FVC = forced vital capacity; GGT = gamma glutamyl transpeptidase; HBsAg = hepatitis 
B surface antigen; hCG = human chorionic gonadotropin; ICF = informed consent form; 
IRT = Interactive Response Technology; HCT = hematocrit; Hg = hemoglobin; 
MB = myocardial band; PK = pharmacokinetics; RBC = red blood cell; SAE = serious 
adverse events; WBC = white blood cell; WOCBP = women of childbearing potential. 
Clarify text. 

Protocol RPL554-CO-211 
 
 
Version 3.0; 14 October 2024 
Verona Pharma plc 
CONFIDENTIAL 
Page 12 of 110 
Sec 1.4 
Note: Additional details on information contained in this table can be found in Section 6.0 
and Section 8.3.1.  Rescue medications should have been withheld for ≥ 4 hours prior to 
spirometry and, if applicable, BID LABA ± ICS medications should have been withheld 
for approximately 24 hours prior to spirometry. 
Add withholding 
periods for meds 
prior to 
spirometry 
Sec 2.3 
Serious adverse events (SAEs) have not been reported in product labels 
for nebulized glycopyrrolate products. No required dose adjustment in 
renal or hepatic impairment COPD patients has been required for 
nebulized glycopyrrolate, 
Remove 
incorrect 
statement 
Sec 3.2.5 
Glycopyrronium free base multiple dose PK parameters (AUC0-12h, 
maximum serum plasma drug concentration [Cmax], time to Cmax [tmax]) 
post-morning dose on Day 7. 
Change serum to 
plasma 
Sec 4.2 
Study Design Justification 
The purpose of this study is to inform the dose selection of 
glycopyrrolate for the planned Phase 2b Study CO-212. Study CO-212 
is planned as a 4-week parallel group study to compare multiple doses 
of glycopyrrolate combined with 3 mg of ensifentrine as a FDC to the 
glycopyrrolate and ensifentrine individual components and placebo.  
This study will use pulmonary function test results and PK analyses to 
perform an initial evaluation of the potential glycopyrrolate doses over 
a dose range. The study intends to enroll a population of subjects with 
stable, moderate to severe COPD. COPD patients can exhibit varying 
degrees of responsiveness to bronchodilators such as albuterol, with 
approximately 20  to 50% of clinical trial populations displaying ≥ 12% 
and ≥ 200  mL increases in FEV1 following dosing with albuterol 
(Hanania et al. 2011; Anzueto et al. 2023). Given that this study is 
intended to inform on dose-responsiveness to a bronchodilator 
(glycopyrrolate), entry criteria is planned to enroll approximately 50% 
of COPD subjects with ≥ 12% and ≥ 200 mL increase in FEV1 
following albuterol, in order to optimally assess differences in dose 
levels. 
 Incorporation of a placebo arm into the study design will allow 
accurate interpretation of these resultstreatment effect for each dose 
level and clear identification of the proper glycopyrrolate doses for use 
in Study CO-212. 
The use of a placebo arm in the study is considered safe for the 
subjectsjustified for the following reasons: 
• 
Subjects will be permitted to be on BID LABA ± ICS 
background therapy to treat their COPD throughout the study. 
• 
Subjects with unstable COPD (i.e., any severe COPD 
exacerbations within 6 months of Screening) are excluded. 
• 
Discontinuation of any maintenance COPD therapies for the 
sole purpose of study eligibility is not recommended. 
• 
The maximum continuous period that a subject could be on 
placebo and no study medication is 3 weeks (1 week of 
placebo therapy between two 1-week wash-out periods). 
• 
The maximum continuous period that a subject could be on 
placebo, low-dose glycopyrrolate, and no active study 
medication is 5 weeks (i.e., 1 week of placebo therapy and 1 
week of low-dose glycopyrrolate, each between two 1-week 
wash-out periods). 
Add further 
design 
justification 

Protocol RPL554-CO-211 
 
 
Version 3.0; 14 October 2024 
Verona Pharma plc 
CONFIDENTIAL 
Page 13 of 110 
Sec 5.3 
3. Significantly abnormal ECG finding, as defined in Appendix 4 , on 
the 12-lead ECG obtained pre-dose at Visit 2at Screening as assessed 
by the investigator or site medical doctor/medically qualified person or 
on the pre dose ECG obtained at Visit 1 before the subject has been 
randomized.  After a subject has been randomized, ECG withdrawal 
criteria () will apply. In the event that the central ECG reviewer 
discovers a significant ECG abnormality meeting an ECG withdrawal 
criterion on the Visit 1 ECG in 2 of 3 triplicate measurements, the 
subject may be discontinued. 
4. Did not meet ≥ 1 of the Inclusion Criteria (Section 5.1) or met ≥ 1 of 
the Exclusion Criteria (Section 5.2) as assessed at Screening (e.g., 
includingthrough overreads or lab values obtained after the day of 
Screeningdata 
Clarifying text 
Sec 5.3 
5. At Screening the subject's albuterol responsiveness test had an FEV1 
increase of < 12% or < 200 mL after 4 puffs of albuterol AND the 
randomization cap of approximately 50% of subjects in that 
responsiveness category has been met. 
Add criterion for 
cap of low-
responsive 
subjects 
Sec 5.5.1 
Subjects may not be rescreened if their post-albuterol spirometry at 
Screening demonstrated any of the following: 
• 
FEV1/FVC ratio ≥ 0.7 OR 
• 
FEV1 < 30% of predicted normal OR 
• 
FEV1 > 70% of predicted normal. 
Rescreening is allowed only once for a screen failure due to both of 
following: 
• 
A subject’s Screening albuterol responsiveness test had an 
FEV1 increase of < 12% or < 200 mL after 4 puffs of albuterol 
AND 
• 
The randomization cap of approximately 50% of subjects in 
that responsiveness category has been met. 
SSubjects who are screen failures for other reason (Section 5.6) may be 
rescreened with approval from the Medical Monitor..  
Rescreened subjects should be assigned a new subject number different 
from the initial Screening event.  
Rescreening is allowed once for a screen failure due to Inclusion 
Criterion #6: ≥ 150 mL increase from pre bronchodilator FEV1, if the 
subject that screen failed was within 10% (15 mL) of this threshold. 
Rescreening due to failure to meet other lung function criteria within 
Criterion #6 is not allowed. 
Clarification and 
add cap of low-
responsive 
subjects 
Sec 6.0 
In this protocol the terms ‘investigational product’, ‘double-blind study 
medication’, and ‘blinded study medication’ are the same and refer to 
the blinded nebulized study medication.  
Subjects taking maintenance BID LABA ± ICS medications should 
take the LABA ± ICS medication prior to taking blinded study 
medication when taking the blinded study medication at home. 
Add guidance on 
timing of 
LABA/ICS 
dosing 
Sec 6.1.1 
• 
If the rescue medications are not withheld for the time 
intervals defined in Section 4 hours prior to spirometry.. 
• 
If the pre-dose FEV1 on Day 1 of the current Treatment Period 
is not within ± 20% of the pre dose FEV1 at Day 1 of the first 
Treatment Period 
• 
For a subject on a maintenance BID LABA ± ICS therapy, if 
the BID LABA ± ICS are not withheld for approximately 12 
hours (e.g. ≥ 12 hoursLABA maintenance therapy taken the 
morning of the clinic visit) prior to spirometry. 
Clarification and 
add withholding 
requirements for 
LABA/ICS 

Protocol RPL554-CO-211 
 
 
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Table 7 
Allow use of 
LABA/ICS 
Sec 6.6.3 
Prohibited medications and therapies are provided in Table 8. All 
prohibited medications are not to be taken during the time periods 
describedstudy conduct, including screening periods, treatment periods, 
washout periods, and the follow up period. 
Discontinuation of any maintenance COPD therapies for the sole 
purpose of study eligibility is not recommended. 
Remove 
washout of 
COPD meds. 
Table 8 
3 6 months prior to Screening and prohibited during the study. 
 
Table 8 
1 day24 hours prior to Screening and prohibited during the study. 
Clarification 
Table 8 
LAMAs 
1. Once-daily LAMAs 
2. BID LAMAs 
 
1. 48 hours prior to Screening and 
prohibited during the study 
2. 24 hours prior to Screening and 
prohibited during the study 
Add LAMA 
restrictions 
Table 8 
Starting or stopping ICS is not allowed during the study.  
ICS monotherapy and high dose ICS (e.g., > 1000 µg of fluticasone 
propionate or equivalent) is not allowed. 
Clarify ICS 
restrictions 
Sec 
8.3.1.2 
o 
Blinded Study Medication: Blinded study medication must be 
withheld until pre-dose spirometry is completed. 
o 
Rescue Medication and: Albuterol must be withheld for ≥ 4 hours. 
BID LABA ± ICS: Must be2412 
o *If the withholding periods above are not met, the visit should be 
rescheduled withheld per Section 6.1.1. 
Add withholding 
for LABA/ICS 
Sec 8.9 
8.9 Data Assessment Committee 
A Data Assessment Committee (DAC) will be established for this study 
for the sole purpose of interpreting the planned interim analysis to 
inform on dose selection for fixed dose combination Study CO 212 
(Section ). The DAC will not be involved in study conduct or decisions 
relating to Study CO 211. Further details as to the composition, 
conduct, and handling of unblinded data can be found in the DAC 
Charter.  
Remove interim 
analysis 

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Appendix 
7 
Male Subjects 
• 
Male subjects with female partners of childbearing potential 
are eligible to participate if they agree to ONE of the following 
from the first dose up to 30 days after the last dose of study 
medication: 
 
Are abstinent from penile vaginal intercourse as their 
usual and preferred lifestyle (abstinent on a long term 
and persistent basis) and agree to remain abstinent. 
­ 
Agree to use a male condom plus partner use of a 
contraceptive method with a failure rate of < 1% per 
year as described in  when having penile vaginal 
intercourse with a woman of childbearing potential 
who is not currently pregnant. 
• 
In addition, male subjects must refrain from donating sperm 
for the duration of the study and for 30 days after the last dose 
of study medication. 
• 
Male subjects with a pregnant or breastfeeding partner must 
agree to remain abstinent from penile vaginal intercourse or 
use a male condom during each episode of penile penetration 
during the study and for 30 days after the last dose of study 
medication. 
Remove Male 
contraception 
Guidance not 
required for 
glycopyrrolate 
Appendix 
7 
Male subjects with partners who become pregnant 
The Investigator will attempt to collect pregnancy information on any 
male subject’s female partner who becomes pregnant while the male 
subject is in the study. This applies only to male subjects who receive 
glycopyrrolate. 
After obtaining the necessary signed informed consent from the 
pregnant female partner directly, the Investigator will record pregnancy 
information on the appropriate form and submit it to the Sponsor within 
24 hours of learning of the partner’s pregnancy. The female partner will 
also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to 
the Sponsor. Generally, the follow up will be no longer than 6 to 
8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
Remove Male 
contraception 
Guidance not 
required for 
glycopyrrolate 
Appendix 
7 
The subject will be approached and asked to consent to be followed to 
determine the outcome of the pregnancy. 
Clarify 
procedure for 
female subjects 
who become 
pregnant 
Table 11 
Neutrophils, absolute 
COVID 19 testing2 
 
Remove 
COVID-19 
testing 
Table 11 
2COVID 19 test (optional) may be performed locally. 
Remove 
COVID-19 
testing 
 
 

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TABLE OF CONTENTS 
TITLE PAGE ...............................................................................................................1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ................................... 3 
TABLE OF CONTENTS .......................................................................................... 16 
1.0 
PROTOCOL SUMMARY ............................................................................ 21 
1.1 
Synopsis ..................................................................................................... 21 
1.2 
Schema ...................................................................................................... 32 
1.3 
Schedule of Activities ............................................................................... 33 
1.4 
Schedule of Spirometry, PK, and In-Clinic Dosing with Blinded Study 
Medication ................................................................................................ 36 
2.0 
INTRODUCTION.......................................................................................... 37 
2.1 
Study Rationale ........................................................................................ 37 
2.2 
Background .............................................................................................. 37 
2.2.1 
Chronic Obstructive Pulmonary Disease ........................................... 37 
2.2.2 
Ensifentrine ........................................................................................ 38 
2.2.3 
Glycopyrrolate ................................................................................... 38 
2.2.4 
Ensifentrine and Glycopyrrolate Combination .................................. 39 
2.3 
Benefit/Risk Assessment .......................................................................... 40 
3.0 
OBJECTIVES AND ENDPOINTS .............................................................. 41 
3.1 
Objectives.................................................................................................. 41 
3.1.1 
Primary Objective .............................................................................. 41 
3.1.2 
Secondary Objectives ........................................................................ 41 
3.1.3 
Exploratory Objective ....................................................................... 41 
3.1.4 
Safety Objective ................................................................................ 41 
3.1.5 
Pharmacokinetics Objective .............................................................. 41 
3.2 
Endpoints .................................................................................................. 41 
3.2.1 
Primary Endpoint ............................................................................... 41 
3.2.2 
Secondary Endpoints ......................................................................... 41 
3.2.3 
Exploratory Endpoint ........................................................................ 42 
3.2.4 
Safety Endpoints ................................................................................ 42 
3.2.5 
Pharmacokinetic Endpoints ............................................................... 42 
4.0 
Study Design ................................................................................................... 43 
4.1 
Overall Design .......................................................................................... 43 
4.2 
Study Design Justification ....................................................................... 45 
4.2.1 
Justification for Dose ......................................................................... 46 
4.2.2 
Justification for Duration ................................................................... 46 
4.3 
End of Study Definition ........................................................................... 47 
5.0 
STUDY POPULATION ................................................................................ 48 
5.1 
Inclusion Criteria ..................................................................................... 48 

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5.2 
Exclusion Criteria .................................................................................... 49 
5.3 
Randomization Criteria........................................................................... 52 
5.4 
Lifestyle Considerations .......................................................................... 53 
5.4.1 
Caffeine and Tobacco ........................................................................ 53 
5.5 
Rescreening ............................................................................................... 53 
5.5.1 
Rescreening of Subjects .................................................................... 53 
5.6 
Screen Failures ......................................................................................... 53 
6.0 
STUDY TREATMENT ................................................................................. 55 
6.1 
Administration of Blinded Study Medication ....................................... 55 
6.1.1 
Dosing in the Clinic ........................................................................... 55 
6.1.2 
Dosing at Home ................................................................................. 56 
6.2 
Investigational Product/Blinded Study Medication .............................. 57 
6.2.1 
Blinded Study Medication Dispensing Information .......................... 58 
6.2.2 
Medical Devices ................................................................................ 58 
6.3 
Preparation/Handling/Storage/Accountability ..................................... 58 
6.4 
Randomization and Blinding .................................................................. 59 
6.5 
Emergency Unblinding ............................................................................ 59 
6.6 
Concomitant Therapy .............................................................................. 60 
6.6.1 
Rescue Medication ............................................................................ 60 
6.6.2 
Permitted Rescue and Background Medications ............................... 60 
6.6.3 
Prohibited Medications/Therapy ....................................................... 61 
6.6.4 
Recording Use of Concomitant Medications .................................... 62 
6.7 
End of Study Procedures ......................................................................... 63 
6.8 
Treatment After the End of Study ......................................................... 63 
7.0 
Discontinuation of Blinded Study Medication and Subject 
Discontinuation/Withdrawal ......................................................................... 64 
7.1 
Discontinuation of Blinded Study Medication ...................................... 64 
7.1.1 
Does Not Meet Criteria for Randomization ...................................... 64 
7.1.2 
Liver Chemistry Stopping Criteria .................................................... 64 
7.1.3 
Electrocardiogram Withdrawal Criteria ............................................ 64 
7.1.4 
Positive Pregnancy Test in Females .................................................. 65 
7.1.5 
COPD Withdrawal Criteria ............................................................... 65 
7.1.6 
Other Criteria ..................................................................................... 65 
7.2 
Blinded Study Medication Compliance ................................................. 65 
7.2.1 
Discontinuation of the Study ............................................................. 65 
7.3 
Subject Discontinuation/Withdrawal from the Study .......................... 66 
7.3.1 
Early Withdrawal/Termination Procedures ....................................... 66 
7.4 
Lost to Follow-up ..................................................................................... 66 
8.0 
STUDY ASSESSMENTS AND PROCEDURES ........................................ 68 
8.1 
Screening Assessments and Procedures ................................................. 68 
8.1.1 
Informed Consent .............................................................................. 68 
8.1.2 
Demographic Variables ..................................................................... 68 
8.1.3 
Medical, Surgical, COPD, and Smoking History .............................. 69 
8.1.4 
Prior/Concomitant Medications/Therapies ........................................ 69 
8.1.5 
Vital Signs ......................................................................................... 69 
8.1.6 
Electrocardiogram ............................................................................. 69 

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8.1.7 
Chest X-Ray ...................................................................................... 69 
8.1.8 
Spirometry Assessment ..................................................................... 69 
8.1.9 
Clinical Laboratory Assessments ...................................................... 69 
8.1.10 
Physical Examination ........................................................................ 70 
8.1.11 
Inclusion/Exclusion Criteria .............................................................. 70 
8.1.12 
Interactive Response Technology ...................................................... 70 
8.1.13 
Nebulizer Equipment Training .......................................................... 70 
8.1.14 
Dispense Rescue Medication ............................................................. 70 
8.2 
Randomization Criteria Assessment – Visit 2 ....................................... 70 
8.3 
Efficacy Assessments ............................................................................... 70 
8.3.1 
Spirometry ......................................................................................... 70 
8.4 
Pharmacokinetic Assessments ................................................................ 71 
8.5 
Safety Assessments ................................................................................... 71 
8.5.1 
Vital Signs ......................................................................................... 72 
8.5.2 
Electrocardiogram ............................................................................. 72 
8.5.3 
Clinical Laboratory Assessments ...................................................... 72 
8.5.4 
Adverse Event Assessment ................................................................ 72 
8.6 
Other Assessments and Procedures ....................................................... 73 
8.6.1 
Concomitant Medication Assessment ............................................... 73 
8.6.2 
Interactive Response Technology ...................................................... 73 
8.6.3 
Randomization ................................................................................... 73 
8.6.4 
Nebulizer Equipment Training .......................................................... 73 
8.6.5 
Training for Spirometry ..................................................................... 73 
8.6.6 
Blinded Study Medication Dosing in the Clinic ................................ 73 
8.6.7 
Dispense Rescue Albuterol ................................................................ 74 
8.6.8 
Dispense/Collect Blinded Study Medication ..................................... 74 
8.7 
Adverse Events ......................................................................................... 74 
8.7.1 
Time Period and Frequency for Collecting AE and SAE Information
 ........................................................................................................... 74 
8.7.2 
Method of Detecting AEs and SAEs ................................................. 75 
8.7.3 
Follow-up of AEs and SAEs ............................................................. 75 
8.7.4 
Regulatory Reporting Requirements for SAEs ................................. 75 
8.7.5 
Pregnancy .......................................................................................... 75 
8.7.6 
Adverse Events of Special Interest .................................................... 76 
8.7.7 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs ............................................................... 76 
8.8 
Treatment of Overdose ............................................................................ 76 
8.9 
Emergency Procedures ............................................................................ 77 
9.0 
STATISTICAL CONSIDERATIONS ......................................................... 78 
9.1 
Statistical Hypotheses .............................................................................. 78 
9.2 
Sample Size Determination ..................................................................... 78 
9.3 
Populations for Analyses ......................................................................... 78 
9.4 
Statistical Methods ................................................................................... 79 
9.5 
Statistical Analyses................................................................................... 79 
9.5.1 
Efficacy Analyses .............................................................................. 79 
9.5.2 
Safety Analyses ................................................................................. 80 
9.5.3 
Pharmacokinetic Analyses ................................................................. 80 
9.5.4 
Other Analyses .................................................................................. 81 
9.5.5 
Missing Data ...................................................................................... 82 

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9.6 
Interim Analyses ...................................................................................... 82 
10.0 
REFERENCE LIST ....................................................................................... 83 
Appendix 1 
Abbreviations ....................................................................................... 85 
Appendix 2 
Regulatory, Ethical, and Study Oversight Consideration .................... 87 
Appendix 3 
Clinical Laboratory Tests ..................................................................... 93 
Appendix 4 
ECG Exclusion Criteria ....................................................................... 95 
Appendix 5 
ECG Withdrawal Criteria .................................................................... 96 
Appendix 6 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting .................................................. 97 
Appendix 7 
Contraceptive Guidance and Collection of Pregnancy Information .. 103 
Appendix 8 
Liver Safety ........................................................................................ 106 
Appendix 9 
Signature of Investigator .................................................................... 110 
 
 
 

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LIST OF IN-TEXT TABLES 
Table 1: Schedule of Assessments and Procedures ..................................................... 33 
Table 2: Schedule of Spirometry and In-Clinic Dosing with Blinded Study Medication
.............................................................................................................. 36 
Table 3: Schedule of PK and In-Clinic Dosing with Blinded Study Medication ........ 36 
Table 4: Glycopyrrolate-containing Products for COPD Treatment Approved in the 
US ........................................................................................................ 39 
Table 5: Dose Levels ................................................................................................... 43 
Table 6: Investigational Product/Blinded Study Medication Details .......................... 57 
Table 7: Permitted Rescue and Background Medications ........................................... 61 
Table 8: Prohibited Medications/Therapy ................................................................... 61 
Table 9: Study Administrative Structure ..................................................................... 90 
Table 10: Medical Monitor .......................................................................................... 90 
Table 11: Protocol Required Laboratory Assessments ................................................ 93 
Table 12: Highly Effective Contraceptive Methods .................................................. 103 
 
LIST OF IN-TEXT FIGURES 
Figure 1: Study Schematic ........................................................................................... 32 
 

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1.0 PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title 
A Phase IIb, randomized, double-blind, placebo-controlled study to assess the efficacy, 
safety, and pharmacokinetics of glycopyrrolate inhalation solution over 1 week in 
subjects with COPD. 
Short Title 
A Phase IIb study of glycopyrrolate inhalation solution over 1 week in subjects with 
COPD. 
Rationale 
Glycopyrrolate is a long-acting muscarinic antagonist (LAMA) which is often referred to 
as an anticholinergic. It has affinity to the subtypes of muscarinic receptors M1 to M5, 
and higher affinity for M3 over M2. In the airways, glycopyrrolate exhibits 
pharmacological effects through inhibition of M3 receptor in smooth muscle leading to 
bronchodilation. The competitive and reversible nature of antagonism has been shown 
with human and animal origin receptors and isolated organ preparations. 
Glycopyrrolate has been formulated in multiple inhaled approved products, both alone 
and in combination with other chronic obstructive pulmonary disease (COPD) 
maintenance therapies, for the maintenance treatment of COPD as a twice-daily (BID) 
treatment in the United States (US). 
Ensifentrine is a novel, small molecule, potent, selective dual inhibitor of 
Phosphodiesterase (PDE)3 and PDE4 being developed as treatment of COPD and other 
conditions.  
A fixed dose combination (FDC) product with ensifentrine and glycopyrrolate could 
provide a single nebulized product with pharmacology equivalent to 2 bronchodilator 
mechanisms and a non-steroidal anti-inflammatory mechanism.  
The new FDC product is proposed to contain ensifentrine in suspension and 
glycopyrrolate in solution in a citric acid-buffered formulation at pH 4.5 (FDC 
formulation) for delivery via a standard jet nebulizer. 
This dose-ranging trial (RPL554-CO-211) with glycopyrrolate solution delivered via 
standard jet nebulizer in the proposed FDC formulation will support the selection of the 
glycopyrrolate dose for further development. 

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Objectives 
Primary Objective 
• The primary objective of this study is to evaluate the bronchodilator effect of BID 
inhaled glycopyrrolate solution in the proposed FDC formulation over a dose 
range administered by standard jet nebulizer in subjects with COPD in terms of 
morning trough FEV1 on Day 7. 
Secondary Objectives 
• To evaluate the bronchodilator effect of BID inhaled glycopyrrolate solution in 
the proposed FDC formulation on Day 7 peak FEV1, average FEV1 area under the 
curve versus time from time 0 to 4 hours (AUC0-4h), average FEV1 AUC0-12h, and 
evening trough FEV1. 
• To evaluate the bronchodilator effect of a single dose of inhaled glycopyrrolate 
solution in the proposed FDC formulation on Day 1 peak FEV1 and 
FEV1 AUC0-4h. 
Exploratory Objective 
• To assess the dose response of BID inhaled glycopyrrolate solution in the 
proposed FDC formulation on peak FEV1, average FEV1 AUC0-12h, and morning 
trough FEV1 on Day 7. 
Safety Objective 
• To evaluate the safety and tolerability of inhaled glycopyrrolate solution in the 
proposed FDC formulation in subjects with COPD. 
Pharmacokinetic Objective 
• To assess the PK profile of multiple doses of inhaled glycopyrrolate solution in 
the proposed FDC formulation in subjects with COPD on Day 7. 
Endpoints 
Primary Endpoint 
• Change from average baseline FEV1 to morning trough FEV1 measured on Day 7. 
Secondary Endpoints 
• Change from average baseline FEV1 to average peak FEV1 measured over 4 hours 
post-dose on Day 7. 
• Change from average baseline FEV1 to average FEV1 AUC0-4h on Day 7. 
• Change from average baseline FEV1 to average FEV1 AUC0-12h on Day 7. 
• Change from average baseline FEV1 to evening trough FEV1 on Day 7. 
• Change from average baseline FEV1 to peak FEV1 measured over 4 hours after 
first dose on Day 1. 
• Change from average baseline FEV1 to average FEV1 AUC0-4h measured after first 
dose on Day 1. 

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Exploratory Endpoint 
• Association between glycopyrrolate dose and peak FEV1, average FEV1 AUC0-12h 
after morning dose on Day 7, and morning trough FEV1 prior to the last dose on 
Day 7. 
Safety Endpoints 
• Incidence of treatment emergent adverse events (AEs). 
• Change from baseline in laboratory safety tests (hematology and blood 
chemistry). 
• Change from baseline to markedly abnormal in laboratory safety tests 
(hematology and blood chemistry). 
• Shifts in laboratory safety tests (hematology and blood chemistry) classified as 
marked abnormalities. 
• Change from baseline in 12-lead ECG (including QTcF and heart rate). 
• Change from baseline to markedly abnormal 12-lead ECG (including QTcF and 
heart rate). 
• Shifts in 12-lead ECG (including QTcF and heart rate) from normal to abnormal. 
• Change from baseline in vital signs (blood pressure and pulse rate). 
• Change from baseline to markedly abnormal in vital signs (blood pressure and 
pulse rate). 
Pharmacokinetic Endpoint 
• Glycopyrronium free base multiple dose PK parameters (AUC0-12h, Cmax, tmax) 
post-morning dose on Day 7. 
Overall Design 
RPL554-CO-211 is a multicenter, randomized, double blind, placebo-controlled, 4-period 
cross-over study to evaluate glycopyrrolate dose-levels administered BID by a standard 
jet nebulizer in the proposed FDC formulation: 0 (placebo), 14 µg, 42.5 µg, and 85 µg 
glycopyrrolate. 
Approximately 40 eligible subjects meeting all inclusion and no exclusion criteria will be 
dosed for 4 consecutive 7-day Treatment Periods. The last dose in each Treatment Period 
will be the morning of the Day 7 clinic visit, and the Treatment Periods will be separated 
by a 7-day washout period (Figure 1).  

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Each subject will take 4 dose levels of blinded study medication, with 1 dose level taken 
during each Treatment Period: 
Dose Level 
Blinded Study Medication 
A 
Glycopyrrolate 85 µg BID  
B 
Glycopyrrolate 42.5 µg BID 
C 
Glycopyrrolate 14 µg BID 
D 
Placebo BID 
Subjects will be randomly assigned to Treatment Sequences 1 to 4 in a 1:1:1:1 ratio to 
receive the 4 dose levels in the following sequences: 
Treatment 
Sequence 
Dose Levels Administer in Each Treatment Period 
Treatment 
Period 1  
(N = 40) 
Treatment 
Period 2  
(N = 40) 
Treatment 
Period 3  
(N = 40) 
Treatment 
Period 4  
(N = 40) 
Sequence 1 
(N = 10) 
A 
D 
B 
C 
Sequence 2 
(N = 10) 
B 
A 
C 
D 
Sequence 3 
(N = 10) 
C 
B 
D 
A 
Sequence 4 
(N = 10) 
D 
C 
A 
B 
Each subject is expected to complete all 4 Treatment Periods. Subjects who do not 
complete at least 2 Treatment Periods may be replaced.  
Spirometry will be assessed pre- and post-dose on Days 1 and 7, as described in Table 2.  
PK sampling will take place on Day 7 in Treatment Periods 1 and 2 only following any 
ECG or lung function assessments, as described in Table 3. 
The pre-dose FEV1 on Day 1 of Treatment Periods 2 to 4 (i.e., Visits 4, 6, and 8) should 
be within ± 20% of the pre-dose FEV1 at Day 1 of Treatment Period 1 (Visit 2) to ensure 
a consistent baseline FEV1 for each Treatment Period. If the FEV1 varies by more than 
20%, the start of the Treatment Period must be rescheduled to occur within 7 days. 
Screening for eligibility will include a responsiveness test (spirometry both pre- and 
post-4 puffs of albuterol) performed between 7 and 14 days before the first dose of 
blinded study medication. The proportion of the study population who have a 
post-albuterol FEV1 increase of < 12% or < 200 mL will be capped at approximately 
50%. 
Prohibited COPD medications prior to and during the study are described in Table 8.  
Discontinuation of any maintenance COPD therapies for the sole purpose of study 
eligibility is not recommended. 

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Stable use of BID LABA ± inhaled corticosteroids (ICS) at a maintenance dose is 
permitted during the study (Table 7). 
At Screening (Visit 1), all subjects will be dispensed albuterol as rescue medication to be 
used as needed during the screening, treatment, and washout periods. Subjects who are 
required to withhold medications prior to Screening (Visit 1) will be dispensed albuterol 
as rescue medication upon signing of the Informed Consent Form (ICF) for use prior to 
Visit 1.  
Subjects should withhold rescue medication use for ≥ 4 hours and, if applicable, BID 
LABA ± ICS use for approximately 24 hours prior to spirometry at all required visits. If 
the rescue medication withholding period is not met or if BID LABA ± ICS medications 
are taken the morning of a clinic visit where spirometry is conducted, the subject will be 
rescheduled for a repeat visit within 7 or 3 days of Day 1 or Day 7, respectively. 
All sites will use standardized spirometry and electrocardiogram (ECG) equipment 
provided by a central vendor, and all spirometry and ECGs will be over-read by the 
blinded central vendor. 
Subjects will be screened for eligibility during a screening period of 7 to 14 days.  
During the treatment period, subjects will complete all assessments and procedures as 
outlined in the Schedule of Activities (Section 1.3) for approximately 10 weeks for each 
subject.  
Subjects completing treatment will complete a Follow-Up Phone Call 7 ± 1 days after the 
last scheduled study visit.  
Subjects who experience ≥ 1 moderate or severe COPD exacerbation during the study 
will discontinue study medication and be withdrawn from the study. 
Subjects who permanently discontinue double-blind study medication will be withdrawn 
from the study. 
Subjects meeting the withdrawal criteria during the study or who withdraw from the study 
for other reasons will be discontinued and requested to complete the Early Termination/ 
Withdrawal Procedures and complete a Follow-Up Phone Call 7 ± 1 days after the Early 
Termination/Withdrawal Visit. 
Number of Investigators and Study Centers 
Approximately 7 Investigators and study centers are expected to participate in this study. 
Number of Subjects 
Approximately 40 randomized subjects are planned. 

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Inclusion Criteria 
1. Capable of giving informed consent indicating that they understand the purpose of 
the study and study procedures and agree to comply with the requirements and 
restrictions listed in the informed consent form (ICF) and in this protocol. 
2. Age: Subject must be 40 to 80 years of age inclusive, at the time of Screening. 
3. Sex: 
• Males are eligible to participate if they agree to use contraception as described 
in the contraceptive guidance (Appendix 7) from Screening and throughout the 
study and for at least 30 days after the last dose of blinded study medication. 
• Females are eligible to participate if they are not pregnant, not breastfeeding, 
and ≥ 1 of the following conditions apply: 
a) Not a woman of childbearing potential (WOCBP) as defined in 
Appendix 7. 
OR 
b) A WOCBP who agrees to follow the contraceptive guidance in 
Appendix 7 from Screening and throughout the study and for at least 
30 days after the last dose of blinded study medication. 
4. Smoking History: Current or former cigarette smokers with a history of cigarette 
smoking ≥ 10 pack years at Screening [number of pack years = (number of 
cigarettes per day / 20) × number of years smoked (e.g., 20 cigarettes per day for 
10 years, or 10 cigarettes per day for 20 years)]. Pipe and/or cigar use cannot be 
used to calculate pack-year history. Former smokers are defined as those who 
have stopped smoking for at least 6 months prior to Screening. Smoking cessation 
programs are permitted during the study. 
5. COPD Diagnosis: Subjects with an established clinical history of COPD as 
defined by the American Thoracic Society (ATS)/European Respiratory Society 
(ERS) guidelines (Celli et al. 2004) with symptoms compatible with COPD. 
6. Post-bronchodilator (4 puffs of salbutamol) spirometry at Screening 
demonstrating both the following: 
a. FEV1/forced vital capacity (FVC) ratio of < 0.70 AND 
b. FEV1 ≥ 30 % and ≤ 70% of predicted normal (Quanjer et al. 2012). 
Note: The proportion of the study population who have a post-albuterol FEV1 
increase of < 12% or < 200 mL will be capped at approximately 50%. 

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7. A posterior-anterior chest x-ray (CXR) at Screening or within 12 months prior to 
Screening showing no clinically significant abnormalities unrelated to COPD. If a 
CXR within the past 12 months is not available but a computed tomography (CT) 
scan within the same time period is available, the CT scan may be reviewed in 
place of a CXR. 
8. Capable of withdrawing from short-acting bronchodilators for 4 hours prior to 
spirometry testing and from BID LABA ± ICS therapy for 24 hours prior to 
spirometry. 
9. Capable of using the study nebulizer correctly. 
10. Ability to perform acceptable spirometry in accordance with ATS/ERS guidelines 
(Graham et al. 2019). 
11. Willing and able to attend all study visits and adhere to all study assessments and 
procedures. 
Exclusion Criteria 
1. Concomitant clinically significant pulmonary disease other than COPD (i.e., 
asthma, tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, 
interstitial lung diseases, sleep apnea (unless controlled with stable continuous 
positive airway pressure [CPAP] use), known alpha-1 antitrypsin deficiency, core 
pulmonale or other non-specific pulmonary disease). 
2. Within 6 months prior to Screening: 
a. COPD exacerbation requiring hospitalization. 
b. Use of therapies for COPD exacerbation (e.g., oral, intravenous, or 
intramuscular glucocorticoids). 
3. Lower respiratory tract infection within 6 weeks of Screening or an active 
infection at Screening. 
4. History of life-threatening COPD, including Intensive Care Unit admission and/or 
requiring intubation. 
5. Previous lung resection or lung reduction surgery within 1-year of Screening. 
6. Long term oxygen use defined as oxygen therapy prescribed for greater than 
12 hours per day. As needed oxygen use (≤ 12 hours per day) is not exclusionary. 
7. Severe comorbidities including unstable cardiac, (e.g., myocardial infarction 
within 1 year prior to screening, unstable angina within 6 months prior to 
screening, or unstable or life-threatening arrhythmia requiring intervention within 

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3 months prior to screening, diagnosis of New York Heart Association (NYHA) 
class III or IV heart disease) or any other clinically significant medical conditions 
including uncontrolled diseases (e.g., endocrine, neurological, hepatic, 
gastrointestinal, renal, hematological, urological, immunological, psychiatric or 
ophthalmic diseases) that would, in the opinion of the Investigator, preclude the 
subject from safely completing the required tests or the study, or is likely to result 
in disease progression that would require withdrawal of the subject. 
8. History of or clinically significant on-going bladder outflow obstruction or history 
of catheterization for relief of bladder outflow obstruction within the previous 
6 months. 
9. History of narrow angle glaucoma. 
10. History of hypersensitivity or intolerance to aerosol medications, salbutamol or 
glycopyrrolate or any of its excipients/components, anticholinergic agents, or 
sympathomimetic amines. 
11. Pulmonary rehabilitation unless such treatment has been stable from 4 weeks prior 
to Screening (Visit 1) and remains stable during the study. Pulmonary 
rehabilitation programs should not be started or completed during participation in 
the study. 
12. Major surgery (requiring general anesthesia) in the 6 weeks prior to Screening, 
lack of full recovery from surgery at Screening, or planned surgery through the 
end of the study. 
13. History of or current malignancy of any organ system, treated or untreated within 
the past 5 years, except for localized basal or squamous cell carcinoma of the skin. 
14. Significant psychiatric disease that would likely result in the subject not being 
able to complete the study, in the opinion of the Investigator. 
15. Findings on physical examination that an investigator considers to be clinically 
significant at Screening. 
16. Use of prohibited medications within the time intervals defined in Section 6.6.3. 
17. Current or history of drug or alcohol abuse within the past 5 years. 
18. Estimated glomerular filtration rate (eGFR) < 30 mL/min. The Chronic Kidney 
Disease Epidemiology Collaboration Creatinine (2021) calculation will be used 
(Inker et al. 2021). 

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19. Alanine aminotransferase (ALT) ≥ 2 × upper limit of normal (ULN), alkaline 
phosphatase and/or bilirubin > 1.5 × ULN (isolated bilirubin > 1.5 × ULN is 
acceptable if fractionated bilirubin < 35%). 
20. Any other abnormal hematology, biochemistry, or viral serology deemed by the 
Investigator to be clinically significant. Abnormal chemistry and/or hematology 
may be repeated during Screening. 
21. Abnormal ECG (Appendix 4) at the screening visit that is clinically significant. 
22. Women who are breast feeding. 
23. Use of an experimental drug within 30 days or 5 half-lives of Screening, 
whichever is longer, and/or participation in a study treatment-free follow-up phase 
of a clinical study within 30 days prior to Screening. 
24. Use of an experimental medical device or participation in a follow-up phase of an 
experimental medical device clinical study within 30 days prior to Screening. 
25. Affiliation with the investigator site, including an Investigator, Sub-Investigator, 
study coordinator, study nurse, other employee of participating investigator or 
study site or a family member of the aforementioned. 
26. A disclosed history or one known to the Investigator of significant noncompliance 
in previous investigational studies or with prescribed medications. 
27. Any other reason that the Investigator considers makes the subject unsuitable to 
participate. 
Treatment Groups and Duration 
Randomization will assign each subject in a crossover fashion to one of 4 treatment 
sequences (see definitions above), representing a unique combination of four 1-week 
treatment periods covering each treatment arm of the study, Periods 1 through 4 will be 
separated by a 7-day washout period. 
All blinded study medications will be double-blind and administered using the inhaled 
route via a standard jet nebulizer supplied by the Sponsor. Nebulization time should be 
approximately 5 to 10 minutes. Subjects taking maintenance BID LABA ± ICS 
medications should take the LABA ± ICS medication prior to taking blinded study 
medication when taking the blinded study medication at home. 
Following Visit 2, subjects will self-administer their daily morning and evening doses at 
home at approximately the same times, approximately 12 hours apart, each day for the 
duration of the Treatment Period, except for clinic visits on Days 1 and 7 of each 
Treatment Period when subjects will have their morning doses administered in the clinic.  

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Statistical Methods 
The aim of this study is to quantify the benefit of each glycopyrrolate dose over placebo 
in efficacy as mean change from baseline in FEV1. The null hypotheses to be tested for 
each efficacy endpoint will be that there is no difference in change from baseline between 
glycopyrrolate and placebo for each glycopyrrolate dose, against the alternative 
hypothesis that change differs between that glycopyrrolate dose and placebo. All tests 
will be two-sided at a 5% significance level. Primary and secondary endpoints will be 
evaluated at a nominal Type 1 error level of 0.05, and Type 1 error will not be adjusted 
for multiplicity.  
In general, unless stated otherwise, continuous variables will be summarized using 
descriptive statistics (number of subjects, mean, standard deviation [SD], median, 
minimum, and maximum values) and for categorical (nominal) variables, the number and 
percentage of subjects will be used. 
Treatments will be characterized and comparisons, when performed, will be made from 
estimates obtained from analysis of covariance models.   
Spirometry parameters will be analyzed as change from average baseline FEV1 on study 
Day 1 and, separately, on Day 7, and will not be transformed prior to analysis.  Models 
will include terms for treatment, period, and subject as fixed effects, and baseline as a 
covariate. A separate model will be fit for each efficacy parameter from Day 1 and from 
Day 7.    
Each efficacy parameter will be summarized both for the absolute value and for change 
from baseline using descriptive statistics (N, mean, median, SD, minimum, and 
maximum) for each treatment, generated separately for each Period as well as overall. 
Average baseline will represent the average of the two pre-treatment FEV1 values prior to 
the first dose of double-blind medication in each Treatment Period. 
Safety analysis will be descriptive and based on the safety set including all randomized 
and treated subjects. Safety analysis will be by actual treatment received. 
The following PK parameters will be calculated from plasma concentrations of 
glycopyrronium on Day 7. 
• AUC0-12h denotes the area under the plasma concentration curve versus time over 
the 12-hour dosing interval following the morning dose. 
• Cmax denotes the highest plasma concentration measured over the dosing interval. 
• Ctrough denotes the plasma concentration measured prior to dose administration. 
• Cavg denotes the plasma average concentration measured over the dosing interval, 
calculated as AUC0-12h divided by the dosing interval. 
•  tmax denotes the time point corresponding to Cmax. 
Other PK parameters may also be calculated. 

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No interim analysis is planned. 
Sample Size 
Estimates obtained from a 6-period multi-dose crossover study of BID nebulized 
glycopyrrolate at Day 7 for change from baseline in trough FEV1 (Saluja et al. 2017). 
Assuming the standard deviation for the differences (SDD) equal to 0.153 L, a sample 
size of 36 subjects provides 85% statistical power to detect a between-group difference 
with placebo in trough FEV1 at Day 7 of at least 81 mL.  The sample size provides 
adequate statistical power for statistical comparisons of each secondary endpoint. 
Subjects who withdraw prior to completing 2 treatment periods may be replaced. 
Assuming approximately 10% of early withdrawals, approximately 40 subjects will be 
enrolled.       

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Abbreviations: AE = adverse event; COPD = Chronic Obstructive Pulmonary Disease; CT = Computed Tomography; CXR = Chest X-Ray; ECG = Electrocardiogram; EOS = End of Study; 
ET/W = Early Termination/Withdrawal; FEV1 = forced expiratory volume over 1 second; FVC = forced vital capacity; hCG = human chorionic gonadotropin; ICF = informed consent form; 
IRT = Interactive Response Technology; PK = pharmacokinetics; SAE = serious adverse events; WOCBP = women of childbearing potential. 
withhold albuterol within 4 hours of their Day 7 visit, to withhold, if applicable,  BID LABA ± ICS use within approximately 24 hours of their Day 7 visit, and to 
bring their unused study medication to the clinic visit the next day. 

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2.0 INTRODUCTION 
2.1 
Study Rationale 
Verona Pharma plc. (Verona) is developing inhaled nebulized ensifentrine and 
glycopyrrolate fixed dose combination (FDC) as a novel therapy for the maintenance 
treatment of chronic obstructive pulmonary disease (COPD). RPL554-CO-211 
(Study CO-211) is the first of 2 planned Phase II studies investigating the ensifentrine and 
glycopyrrolate combination. Study CO-211 will assess a dose-range for glycopyrrolate 
solution delivered via standard jet nebulizer in the proposed FDC formulation. The results 
from this study will inform the dose selection for the second Phase II study, 
RPL554-CO-212 (Study CO-212), which will assess combinations of ensifentrine and 
glycopyrrolate, with planned comparisons to individual components, ensifentrine and 
glycopyrrolate. 
2.2 
Background 
2.2.1 
Chronic Obstructive Pulmonary Disease 
COPD is characterized by progressive airflow obstruction which is largely irreversible. 
Chronic inflammation of the respiratory tract, acute exacerbations primarily caused by 
viral and/or bacterial infections, airway remodeling, and excessive mucus production are 
believed to contribute to the airflow obstruction and lung parenchymal destruction. COPD 
is predicted to be the third leading cause of death and fourth most common cause of 
disability worldwide by 2030, and chronic tobacco smoke exposure is believed to be a 
key etiological factor (STUCKLER 2008). Current standard-of-care treatments include 
inhaled short- and long-acting bronchodilators (i.e., muscarinic antagonists and 
β2 agonists) and inhaled corticosteroids (ICS). One oral phosphodiesterase (PDE) 4 
inhibitor, roflumilast, has been approved for the reduction in risk of COPD exacerbations 
in patients with severe COPD associated with chronic bronchitis and a history of 
exacerbations. These therapies have little or no effect on disease progression or mortality, 
although there is evidence that they reduce exacerbation rates and improve quality of life 
(Rabe et al. 2005; Calverley et al. 2007; Rennard et al. 2011; Singh 2015). 
Current therapies in the COPD market (e.g., long-acting muscarinic antagonists 
[LAMAs], long-acting β2-agonists [LABAs], ICS, Daliresp [PDE4 inhibitor]) are 
typically used in combination to optimize treatment effects in patients. In the United 
States (US), > 80% of COPD patients are currently treated with combination products 
(Mannino et al. 2022). This is also further emphasized in the Global Initiative for Chronic 
Obstructive Lung Disease (GOLD) 2024 update, which recommends LAMA/LABA 
combination therapy as the first treatment option for patients with COPD (GOLD 2024). 
Several fixed-dose combination products have been approved for the treatment of COPD. 
DuoNeb® (short acting) is the only nebulized FDC product, while all the other FDC 

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products are formulated for dry powder inhaler (DPI) or pressurized metered dose inhaler 
(pMDI) delivery. 
There is a need for nebulized combination maintenance therapies for COPD patients, as 
none are currently available or in development. Nebulized therapies offer ease of use 
compared to current handheld delivery systems and are often used and preferred by 
patients. Nebulizers can be ideal delivery devices for any COPD patient, particularly 
patients with low inspiratory flow levels and/or cognitive and dexterity issues which limit 
overall effectiveness of DPI or pMDI delivery devices. In fact, up to 90% of COPD 
patients do not use inhalers correctly (Dijk et al. 2023), which can lead to continued 
symptoms and future exacerbations. 
2.2.2 
Ensifentrine 
Ensifentrine is a novel, small molecule, potent, and selective dual inhibitor of PDE3 and 
PDE4. This dual mechanism of action has the potential to offer an important maintenance 
treatment option for the treatment of obstructive and inflammatory diseases of the 
respiratory tract, such as COPD, non-cystic fibrosis bronchiectasis (NCFBE), cystic 
fibrosis, and asthma. 
Ensifentrine has been evaluated in 22 completed clinical studies involving approximately 
3,000 subjects, of which 16 studies involving over 2,800 subjects comprise the COPD 
development program including pharmacokinetic (PK), pharmacodynamic (PD), 
Phase IIb, and Phase III studies. One additional PK study in Chinese healthy volunteers 
has been completed. In the COPD clinical program, ensifentrine has demonstrated 
pronounced and consistent bronchodilator effects as well as substantial reductions in 
moderate and severe COPD exacerbation rate and risk, as measured by time to first event. 
In addition, subjects treated with ensifentrine experienced improvements in symptoms 
and quality of life. Overall, ensifentrine was well-tolerated with a low incidence of 
adverse events (AEs), with rates generally similar to placebo (please refer to the 
Investigator’s Brochure [IB] for further detail). 
A New Drug Application for ensifentrine (3 mg) inhalation suspension for the 
maintenance treatment of COPD was submitted to the US Food and Drug Administration 
(FDA) on 26 June 2023 and is currently under review by the FDA with a Prescription 
Drug User Fee Act target action date of 26 June 2024. 
2.2.3 
Glycopyrrolate 
Glycopyrrolate is a LAMA which is often referred to as an anticholinergic (Chabicovsky 
et al. 2019). It has affinity to the subtypes of muscarinic receptors M1 to M5, and higher 
affinity for M3 over M2. In the airways, glycopyrrolate exhibits pharmacological effects 
through inhibition of M3 receptor at the smooth muscle leading to bronchodilation. The 
competitive and reversible nature of antagonism was shown with human and animal 
origin receptors and isolated organ preparations. 

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Glycopyrrolate has been formulated in multiple approved inhaled products for the 
maintenance treatment of COPD as a twice-daily (BID) treatment in the US (Table 4), 
including Lonhala Magnair (nebulized glycopyrrolate solution) (Sunovion 2019). 
Table 4: Glycopyrrolate-containing Products for COPD Treatment Approved in the 
US 
Drug Name 
Active Ingredients 
Strength/Dose 
Dosage 
Form 
Action Date 
Marketing 
Status 
UTIBRON™ 
NEOHALER® 
Glycopyrrolate; 
Indacaterol Maleate 
15.6 µg/inh; 
27.5 µg/inh, 
BID 
Powder, 
oral 
inhalation 
29-Oct-2015 
Discontinued 
SEEBRI™ 
NEOHALER® 
Glycopyrrolate 
15.6 µg/inh, 
BID 
Powder, 
oral 
inhalation 
29-Oct-2015 
Discontinued 
BEVESPI 
AEROSPHERE™ 
Formoterol 
Fumarate; 
Glycopyrrolate 
4.8 µg/inh; 
9 µg/inh 
 
Total dose = 
2 inh, BID 
Pressurized 
metered 
dose 
inhaler  
25-Apr-2016 
Prescription 
LONHALA™ 
MAGNAIR™ 
Glycopyrrolate 
25 µg in 
1 mL, BID 
Solution, 
inhalation 
5-Dec-2017 
Discontinued 
BREZTRI 
AEROSPHERE™ 
Budesonide; 
Formoterol 
Fumarate; 
Glycopyrrolate 
160 µg/inh; 
4.8 µg/inh; 
9 µg/inh 
 
Total dose = 
2 inh, BID 
Pressurized 
metered 
dose 
inhaler 
23-Jul-2020 
Prescription 
Abbreviations: BID = twice daily; inh = inhaled; US = United States. 
2.2.4 
Ensifentrine and Glycopyrrolate Combination 
An FDC product with ensifentrine and another bronchodilator could provide a single 
nebulized product with pharmacology equivalent to 2 bronchodilator mechanisms and a 
non-steroidal anti-inflammatory mechanism. Clinical data with ensifentrine added on to 
LAMAs compared with placebo added onto LAMAs demonstrate complementary 
efficacy in terms of lung function improvement, symptoms, quality of life, and 
exacerbation reduction (see the IB for details). The pharmacological profile of 
ensifentrine added to a LAMA strongly supports development of a FDC product. As 
clinical data support BID inhaled dosing via nebulizer for both ensifentrine and 
glycopyrrolate and with nonclinical evidence of a synergistic effect, glycopyrrolate has 
been selected as the combination partner. 
The new FDC product is proposed to contain ensifentrine in suspension and 
glycopyrrolate in solution in a citric acid-buffered formulation at pH 4.5 for delivery via a 
standard jet nebulizer. The proposed formulation for the FDC of glycopyrrolate and 
ensifentrine has not been evaluated in humans to date with either medicine. 

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2.3 
Benefit/Risk Assessment 
Risks for nebulized glycopyrrolate include paradoxical bronchospasm, immediate 
hypersensitivity reactions, worsening of narrow-angle glaucoma, and worsening of 
urinary retention (Sunovion 2019).  Data from clinical studies of nebulized glycopyrrolate 
suggest a potential for dyspnea and urinary tract infection with short-term (12-week) 
treatment. Although the glycopyrrolate formulation nebulized in this study has not been 
administered previously, nebulized glycopyrrolate in a citric acid buffered solution at 
pH 4 (Lonhala) has been well tolerated in moderate-severe COPD patients (Sunovion 
2019). No required dose adjustment in renal or hepatic impairment COPD patients has 
been required for nebulized glycopyrrolate, and no clinically relevant changes in cardiac 
electrophysiology have been observed.  Nebulized glycopyrrolate has not been associated 
with teratogenic effects or effects on embryo-fetal survival and development in the rat or 
rabbit. Glycopyrronium has been detected in the milk of lactating rats. 
Significant improvement in morning trough forced expiratory volume in 1 second (FEV1) 
and FEV1 area under the curve versus time from time 0 to 12 hours (AUC0-12h) have been 
demonstrated following treatment with nebulized glycopyrrolate after 7 days of treatment 
at doses of ≥ 6.25 µg BID.  Glycopyrrolate is to be administered for approximately 
21 days (42 doses) in this study; any benefit to study subjects will be limited to the 
duration of the study. 

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3.0 OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
3.1.1 
Primary Objective 
• To evaluate the bronchodilator effect of BID inhaled glycopyrrolate solution in 
the proposed FDC formulation over a dose range administered by standard jet 
nebulizer in subjects with COPD in terms of morning trough FEV1 on Day 7. 
3.1.2 
Secondary Objectives 
• To evaluate the bronchodilator effect of BID inhaled glycopyrrolate solution in 
the proposed FDC formulation on Day 7 peak FEV1, average FEV1 area under the 
curve versus time from time 0 to 4 hours (AUC0-4h), average FEV1 AUC0-12h, and 
evening trough FEV1. 
• To evaluate the bronchodilator effect of a single dose of inhaled glycopyrrolate 
solution in the proposed FDC formulation on Day 1 peak FEV1 and 
FEV1 AUC0-4h. 
3.1.3 
Exploratory Objective 
• To assess the dose response of BID inhaled glycopyrrolate solution in the 
proposed FDC formulation on peak FEV1, average FEV1 AUC0-12h, and morning 
trough FEV1 on Day 7. 
3.1.4 
Safety Objective 
• To evaluate the safety and tolerability of inhaled glycopyrrolate solution in the 
proposed FDC formulation in subjects with COPD. 
3.1.5 
Pharmacokinetics Objective 
• To assess the PK profile of multiple doses of inhaled glycopyrrolate solution in 
the proposed FDC formulation in subjects with COPD on Day 7. 
3.2 
Endpoints 
3.2.1 
Primary Endpoint 
• Change from average baseline in morning trough FEV1 measured on Day 7. 
3.2.2 
Secondary Endpoints 
• Change from average baseline FEV1 to average peak FEV1 measured over 4 
hours -post dose on Day 7. 
• Change from average baseline FEV1 to average FEV1 AUC0-4h on Day 7. 
• Change from average baseline FEV1 to average FEV1 AUC0-12h on Day 7. 
• Change from average baseline FEV1 to evening trough FEV1 on Day 7. 

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• Change from average baseline FEV1 to peak FEV1 measured over 4 hours after 
first dose on Day 1. 
• Change from average baseline FEV1 to average FEV1 AUC0-4h measured after first 
dose on Day 1. 
3.2.3 
Exploratory Endpoint 
• Association between glycopyrrolate dose and peak FEV1, average FEV1 AUC0-12h 
after morning dose on Day 7, and morning trough FEV1 prior to the last dose on 
Day 7. 
3.2.4 
Safety Endpoints 
• Incidence of AEs. 
• Change from baseline in laboratory safety tests (hematology and blood 
chemistry). 
• Markedly abnormal changes in laboratory safety tests (hematology and blood 
chemistry). 
• Shifts in laboratory safety tests (hematology and blood chemistry) classified as 
marked abnormalities. 
• Change from baseline in 12-lead electrocardiogram (ECG) (including QT interval 
corrected for heart rate using Fridericia’s formula [QTcF] and heart rate). 
• Shifts in 12-lead ECG (including QTcF and heart rate) from normal to abnormal. 
• Change from baseline in vital signs (blood pressure and pulse rate). 
• Shifts in vital signs (blood pressure and pulse rate) classified as marked 
abnormalities. 
3.2.5 
Pharmacokinetic Endpoints 
• Glycopyrronium free base multiple dose PK parameters (AUC0-12h, maximum 
plasma drug concentration [Cmax], time to Cmax [tmax]) post-morning dose on 
Day 7. 

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4.0 Study Design 
4.1 
Overall Design 
Study CO-211 is a multicenter, randomized, double blind, placebo-controlled, 4-period 
cross-over study to evaluate glycopyrrolate dose-levels administered BID by a standard 
jet nebulizer in the proposed FDC formulation: 0 (placebo), 14 µg, 42.5 µg, and 85 µg 
glycopyrrolate. 
Approximately 40 eligible subjects meeting all inclusion and no exclusion criteria will be 
dosed for 4 consecutive 7-day Treatment Periods. The last dose in each Treatment Period 
will be the morning of the Day 7 clinic visit, and the Treatment Periods will be separated 
by a 7-day washout period (Figure 1).  
Each subject will take 4 dose levels of blinded study medication, with one dose level 
taken during each of the Treatment Periods (Table 5). 
Table 5: Dose Levels 
Dose Level 
Treatment 
A 
glycopyrrolate (85 µg) BID 
B 
glycopyrrolate (42.5 µg) BID  
C 
glycopyrrolate (14 µg) BID 
D 
placebo BID 
Subjects will be randomly assigned to Treatment Sequences 1 to 4 in a 1:1:1:1 ratio to 
receive the 4 dose levels in the following sequences: 
Treatment 
Sequence 
Dose Levels Administer in Each Treatment Period 
Treatment 
Period 1  
(N = 40) 
Treatment 
Period 2  
(N = 40) 
Treatment 
Period 3  
(N = 40) 
Treatment 
Period 4  
(N = 40) 
Sequence 1 
(N = 10) 
A 
D 
B 
C 
Sequence 2 
(N = 10) 
B 
A 
C 
D 
Sequence 3 
(N = 10) 
C 
B 
D 
A 
Sequence 4 
(N = 10) 
D 
C 
A 
B 
Each subject is expected to complete all 4 Treatment Periods. Subjects who do not 
complete at least 2 Treatment Periods may be replaced. 
Spirometry will be assessed pre- and post-dose on Days 1 and 7, as described in Table 2.  

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PK sampling will take place on Day 7 in Treatment Periods 1 and 2 only following any 
ECG or lung function assessments, as described in Table 3. 
The pre-dose FEV1 at on Day 1 of Treatment Periods 2 to 4 (i.e., Visits 4, 6, and 8) 
should be within ± 20% of the pre-dose- FEV1 at Day 1 of Treatment Period 1 (Visit 2) to 
ensure a consistent baseline FEV1 for each Treatment Period. If the FEV1 varies by more 
than 20%, the start of the Treatment Period must be rescheduled to occur within 7 days 
(Section 6.1.1). 
Screening for eligibility will include a responsiveness test (spirometry both pre- and 
post-4 puffs of albuterol) between 7 and 14 days before the first dose of blinded study 
medication at Visit 2. The proportion of the study population who have a post-albuterol 
FEV1 increase of < 12% or < 200 mL will be capped at approximately 50%. 
Prohibited medications and the prohibited time intervals prior to Screening are described 
in Section 6.6.3. Discontinuation of any maintenance COPD therapies for the sole 
purpose of study eligibility is not recommended. 
Stable use of BID LABA ± ICS at a maintenance dose is permitted during the study 
(Table 7). 
At the Screening (Visit 1), all subjects will be dispensed albuterol as rescue medication to 
be used as needed during the screening, treatment, and washout periods.  Subjects who 
are required to withhold medications prior to Screening (Visit 1) will be dispensed 
albuterol as rescue medication upon signing of the Informed Consent Form (ICF) for use 
prior to Visit 1.  
Subjects should withhold rescue medication use for ≥ 4 hours and, if applicable, BID 
LABA ± ICS use for approximately 24 hours prior to spirometry at all required visits. If 
the rescue medication withholding period is not met or if BID LABA ± ICS medications 
are taken the morning of a clinic visit where spirometry is conducted, the subject will be 
rescheduled for a repeat visit within 7 or 3 days of Day 1 or Day 7, respectively 
(Section 6.1.1).  
All sites will use standardized spirometry and ECG equipment provided by a central 
vendor, and all spirometry and ECGs will be over-read by the blinded central vendor. 
Subjects will be screened for eligibility during a screening period of 7 to 14 days.  
During each Treatment Period, subjects will complete all assessments and procedures as 
outlined in the Schedule of Activities (SoA; Table 1). Subjects will receive a phone call 
reminder on Day 6 of each Treatment Period to remind them to take their evening dose of 
blinded study medication approximately 12 hours prior to the anticipated arrival time to 
the clinic on Day 7, to note the time of the Day 6 evening dose was taken, to report that 
time to site staff at the Day 7 visit, to withhold the Day 7 morning dose until at the clinic, 
to withhold albuterol within 4 hours of their Day 7 visit, if applicable, to withhold BID 

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LABA ± ICS within approximately 24 hours of their Day 7 visit, and to bring their 
unused study medication to the clinic visit the next day. 
Subjects completing treatment will complete a Follow-Up Phone Call 7 ± 1 days after the 
last scheduled study visit.  
Subjects who experience ≥ 1 moderate or severe COPD exacerbation during the study 
will discontinue study medication and be withdrawn from the study. 
Subjects who permanently discontinue double-blind study medication will be withdrawn 
from the study. 
Subjects meeting the withdrawal criteria during the study or who withdraw from the study 
for other reasons will be discontinued and requested to complete the Early 
Termination/Withdrawal Procedures and complete a Follow-Up Phone Call 7 ± 1 days 
after the Early Termination/Withdrawal Visit. 
4.2 
Study Design Justification 
The purpose of this study is to inform the dose selection of glycopyrrolate for the planned 
Phase 2 Study CO-212. Study CO-212 is planned as a 4-week parallel group study to 
compare multiple doses of glycopyrrolate combined with 3 mg of ensifentrine as a FDC 
to the glycopyrrolate and ensifentrine individual components and placebo.  
This study will use pulmonary function test results and PK analyses to perform an initial 
evaluation of glycopyrrolate doses over a dose range. The study intends to enroll a 
population of subjects with stable, moderate to severe COPD. COPD patients can exhibit 
varying degrees of responsiveness to bronchodilators such as albuterol, with 
approximately 20 to 50% of clinical trial populations displaying ≥ 12% and ≥ 200 mL 
increases in FEV1 following dosing with albuterol (Hanania et al. 2011; Anzueto et al. 
2023). Given that this study is intended to inform on dose-responsiveness to a 
bronchodilator (glycopyrrolate), entry criteria is planned to enroll approximately 50% of 
COPD subjects with ≥ 12% and ≥ 200 mL increase in FEV1 following albuterol in order 
to optimally assess differences in dose levels. 
Incorporation of a placebo arm into the study design will allow accurate interpretation of 
treatment effect for each dose level and clear identification of the proper glycopyrrolate 
doses for use in Study CO-212. 
The use of a placebo arm in the study is justified for the following reasons: 
• Subjects will be permitted to be on BID LABA ± ICS background therapy to treat 
their COPD throughout the study. 
• Subjects with unstable COPD (i.e., any severe COPD exacerbations within 
6 months of Screening) are excluded. 

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• Discontinuation of any maintenance COPD therapies for the sole purpose of study 
eligibility is not recommended. 
• The maximum continuous period that a subject could be on placebo and no study 
medication is 3 weeks (1 week of placebo therapy between two 1-week wash-out 
periods). 
• The maximum continuous period that a subject could be on placebo, low-dose 
glycopyrrolate, and no active study medication is 5 weeks (i.e., 1 week of placebo 
therapy and 1 week of low-dose glycopyrrolate, each between two 1-week wash-
out periods). 
 
4.2.1 
Justification for Dose 
The Lonhala Magnair (glycopyrrolate) inhalation solution (25 µg/1 mL) aerosol 
performance has been reported in the literature (Pleasants and II 2019; Sunovion 2019). 
An appropriate dose range for glycopyrrolate solution in the proposed FDC formulation 
delivered via standard jet nebulizer (Pari Sprint) was determined based on performance 
characteristics of Lonhala Magnair. Based on the fine particle dose and delivered dose 
comparison to Lonhala 25 µg (the approved BID dose), it is expected that a 42.5 µg BID 
dose level will approximate the aerosol characteristics of the Lonhala Magnair (eFlow) 
glycopyrrolate 25 µg dose. Additionally, a higher dose of 85 µg (equivalent to 50 µg 
Lonhala dose) and lower dose of 14 µg (equivalent to 6.25 µg Lonhala dose, which 
produced a suboptimal FEV1 response in subjects with COPD) are planned in order to 
characterize the dose-response and confirm appropriate glycopyrrolate dose selection in 
subjects with COPD when delivered via standard jet nebulizer in the proposed FDC 
formulation.  
4.2.2 
Justification for Duration 
The Lonhala Phase II development program confirmed that PK and pharmacodynamic 
steady state was achieved within 7 days of BID glycopyrrolate inhalation solution dosing 
(Pleasants and II 2019; Sunovion 2019). Regarding PK, the mean AUC0-t for 12.5 µg and 
50 µg glycopyrrolate were 89 and 255 pg∙hr/mL at Day 7 (BID dosing) with 
corresponding accumulation indices of 2.051 and 1.398, respectively (Saluja et al. 
2017).  Assuming t = 12 hours and linear pharmacokinetics, elimination rate constants of 
0.0557 and 0.1047, respectively, were derived.  These parameters were used to estimate 
that greater than 99% steady state was reached after the seventh and fourth dose 
(respectively) of glycopyrrolate BID treatment.  In this study, we anticipate PK sampling 
on Day 7 will represent glycopyrrolate steady state. In Lonhala Phase IIb program, a 
similar magnitude of effect in morning trough FEV1 was shown with a 50 µg BID dose 
after 1 week of dosing compared with 4 weeks of dosing (placebo-corrected change from 
baseline 146 mL) (Karimi-Shah 2017), supporting that a 1-week duration is sufficient to 
inform on lung function effects of BID inhaled glycopyrrolate solution in the proposed 

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FDC formulation. A 7-day washout is planned to ensure that all subjects exceed 
5 elimination half-lives for glycopyrrolate between treatment periods. 
4.3 
End of Study Definition 
A subject is considered to have completed the study if he/she has successfully completed 
all scheduled visits and completed follow-up contact. With no rescheduled visits, the 
study should last approximately 10 weeks for each subject. 
The end of the study is defined as the date of the last follow-up contact of the last subject 
in the study. 

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5.0 STUDY POPULATION 
Prospective approvals of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, are not permitted. 
5.1 
Inclusion Criteria 
Informed Consent 
1. Capable of giving informed consent indicating that they understand the purpose of 
the study and study procedures and agree to comply with the requirements and 
restrictions listed in the informed consent form (ICF) and in this protocol. 
Age and Sex 
2. Age: Subject must be 40 to 80 years of age inclusive, at the time of Screening. 
3. Sex: 
• Males are eligible to participate if they agree to use contraception as described 
in the contraceptive guidance (Appendix 7) from Screening and throughout the 
study and for at least 30 days after the last dose of blinded study medication. 
• Females are eligible to participate if they are not pregnant, not breastfeeding, 
and ≥ 1 of the following conditions apply: 
a) Not a woman of childbearing potential (WOCBP) as defined in 
Appendix 7. 
OR 
b) A WOCBP who agrees to follow the contraceptive guidance in 
Appendix 7 from Screening and throughout the study and for at least 
30 days after the last dose of blinded study medication. 
Smoking History 
4. Smoking History: Current or former cigarette smokers with a history of cigarette 
smoking ≥ 10 pack years at Screening [number of pack years = (number of 
cigarettes per day / 20) × number of years smoked (e.g., 20 cigarettes per day for 
10 years, or 10 cigarettes per day for 20 years)]. Pipe and/or cigar use cannot be 
used to calculate pack-year history. Former smokers are defined as those who 
have stopped smoking for at least 6 months prior to Screening. Smoking cessation 
programs are permitted during the study. 

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COPD Diagnosis, Symptoms, Severity and Maintenance Therapy 
5. COPD Diagnosis: Subjects with an established clinical history of COPD as 
defined by the American Thoracic Society (ATS)/European Respiratory Society 
(ERS) guidelines (Celli et al. 2004) with symptoms compatible with COPD. 
6. Post-bronchodilator (4 puffs of salbutamol) spirometry at Screening 
demonstrating both the following: 
a. FEV1/forced vital capacity (FVC) ratio of < 0.70 AND 
b. FEV1 ≥ 30 % and ≤ 70% of predicted normal (Quanjer et al. 2012). 
Note: The proportion of the study population who have a post-albuterol FEV1 
increase of < 12% or < 200 mL will be capped at approximately 50%. 
7. A posterior-anterior chest x-ray (CXR) at Screening or within 12 months prior to 
Screening showing no clinically significant abnormalities unrelated to COPD. If a 
CXR within the past 12 months is not available but a computed tomography (CT) 
scan within the same time period is available, the CT scan may be reviewed in 
place of a CXR. 
8. Capable of withdrawing from short-acting bronchodilators for 4 hours prior to 
spirometry testing and from BID LABA ± ICS therapy for 24 hours prior to 
spirometry. 
Other Requirements for Inclusion 
9. Capable of using the study nebulizer correctly. 
10. Ability to perform acceptable spirometry in accordance with ATS/ERS guidelines 
(Graham et al. 2019). 
11. Willing and able to attend all study visits and adhere to all study assessments and 
procedures. 
5.2 
Exclusion Criteria 
Current Condition or Medical History 
1. Concomitant clinically significant pulmonary disease other than COPD (i.e., 
asthma, tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, 
interstitial lung diseases, sleep apnea (unless controlled with stable continuous 
positive airway pressure [CPAP] use), known alpha-1 antitrypsin deficiency, core 
pulmonale or other non-specific pulmonary disease). 

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2. Within 6 months prior to Screening: 
a. COPD exacerbation requiring hospitalization. 
b. Use of therapies for COPD exacerbation (e.g., oral, intravenous, or 
intramuscular glucocorticoids). 
3. Lower respiratory tract infection within 6 weeks of Screening or an active 
infection at Screening. 
4. History of life-threatening COPD, including Intensive Care Unit admission and/or 
requiring intubation. 
5. Previous lung resection or lung reduction surgery within 1-year of Screening. 
6. Long term oxygen use defined as oxygen therapy prescribed for greater than 
12 hours per day. As needed oxygen use (≤ 12 hours per day) is not exclusionary. 
7. Severe comorbidities including unstable cardiac, (e.g., myocardial infarction 
within 1 year prior to screening, unstable angina within 6 months prior to 
screening, or unstable or life-threatening arrhythmia requiring intervention within 
3 months prior to screening, diagnosis of New York Heart Association (NYHA) 
class III or IV heart disease) or any other clinically significant medical conditions 
including uncontrolled diseases (e.g., endocrine, neurological, hepatic, 
gastrointestinal, renal, hematological, urological, immunological, psychiatric or 
ophthalmic diseases) that would, in the opinion of the Investigator, preclude the 
subject from safely completing the required tests or the study, or is likely to result 
in disease progression that would require withdrawal of the subject. 
8. History of or clinically significant on-going bladder outflow obstruction or history 
of catheterization for relief of bladder outflow obstruction within the previous 
6 months. 
9. History of narrow angle glaucoma. 
10. History of hypersensitivity or intolerance to aerosol medications, salbutamol or 
glycopyrrolate or any of its excipients/components, anticholinergic agents, or 
sympathomimetic amines. 
11. Pulmonary rehabilitation unless such treatment has been stable from 4 weeks prior 
to Screening (Visit 1) and remains stable during the study. Pulmonary 
rehabilitation programs should not be started or completed during participation in 
the study. 

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12. Major surgery (requiring general anesthesia) in the 6 weeks prior to Screening, 
lack of full recovery from surgery at Screening, or planned surgery through the 
end of the study. 
13. History of or current malignancy of any organ system, treated or untreated within 
the past 5 years, except for localized basal or squamous cell carcinoma of the skin. 
14. Significant psychiatric disease that would likely result in the subject not being 
able to complete the study, in the opinion of the Investigator. 
15. Findings on physical examination that an investigator considers to be clinically 
significant at Screening. 
Prior/Concomitant Therapy 
16. Use of prohibited medications within the time intervals defined in Section 6.6.3. 
History of Drug or Alcohol Abuse 
17. Current or history of drug or alcohol abuse within the past 5 years. 
Laboratory and Other Diagnostic Parameters 
18. Estimated glomerular filtration rate (eGFR) < 30 mL/min. The Chronic Kidney 
Disease Epidemiology Collaboration Creatinine (2021) calculation will be used 
(Inker et al. 2021). 
19. Alanine aminotransferase (ALT) ≥ 2 × upper limit of normal (ULN), alkaline 
phosphatase and/or bilirubin > 1.5 × ULN (isolated bilirubin > 1.5 × ULN is 
acceptable if fractionated bilirubin < 35%). 
20. Any other abnormal hematology, biochemistry, or viral serology deemed by the 
Investigator to be clinically significant. Abnormal chemistry and/or hematology 
may be repeated during Screening. 
21. Abnormal ECG (Appendix 4) at the screening visit that is clinically significant. 
Other Exclusions 
22. Women who are breast feeding. 
23. Use of an experimental drug within 30 days or 5 half-lives of Screening, 
whichever is longer, and/or participation in a study treatment-free follow-up phase 
of a clinical study within 30 days prior to Screening. 
24. Use of an experimental medical device or participation in a follow-up phase of an 
experimental medical device clinical study within 30 days prior to Screening. 

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25. Affiliation with the investigator site, including an Investigator, Sub-Investigator, 
study coordinator, study nurse, other employee of participating investigator or 
study site or a family member of the aforementioned. 
26. A disclosed history or one known to the Investigator of significant noncompliance 
in previous investigational studies or with prescribed medications. 
27. Any other reason that the Investigator considers makes the subject unsuitable to 
participate. 
5.3 
Randomization Criteria 
If a subject does not meet all inclusion criteria, meets any exclusion criteria, and meets 
one of the following criteria at Visit 2 prior to randomization, the subject will be 
considered a screen failure. Subjects discontinued prior to randomization may be 
replaced. The discontinued subject may be rescreened if the procedure outlined in 
Section 5.5.1 is followed. 
Criteria for Exclusion from Randomization 
1. COPD exacerbation or lower respiratory tract infection between Screening and 
Randomization (defined as use of any additional treatment other than current 
treatment and rescue medication and/or emergency department or hospital visit). 
Subjects with a severe COPD exacerbation that requires hospitalization may not 
be rescreened. 
2. Prohibited medication use between Screening and Visit 2. 
3. Significantly abnormal ECG finding, as defined in Appendix 4, on the 12-lead 
ECG obtained pre-dose at Visit 2 as assessed by the investigator or site medical 
doctor/medically qualified person before the subject has been randomized.   
4. Did not meet ≥ 1 of the Inclusion Criteria (Section 5.1) or met ≥ 1 of the 
Exclusion Criteria (Section 5.2) as assessed through data or analyses produced 
between Screening and Randomization. 
5. At Screening the subject's albuterol responsiveness test had an FEV1 increase of 
< 12% or < 200 mL after 4 puffs of albuterol AND the randomization cap of 
approximately 50% of subjects in that responsiveness category has been met. 

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5.4 
Lifestyle Considerations 
5.4.1 
Caffeine and Tobacco 
Recommendation/request: Subjects should refrain from smoking and/or caffeinated 
beverages prior to Spirometry and ECGs for the withholding periods below: 
• Smoking: No smoking for at least 1-hour prior to each spirometry and ECG 
assessment. 
• Caffeinated Beverages: Abstain from drinking caffeinated beverages (e.g., tea, 
coffee) for 2 hours prior to each spirometry and ECG assessment. 
5.5 
Rescreening 
Clinically significant abnormal chemistry and/or hematology may be repeated during 
Screening. 
5.5.1 
Rescreening of Subjects 
Subjects may not be rescreened if their post-albuterol spirometry at Screening 
demonstrated any of the following: 
• FEV1/FVC ratio ≥ 0.7 OR 
• FEV1 < 30% of predicted normal OR 
• FEV1 > 70% of predicted normal. 
Rescreening is allowed only once for a screen failure due to both of following: 
• A subject’s Screening albuterol responsiveness test had an FEV1 increase of 
< 12% or < 200 mL after 4 puffs of albuterol AND 
• The randomization cap of approximately 50% of subjects in that responsiveness 
category has been met. 
Subjects who are screen failures for other reason (Section 5.6) may be rescreened with 
approval from the Medical Monitor.  
Rescreened subjects should be assigned a new subject number different from the initial 
Screening event.  
5.6 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but 
were not randomized to receive blinded study medication. See Section 7.1.1 for 
instructions on managing subjects who did not meet the criteria for randomization but 
were randomized in error. 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure subjects to meet the Consolidated Standards of Reporting Trials publishing 

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requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAEs. 

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6.0 STUDY TREATMENT 
Subjects will be randomly assigned to 1 of 4 dosing sequences (Section 4.1) which 
prescribe the specific order for treatment with each of the glycopyrrolate doses and 
placebo (Table 5).  Subjects will receive double-blind study medication (either 
glycopyrrolate or placebo) in the proposed FDC formulation administered by inhalation 
via a standard jet nebulizer (Section 6.2.2) supplied by the Sponsor. To account for visit 
windows, sufficient drug supply will be dispensed for up to 11 days of treatment for each 
treatment period.  
In this protocol the terms ‘investigational product’, ‘double-blind study medication’, and 
‘blinded study medication’ are the same and refer to the blinded nebulized study 
medication.  
Subjects taking maintenance BID LABA ± ICS medications should take the LABA ± ICS 
medication prior to taking blinded study medication when taking the blinded study 
medication at home. 
6.1 
Administration of Blinded Study Medication 
6.1.1 
Dosing in the Clinic 
The Day 1 Clinic Visit MUST BE RESCHEDULED to occur within 7 days of the 
scheduled visit if any of the following apply: 
• If the rescue medications are not withheld for 4 hours prior to spirometry. 
• If the pre-dose FEV1 on Day 1 of the current Treatment Period is not within 
± 20% of the pre dose FEV1 at Day 1 of the first Treatment Period 
• For a subject on a maintenance BID LABA ± ICS therapy, if the BID 
LABA ± ICS are not withheld for approximately 12 hours (e.g. LABA 
maintenance therapy taken the morning of the clinic visit) prior to spirometry. 
The Day 7 Clinic Visit MUST BE RESCHEDULED to occur within 3 days of the 
scheduled visit if any of the following apply: 
• If the rescue medications are not withheld for 4 hours prior to spirometry. 
• For a subject on a maintenance BID LABA ± ICS therapy, if the BID 
LABA ± ICS are not withheld for approximately 12 hours (e.g. LABA 
maintenance therapy taken the morning of the clinic visit) prior to spirometry. 
• If the morning dose of blinded study medication is not withheld. 
• If the subject has not brought the unused ampule for the Day 7 morning dose to 
the clinic. 
Dosing Visit Schedule and Time(s) of Day 

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Coordination of the timing of spirometry and in-clinic dosing with blinded study 
medication is critical. See Section 1.4, for the Schedule of Spirometry and In-Clinic 
Dosing with Blinded Study Medication. 
Blinded Study Medication Administration 
A PARI LC Sprint® jet nebulizer (study supplied nebulizer), with a PARI PRONEB® 
Max Aerosol Delivery System or equivalent (study supplied compressor) will be 
dispensed to the subject on Visit 2 and used to dose the blinded study medication in the 
clinic (Visit 2 only) and at home.  A new PARI LC Sprint® jet nebulizer will be supplied 
at each Day 1 of a treatment period (i.e., Visits, 4, 6, and 8). 
• Blinded study medication will be administered by inhalation of an aerosol 
generated by the reusable study supplied nebulizer attached to a study supplied 
compressor. 
• Site staff must place blinded study medication at room temperature for 
approximately 15 minutes prior to shaking and opening the ampule.  
• The site staff member will need to follow the nebulizer Set-Up instructions 
provided with the nebulizer and the Pharmacy Manual to prepare and administer 
the blinded study medication. 
• Administration of nebulized blinded study medication will be observed by the site 
staff member from start of nebulization until end time of nebulization. The site 
staff member MUST administer and observe blinded study medication at all in-
clinic dosing times.  
• Blinded study medication nebulization time should be approximately 5 to 
10 minutes. 
• The end time of blinded study medication nebulization is when a slight sputtering 
sound from the nebulizer is heard. This will be considered Time 0 for the purposes 
of scheduling all post-dose study procedures. 
• The date, the start time, and the end time of blinded study medication nebulization 
will be recorded by the site staff member in the subject source document and the 
electronic case report form (eCRF). 
Subjects will take their study supplied nebulizer and study supplied compressor as well as 
instructions home for use during the study. Only a study supplied nebulizer and a study 
supplied compressor may be used to administer blinded study medication during the 
study. The study supplied nebulizer and a study supplied compressor should be used only 
for the administration of blinded study medication. 
6.1.2 
Dosing at Home 
Following Visit 2, subjects will self-administer their daily morning and evening doses at 
home at approximately the same times, approximately 12 hours apart, each day for the 
duration of the Treatment Period, except for clinic visits on Days 1 and 7 of each 
Treatment Period when subjects will have their morning doses administered in the clinic. 

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Subjects should note the time of their evening dose on Day 6 for each Treatment Period 
and report that time to the clinic site staff at the Day 7 Visit. 
Blinded Study Medication Administration 
• Each subject will follow the Nebulizer Set-Up instructions and blinded study 
medication label to prepare and self-administer the blinded study medication by 
inhalation using the reusable study supplied nebulizer attached to the study 
supplied compressor. 
• Subjects must place blinded study medication at room temperature for 
approximately 15 minutes prior to shaking and opening the ampule.  
• Blinded study medication nebulization time should be approximately 5 to 
10 minutes. 
• The end time of blinded study medication nebulization is considered to be when a 
slight sputtering sound from the nebulizer is heard.  
Used Blinded Study Medication 
• Subjects will be instructed to discard all used ampules and open foil pouches of 
blinded study medication at home. 
Unused Blinded Study Medication 
• Subjects should be instructed to bring all unused blinded study medication to the 
clinic at each clinic visit for Day 7 morning dosing, collection, and assessment of 
medication compliance by a site staff member. 
6.2 
Investigational Product/Blinded Study Medication 
Investigational product/blinded study medication is described in Table 6. 
Table 6: Investigational Product/Blinded Study Medication Details 
Name 
Glycopyrrolate  
Placebo 
Dosage Formulation: 
Nebulizer solution 
Nebulizer solution 
Unit Dose: 
14, 42.5, or 85 µg 
0 mg 
Volume of dose 
2.5 mL 
2.5 mL 
Route of Administration 
Inhalation 
Inhalation 
Dosing Instructions: 
1 ampule (2.5 mL) per dose 
1 ampule (2.5 mL) per dose 
Manufacturer 
The Ritedose Corporation,  
Columbia, SC, USA  
The Ritedose Corporation, 
Columbia, SC, USA 
The glycopyrrolate formulation is a sterile solution of dissolved glycopyrrolate in 
 
 saline and is supplied as a 2.5 mL nominal fill in single unit-
dose -low-density polyethylene (LDPE) translucent ampule overwrapped in a foil pouch. 

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The placebo is the same as the glycopyrrolate solution except that the active 
glycopyrrolate ingredient is omitted, (i.e., it consists of 
) and is 
also supplied as a single unit-dose LDPE translucent ampule overwrapped in a foil pouch. 
Both glycopyrrolate and placebo are manufactured using aseptic manufacturing 
techniques in accordance with Good Manufacturing Practice guidelines and will be 
provided to the sites as subject kits. 
6.2.1 
Blinded Study Medication Dispensing Information 
Subjects will be dispensed blinded study medication kit(s) as per the schedule outlined in 
the SoA (Table 1). 
6.2.2 
Medical Devices 
No Sponsor manufactured medical device is used in this study. 
Other medical devices provided for use in this study are: 
• PARI LC ®Sprint nebulizer 
• PARI PRONEB ®Max Aerosol Delivery System or equivalent 
Instructions for medical device use are provided in the package insert. 
The blinded study medication should only be administered with the study provided 
nebulizer. No medications other than the blinded study medication should be 
administered with the study provided nebulizer. 
6.3 
Preparation/Handling/Storage/Accountability 
Blinded study medication should be stored in a refrigerator between 2°C and 8°C (36°F 
and 46°F) and should not be frozen. 
An investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all blinded study medication received and any discrepancies 
are reported and resolved before use of the blinded study medication. 
All blinded study medication must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage conditions 
with access limited to the Investigator and authorized study center staff. 
The temperature should be monitored, and logs maintained in areas where blinded study 
medication is stored. If temperature conditions have been compromised or any blinded 
study medication has not been stored appropriately, this should be documented, and the 
blinded study medication quarantined until the Sponsor has been notified and confirmed 
whether it may be used. 

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Blinded study medication should be placed at room temperature for approximately 
15 minutes prior to shaking and opening the ampule. 
Only subjects meeting the Randomization Criteria in the study may receive blinded study 
medication, and only authorized study center staff may supply or administer blinded 
study medication. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for blinded study medication accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused blinded study 
medication are provided in the Pharmacy Manual. 
The Investigator, a member of the study center staff, the site pharmacist, or pharmacy 
team member must maintain an adequate record of the receipt and distribution of all 
blinded study medication using the Drug Accountability Form. These forms must be 
available for inspection at any time. 
6.4 
Randomization and Blinding 
Both glycopyrrolate and placebo study medication and pouches and packaging are 
identical in appearance. 
Packaging of both glycopyrrolate and placebo will have a blinded description applied and 
all packs will have a unique kit number applied for identification. 
Deliveries of both glycopyrrolate and placebo will not indicate the actual product but will 
instead indicate a blinded description. 
Subjects will be randomized to a sequence which prescribes the order they will receive 
each glycopyrrolate dose and placebo dose over each treatment period using an electronic 
Interactive Response Technology (IRT). The IRT will not indicate the treatment sequence 
during the randomization process but will indicate the unique kit numbers to be dispensed 
to the subject at Visits 2, 4, 6, and 8. 
Site staff will only have access to blinded reports within the IRT. 
6.5 
Emergency Unblinding 
The blind will be broken only if specific emergency treatment would require knowing the 
treatment status of the subject. If the blind needs to be broken, the Investigator will 
contact the Sponsor or Medical Monitor as soon as feasible. The Investigator may unblind 
the blinded study medication immediately if he/she feels it is necessary prior to 
contacting the Sponsor or Medical Monitor. However, the Investigator should promptly 
document and explain any premature unblinding to the Sponsor and Medical Monitor. 

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Otherwise, all blinding will be maintained until all queries are resolved and the database 
is locked. 
Unblinding that occurs for any other reason, including unintentional unblinding, will be 
documented and promptly reported to the Sponsor and Medical Monitor. 
6.6 
Concomitant Therapy 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy (Table 10). 
6.6.1 
Rescue Medication 
All subjects will be dispensed albuterol as rescue medication to be used as needed during 
the screening, treatment, and washout periods at Screening (Visit 1).  Subjects who are 
required to withhold medications prior to Screening (Visit 1) will be dispensed albuterol 
as rescue medication upon signing of the ICF for use prior to Visit 1.  
6.6.1.1 
Documentation of Rescue Medication Use 
Documentation of albuterol during the study should be recorded on the concomitant 
medication page of the eCRF along with reason for use, dates of administration (start and 
end dates), and dosing information (dose and frequency). End date should be documented 
as “Ongoing.” 
Rescue albuterol used during clinic visits where spirometry will be conducted should be 
recorded in a module provided in the eCRF for each specific spirometry visit. Details 
(e.g., dose [number of puffs], date, and time of administration) will be recorded. 
6.6.2 
Permitted Rescue and Background Medications 
Permitted rescue and background medications are provided in Table 7. 
Any vaccine that is recommended by the subject’s healthcare provider is permitted during 
the study and should be recorded in the eCRF.  

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Table 7: Permitted Rescue and Background Medications 
Medication 
Condition 
Albuterol 
Used as rescue medication as needed during the study. 
Must be withheld for at least 4 hours prior to spirometry.1 Should be 
withheld for at least 4 hours prior to ECGs. 
BID LABA ± ICS 
Stable use of BID LABA ± ICS is permitted ONLY IF the subject: 
1. Has been taking LABA ± ICS at any dosing frequency at a stable 
dose for at least 4 weeks prior to Screening AND 
2. If on a non-BID LABA ± ICS therapy, can transition, to a BID 
LABA ± ICS ≥ 7 days prior to randomization for use for remaining 
duration of the study AND 
3. Can withhold use of the BID LABA ± ICS for approximately 24 h 
prior to any clinic visit where spirometry will be performed (i.e., 
Visits 1 through 9).1 
BID LABA ± ICS use should not be initiated, dose modified, or discontinued 
during the study after randomization. 
ICS monotherapy and high dose ICS (e.g., > 1000 µg of fluticasone 
propionate or equivalent) is not allowed. 
1If the withholding periods are not met the visit should be rescheduled (Section 6.1.1). 
Abbreviations: ECG = electrocardiogram; ICS = inhaled corticosteroids. 
6.6.3 
Prohibited Medications/Therapy 
Prohibited medications and therapies are provided in Table 8. All prohibited medications 
are not to be taken during the time periods described. 
Discontinuation of any maintenance COPD therapies for the sole purpose of study 
eligibility is not recommended. 
Table 8: Prohibited Medications/Therapy 
Medication 
Time Interval  
Oral Therapies for COPD (e.g., oral 
steroids, theophylline, and roflumilast). 
Oral mucolytics are allowed. 
6 months prior to Screening and prohibited during the study. 
Terbutaline 
24 hours prior to Screening and prohibited during the study. 
LAMAs 
1. Once-daily LAMAs 
2. BID LAMAs 
 
1. 48 hours prior to Screening and prohibited during the study 
2. 24 hours prior to Screening and prohibited during the study 
Non-BID LABAs 
Any LABAs that are not dosed BID (e.g., once daily) must 
be discontinued ≥ 7 days prior to Randomization and are 
prohibited during the study. 
 
 

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Medication 
Time Interval  
SAMA, including SAMA/SABA 
combination therapy (i.e., 
ipratropium/albuterol combination 
products) 
24 hours prior to Screening and prohibited during the study. 
Oral or systemic muscarinic antagonists 
(e.g., darifenacin, fesoterodine, 
imidafenacin, oxybutynin, and 
solifenacin, benztropine and 
trihexyphenidyl, atropine) 
7 days prior to Screening and prohibited during the study. 
Non-study provided nebulized therapies 
 
4 weeks prior to Screening and prohibited during the study. 
ICS 
Starting or stopping ICS is not allowed during the study.  
ICS monotherapy and high dose ICS (e.g., > 1000 µg of 
fluticasone propionate or equivalent) is not allowed. 
Abbreviations: BID = twice daily; COPD = chronic obstructive pulmonary disease; ICS = inhaled 
corticosteroids; LAMA = long-acting muscarinic antagonist; LABA = long-acting β2 agonist; 
SAMA = short-acting muscarinic antagonists; SABA = short-acting β2 agonist. 
6.6.4 
Recording Use of Concomitant Medications 
6.6.4.1 
Recording of Rescue Medication During the Study 
Rescue medication (albuterol) use during the study should be recorded as described in 
Section 6.6.1. 
6.6.4.2 
Recording of COPD Medications  
All COPD medication use during the 6 months prior to Screening and during the study 
should be recorded on the concomitant medication page of the eCRF along with reason 
for use, dates of administration (start and end dates), and dosing information (dose and 
frequency).  
6.6.4.3 
Recording of Medications other than Rescue Medication and COPD 
Medications During the Study 
All non-COPD medications will be recorded in the eCRF starting at Screening and 
changes recorded during the study. Information recorded will include, but may not be 
limited to items such as: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including route, dose, and frequency. 

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6.7 
End of Study Procedures 
Seven ± 1 days after either the Study Visit 9 or after the Early Termination/Withdrawal 
Visit (Table 1), the site should contact the subject by telephone to complete the following 
assessments: 
• Concomitant medications 
• AEs and SAEs 
6.8 
Treatment After the End of Study 
There are no plans to provide post-study treatment, including study medication for 
compassionate use, following study completion. 
After the End of Study Follow-up Phone Call (Table 1), subjects may resume 
conventional COPD therapy as prescribed by the investigator or other physician. 
Medications initiated after the end of study should not be entered into the eCRF except 
for those given for a SAE. 

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7.0 Discontinuation of Blinded Study Medication and Subject 
Discontinuation/Withdrawal 
7.1 
Discontinuation of Blinded Study Medication 
Subjects may permanently discontinue blinded study medication before the end of the 
study if they choose to or at the Investigator’s discretion. Subjects who permanently 
discontinue blinded study medication are required to withdraw from the study after 
completion of the Early Withdrawal/Termination procedures described in Table 1 and 
Section 7.3 as soon as possible.  
Circumstances potentially requiring or actually resulting in discontinuation of blinded 
study medication are described below. 
7.1.1 
Does Not Meet Criteria for Randomization 
A subject who does not meet the Randomization Criteria (Section 5.3) should not be 
randomized, will be considered a screen failure (Section 5.6), and may be eligible for 
rescreening (Section 5.5.1). 
If a subject who does not meet the Randomization Criteria (Section 5.3) is inadvertently 
randomized and receives blinded study medication, the Medical Monitor must be 
contacted and will consult with the Sponsor to determine if the subject may continue, 
must be discontinued from blinded study medication, and/or discontinued from the study. 
Such inadvertently randomized subjects, if discontinued, may be replaced, but are not 
eligible for rescreening (Section 5.5.1). 
7.1.2 
Liver Chemistry Stopping Criteria 
Discontinuation of blinded study medication for abnormal liver function should be 
considered by the Investigator when a subject meets 1 of the conditions outlined in 
Appendix 8 or if the Investigator believes that it is in best interest of the subject. 
7.1.3 
Electrocardiogram Withdrawal Criteria 
All ECGs conducted or overread after a subject has been randomized will be subject to 
ECG Withdrawal Criteria (Appendix 5). Subjects may be discontinued from blinded 
study medication if they experience a significant abnormality(ies) on their ECG 
including, but not limited to those listed in the ECG Withdrawal Criteria, and in 
consideration with the subject’s medical history and baseline ECG measurements. 
Clinically significant abnormalities as determined by the Investigator may also result in 
subject discontinuation from study medication per the Investigator’s judgement. 
Triplicate ECGs (over a brief period of time) should be performed on subjects 
experiencing a significant abnormality on their ECG or other clinically significant 
abnormality as determined by the Investigator. The intent of triplicate ECG measurements 

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is to differentiate significant abnormalities from artifact. Abnormalities should be 
confirmed in 2 of 3 triplicate ECG measurements. 
7.1.4 
Positive Pregnancy Test in Females 
Women who are pregnant or breastfeeding are not eligible to participate. Pregnancy 
testing will be conducted in women of childbearing potential at Screening and at other 
times specified in the SoA (Table 1). 
Women exhibiting a positive pregnancy test (Appendix 3) during the study will be 
discontinued from blinded study medication and followed-up per the Collection of 
Pregnancy Information guidelines in Section 8.7.5 and Appendix 7. 
7.1.5 
COPD Withdrawal Criteria 
Subjects who experience ≥ 1 moderate (i.e., requiring at least 3 days oral/systemic 
corticosteroids or antibiotics) or severe COPD exacerbation (i.e., requiring 
hospitalization) during the study will be discontinued from the blinded study medication 
and be withdrawn from the study. 
7.1.6 
Other Criteria 
Other criteria that may or may not require permanent discontinuation of blinded study 
medication include but are not limited to AE, lack of efficacy, protocol deviation, non-
compliance, study or site closed/terminated, investigator discretion, or subject withdrawal 
of consent. 
7.2 
Blinded Study Medication Compliance 
The prescribed dosage, timing, and mode of administration may not be changed. Any 
departures from the intended regimen must be recorded in the eCRFs. 
At the Day 7 visit, previously dispensed unused blinded study medication (i.e., unopened, 
or unused blinded study medication in taped foil pouches) will be retrieved by the site 
staff and compliance will be assessed. Subjects exhibiting poor compliance as assessed by 
the number of ampule/foil pouch counts dispensed and returned should be counseled on 
the importance of good compliance to the study dosing regimen and this counseling 
should be documented in the subject source document. 
Noncompliance is defined as taking less than 70% of blinded study medication during 
any evaluation period (visit to visit). 
7.2.1 
Discontinuation of the Study 
If the Sponsor discontinues development of the FDC product or terminates the study, all 
subjects will be permanently discontinued from blinded study medication and should 

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complete the Early Withdrawal/Termination procedures described in Table 1 and 
Section 7.3 as soon as possible. 
7.3 
Subject Discontinuation/Withdrawal from the Study 
A subject may withdraw from the study at any time at his/her own request or may be 
withdrawn from administration of blinded study medication and from all study 
participation at the discretion of the Investigator at any time for safety, behavioral, 
compliance, or administrative reasons. See the SoA (Table 1) for data to be collected at 
the time of study discontinuation and follow-up and for any further evaluations that need 
to be completed. 
• If the subject withdraws consent for disclosure of future information, the Sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• If a subject withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the Investigator must document this in the study 
center study records. 
Subjects who permanently discontinue the blinded study medication will be withdrawn 
from the study. 
Subjects who require an extended washout period > 28 days will be withdrawn from the 
study. 
Subjects who withdraw prior to completing 2 treatment periods may be replaced. 
7.3.1 
Early Withdrawal/Termination Procedures 
If a subject is withdrawn prior to completion of the study, every attempt should be made 
to have the subject complete the Early Withdrawal/Termination procedures in the SoA 
(Table 1) as soon as possible and the End of Study follow-up phone call (Section 6.7). 
7.4 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she fails to return for scheduled 
visits and is unable to be contacted by the study center. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
• The study center must attempt to contact the subject and reschedule the missed 
visit as soon as possible and counsel the subject on the importance of maintaining 
the assigned visit schedule and ascertain whether the subject wishes to and/or 
should continue in the study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the subject (where possible, 3 telephone 
calls and, if necessary, a certified letter to the subject’s last known mailing address 

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or local equivalent methods). These contact attempts should be documented in the 
subject’s medical record. 
• Should the subject continue to be unreachable, he/she will be considered to be lost 
to follow-up and will be discontinued from the study. 

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8.0 STUDY ASSESSMENTS AND PROCEDURES 
Subjects may not complete any Screening Visit Procedures including the Spirometry 
Assessment unless all prohibited medications/therapy described in Section 6.6.3 have 
been withheld for the defined time interval. 
Study procedures and their timing are summarized in the SoA (Table 1). 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue 
blinded study medication. 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. In the event a public emergency or natural 
disaster impacts a subject’s ability to complete study requirements, refer to Section 8.9.  
All Screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The Investigator will maintain a Screening log to 
record details of all subjects screened and to CONFIRM eligibility or record reasons for 
Screening failure, as applicable. 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be utilized for Screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA (Table 1). 
The maximum amount of blood collected from each subject over the duration of the 
study, including any extra assessments that may be required, will not exceed 300 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
See Section 5.6 for specific information to be collected for screen failures. 
8.1 
Screening Assessments and Procedures 
8.1.1 
Informed Consent 
Informed consent must be obtained according to the informed consent process described 
in Appendix 2. 
8.1.2 
Demographic Variables 
Demographic variables will include items such as age, sex, ethnicity, and race. 

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8.1.3 
Medical, Surgical, COPD, and Smoking History 
A history of relevant current or past medical conditions, surgical history, COPD history, 
and smoking history (current or former [yes or no]) will be obtained: 
• Minor surgical procedures (e.g., tonsillectomy, appendectomy) performed more 
than 5 years prior to Screening do not need to be recorded. 
• COPD history will include COPD exacerbation history and COPD type 
(emphysema and/or chronic bronchitis), as assessed by the investigator or medical 
professional). Chronic bronchitis is defined as “regular production of sputum for 3 
or more months in 2 consecutive years (in the absence of other conditions that 
may explain it)” (GOLD 2024). 
• Former smokers are defined as those who have stopped smoking for at least 
6 months prior to Screening. 
Medical and COPD condition(s) identified during the Screening Visit will be documented 
as medical history and not as an AE(s) unless the condition worsens during the study and 
meets the definition of an AE. 
8.1.4 
Prior/Concomitant Medications/Therapies 
A history of prior medications used will be obtained and recorded as described in 
Section 6.6.4. 
8.1.5 
Vital Signs 
Vital signs will be completed at Screening per the instructions in Section 8.5.1. In 
addition, height in centimeters (cm), weight in kilograms (kg), and body mass index will 
also be measured and recorded at Screening. 
8.1.6 
Electrocardiogram 
12-Lead ECGs will be completed per the instructions in Section 8.5.2. 
8.1.7 
Chest X-Ray 
A CXR (posterior-anterior) will be obtained at Screening or obtained within 12 months 
prior to Screening. If a CXR within the past 12 months is not available but a CT scan 
within the same time period is available, the CT scan can be reviewed in place of a CXR. 
8.1.8 
 Spirometry Assessment 
Spirometry at Screening will be completed per the instructions in Section 8.3.1. 
8.1.9 
Clinical Laboratory Assessments 
Clinical laboratory tests will be conducted per the instructions in Section 8.5.3. Clinically 
significant abnormal chemistry and/or hematology may be repeated during Screening. 

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8.1.10 
Physical Examination 
A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal, and Neurological systems. 
Investigators should pay special attention to clinical signs to ensure subjects have had no 
previous serious physical or mental illness(es). 
8.1.11 
Inclusion/Exclusion Criteria 
Subject eligibility will be assessed using the inclusion criteria (Section 5.1) and exclusion 
criteria (Section 5.2). 
8.1.12 
Interactive Response Technology 
Subjects will be registered in the IRT system. 
8.1.13 
Nebulizer Equipment Training 
See Section 8.6.4 for details on nebulizer equipment training. At the Screening Visit 1, 
site staff will review the information and instructions provided by the manufacturer with 
the subject (e.g., Instructions for Use, located in the Pharmacy Manual). Hands-on 
training with the nebulizer equipment will not occur until the Randomization Visit 
(Visit 2). 
8.1.14 
Dispense Rescue Medication 
Rescue medication (albuterol) will be dispensed for use as needed during the study but 
must be withheld for at least 4 hours prior to spirometry and should be withheld for at 
least 4 hours prior to ECGs. See Section 6.6.2 for additional details. 
8.2 
Randomization Criteria Assessment – Visit 2 
The criteria for Randomization are described in Section 5.3. 
8.3 
Efficacy Assessments 
Planned timepoints for all efficacy assessments are provided in the SoA (Table 1). 
8.3.1 
Spirometry 
Spirometry will be obtained using spirometry equipment provided by the central 
spirometry vendor that meets or exceeds the ATS minimal performance recommendations 
(Graham et al. 2019). 
The central spirometry vendor will provide a spirometry manual with additional 
instructions and details. 

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All Spirometry will be reviewed and over-read by the central spirometry vendor and the 
spirometry vendor’s determination of acceptable endpoint measurements will override 
determination by the investigative site. 
• Acceptable spirometry efforts should have a satisfactory start of test and end of 
forced expiration (plateau in the volume-time curve) and be free from artifacts due 
to cough, glottic closure, early termination, poor effort, obstructed mouthpiece, 
equipment malfunction, or other reason (Graham et al. 2019). 
• For FEV1 and FVC determinations, at least 3 but no more than 8 acceptable 
spirometry efforts should be obtained. 
• The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even 
if they do not come from the same effort. 
8.3.1.1 
Spirometry Training 
Prior to the first spirometry measurement at each clinic visit requiring Spirometry, the site 
staff will train each subject on how to perform acceptable spirometry maneuvers 
according to instructions provided by the central spirometry vendor. 
8.3.1.2 
Spirometry must be performed as follows: 
• Coordination of the timing of spirometry and in-clinic dosing with blinded study 
medication is critical. See Section 1.4 for the Schedule of Spirometry and In-
Clinic Dosing with Blinded Study Medication. 
• Spirometry Start Time: between 06:00 AM and 10:00 AM. 
• Withhold the Following or Reschedule the Visit: 
o Blinded Study Medication: Blinded study medication must be withheld 
until pre-dose spirometry is completed. 
o Rescue Medication and BID LABA ± ICS: Must be withheld per 
Section 6.1.1. 
Recommendation/Request: Subjects should refrain from smoking and/or caffeinated 
beverages prior to Spirometry for the withholding periods described in Section 5.4.1. 
8.4 
Pharmacokinetic Assessments 
At both Visits 3 and 5, blood samples of approximately 6 mL per time point will be 
collected at the 10 time points specified in Table 3 by venipuncture or via indwelling 
cannula in the forearm into lithium heparin tubes and will be immediately chilled (ice 
bath). The exact date/time of each blood sample collection will be recorded in the 
subject’s eCRF. Please refer to the Laboratory Manual for details of PK sample handling.  
8.5 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Table 1). 

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8.5.1 
Vital Signs 
Vital signs should be obtained prior to blinded study medication dosing at all visits. 
Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
Supine blood pressure and pulse measurements should be obtained after the subject has 
been at rest for at least 5 minutes in the supine position and located in a quiet setting 
without distractions (e.g., television, cell phones). 
8.5.2 
Electrocardiogram 
12-lead ECG will be obtained using standardized ECG equipment provided by the 
centralized vendor. Albuterol should be withheld for at least 4 hours prior to ECG 
assessments. It is recommended that ECG assessments should be obtained after subjects 
have rested for approximately 5 minutes. 
The central ECG vendor will provide an ECG manual with additional instructions and 
details. 
All ECGs will be reviewed and over-read by the central ECG vendor and the ECG 
vendor’s interpretation of the measurement(s) will override the interpretation by the 
investigative site if consensus is not reached. 
8.5.2.1 
Randomization/Visit 2: ECGs at Pre-Dose 
At Day 1/Randomization/Visit 2 prior to dosing (pre-dose), an ECG must be performed. 
8.5.2.2 
Clinically Significant Abnormality 
Review the ECG Withdrawal Criteria. If a clinically significant ECG abnormality is 
identified post-randomization, even if the assessment was pre-dose, the ECG Withdrawal 
Criteria in Appendix 5 should be reviewed and triplicate ECGs (over a brief period of 
time) should be performed to confirm the abnormality in 2 of 3 measurements. 
8.5.2.3 
Recommendation/Request 
Subjects should refrain from smoking and/or caffeinated beverages prior to ECGs for the 
withholding periods described in Section 5.4.1. 
8.5.3 
Clinical Laboratory Assessments 
See Appendix 3 for the list of clinical laboratory tests to be performed and additional 
instructions. 
8.5.4 
Adverse Event Assessment 
The method of detecting AEs will be performed as described in Section 8.7 and 
Appendix 6. 

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8.6 
Other Assessments and Procedures 
Planned timepoints for all other assessments and procedures are provided in the SoA, 
Table 1. 
8.6.1 
Concomitant Medication Assessment 
Subjects must be queried for concomitant medication use at each contact (clinic visit or 
phone contact). Concomitant medications must be documented in the eCRF. Concomitant 
medications/therapy and documentation are described in Section 6.6. The list of permitted 
rescue and background medications is provided in Section 6.6.2. The list of prohibited 
medications/therapy is provided in Section 6.6.3. 
8.6.2 
Interactive Response Technology 
Sites will enter information into the IRT at specified visits. All subjects consented will be 
assigned a subject identification number upon signing of the ICF. 
8.6.3 
Randomization 
Subjects meeting all inclusion criteria (Section 5.1) and none of the Randomization 
Criteria (Section 5.3) and exclusion criteria (Section 5.2) will be randomly assigned to a 
dosing sequence (Section 4.1) prescribing the order of blinded study medication use for 
each of the 4 treatment Periods via the IRT (Section 8.6.2) at Visit 2. 
8.6.4 
Nebulizer Equipment Training 
Subjects and site staff will be trained in the use of the PARI LC Sprint nebulizer and 
PARI PRONEB Max Aerosol Delivery System, which will be used for inhalation of 
blinded study medication during the study period. Once the site staff have been trained, 
they will review the information and instructions provided by the manufacturer with the 
subject (e.g., Instructions for Use, located in the product box and also in the Pharmacy 
Manual). Hands on training with the nebulizer will occur at randomization with 
administration of the first dose of blinded study medication. 
8.6.5 
Training for Spirometry 
Training for spirometry maneuvers will be conducted by the site staff as per the 
guidelines in the spirometry manual provided by the central spirometry vendor. 
8.6.6 
Blinded Study Medication Dosing in the Clinic 
Blinded study medication dosing in the clinic will be conducted as described in 
Section 6.1.1. 

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8.6.7 
Dispense Rescue Albuterol 
Albuterol will be dispensed at specified study visits for use as needed. See Section 6.6.1 
for additional detail. 
8.6.8 
Dispense/Collect Blinded Study Medication 
Blinded study medication will be dispensed/collected at Days 1 and 7 of each Treatment 
Period (Table 1). 
8.7 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 6. 
AEs will be reported by the subject. 
The Investigator and any designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the blinded study medication or 
study procedures, or that caused the subject to discontinue the study (Appendix 6). 
As stated in Section 8.1.3, medical and COPD condition(s) identified during the 
Screening Visit will be documented as medical history and not as an AE unless the 
condition worsens during the study and meets the definition of an AE. 
8.7.1 
Time Period and Frequency for Collecting AE and SAE Information 
AEs and SAEs will be collected from time of first dose of blinded study medication 
through the follow-up contact with 1 exception. SAEs assessed as related to study 
participation (e.g., study treatment, protocol-mandated procedures, invasive tests or 
change in existing therapy) will be collected from the time of consent through the follow-
up contact. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix 6. The Investigator will submit any updated SAE data to the 
Sponsor designee within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the event to 
be reasonably related to the blinded study medication or study participation, the 
Investigator must promptly notify the Sponsor. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 6. 

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8.7.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences. 
8.7.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, through the follow-up contact, or the 
subject is lost to follow-up (as defined in Section 7.4). Further information on follow-up 
of AEs and SAEs is given in Appendix 6. 
8.7.4 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a 
blinded study medication under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study medication under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators, as necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
8.7.5 
Pregnancy 
Details of all pregnancies in female subjects will be collected after the start of blinded 
study medication and until 30 days after the last dose of blinded study medication. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 7. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 

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8.7.6 
Adverse Events of Special Interest 
AEs of special interest that have been identified for glycopyrrolate: 
• Paradoxical bronchospasm 
o As with other inhaled medicines, inhaled glycopyrrolate can produce 
paradoxical bronchospasm that may be life-threatening. If paradoxical 
bronchospasm occurs following dosing, it should be treated immediately 
with an inhaled, short-acting bronchodilator; blinded study medication 
should be discontinued. 
• Immediate hypersensitivity reactions 
o Immediate hypersensitivity reactions may occur after administration of 
inhaled glycopyrrolate. If signs suggesting allergic reactions occur, in 
particular, angioedema (including difficulties in breathing or swallowing, 
swelling of the tongue, lips, and face), urticaria, or skin rash, blinded study 
medication should be discontinued. 
• Worsening of narrow-angle glaucoma 
o Subjects with narrow-angle glaucoma are excluded from this study 
(Section 5.2). Subjects and investigators should be alert for signs and 
symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, 
blurred vision, visual halos or colored images in association with red eyes 
from conjunctival congestion and corneal edema). 
• Worsening of urinary retention 
o Subjects with obstructed urine flow are excluded from this study 
(Section 5.2). Subjects and investigators should be alert for signs and 
symptoms of urinary retention (e.g., difficulty passing urine, painful 
urination), especially in subjects with prostatic hyperplasia or bladder-neck 
obstruction. Instruct subjects to consult a physician immediately should 
any of these signs or symptoms develop. 
8.7.7 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs 
COPD exacerbations are an expected disease-related outcome. COPD exacerbations 
including daily expected COPD symptoms (e.g., dyspnea, chest tightness, wheezing, 
cough, sputum, that are not associated with the dosing event) will not be collected as an 
AE unless they meet the definition of an SAE. 
8.8 
Treatment of Overdose 
An overdose is defined as a dose greater than the total daily doses prescribed in this study 
which results in clinical signs and symptoms. These should be recorded by the 
investigator on the AE/SAE pages. 

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In the event of an overdose the investigator should use clinical judgement in treating the 
overdose and contact the study Medical Monitor. Verona Pharma is not recommending 
specific treatment guidance for overdose and toxicity management. 
8.9 
Emergency Procedures 
Sufficient study drug is provided to enable up to 11 days of dosing in a given treatment 
period. In the event of a public emergency or natural disaster, the dosing interval may be 
extended up to 11 days to allow at least 6 consecutive days of dosing prior to the End of 
Treatment Period Visit (nominal Day 7 Visit) which may occur between Day 7 and Day 
11. If a public emergency or natural disaster results in a subject being unable to complete 
at least 6 consecutive days of dosing prior to the End of Treatment Period Visit (nominal 
Day 7 visit which may occur between Days 7 and 11), the treatment period should be 
repeated with the repeat Day 1 visit occurring at least 7 days after the last administered 
dose of blinded study medication. In the event of a public emergency or natural disaster, 
the 7-day washout period may be extended up to 28 days. Subjects requiring a washout 
period > 28 days will be withdrawn from the study.  

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9.0 STATISTICAL CONSIDERATIONS 
Further details of the analyses to be performed can be found in the Statistical Analysis 
Plan (SAP). 
9.1 
Statistical Hypotheses 
The aim of this study is to quantify the benefit of each glycopyrrolate dose over placebo 
in efficacy as mean change from baseline for spirometry. The null hypotheses to be tested 
for each efficacy endpoint will be that there is no difference in change from baseline 
between glycopyrrolate and placebo for each glycopyrrolate dose, against the alternative 
hypothesis that change differs between that glycopyrrolate dose and placebo. All tests 
will be two-sided at a 5% significance level. Primary and secondary endpoints will be 
evaluated at a nominal Type 1 error level of 0.05, and Type 1 error will not be adjusted 
for multiplicity.   
9.2 
Sample Size Determination 
Estimates obtained from a 6-period multi-dose crossover study of BID nebulized 
glycopyrrolate at Day 7 for change from baseline in trough FEV1 (Saluja et al. 2017). 
Assuming the standard deviation for the differences (SDD) equal to 0.153 L, a sample 
size of 36 subjects provides 85% statistical power to detect a between-group difference 
with placebo in trough FEV1 at Day 7 of at least 81 mL.  The sample size provides 
adequate statistical power for statistical comparisons of each secondary endpoint. 
Subjects who withdraw prior to completing 2 treatment periods may be replaced. 
Assuming approximately 10% of early withdrawals, approximately 40 subjects will be 
enrolled.   
9.3 
Populations for Analyses 
Allocation of subjects to the analysis populations (and whether any subjects or specific 
data from a subject will be excluded) will be determined at the pre-database lock meeting. 
The randomized set will consist of all randomized subjects.  
The Full Analysis Set (FAS) will consist of all randomized subjects that took at least 
1 dose of double-blind study treatment with a non-missing baseline FEV1, that have non-
missing post-dose spirometry parameter values from at least two periods.  Analyses will 
be by actual treatment received. 
The Completers Analysis Set (CAS) will consist of all subjects in the FAS that complete 
all visits and that do not have missing values for spirometry parameters. 
The Per Protocol Set (PPS) will consist of all subjects in the CAS set that did not deviate 
significantly from the terms and conditions in the study protocol. 

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The Safety Analysis Set (SAS) will consist of all randomized subjects who took at least 
one dose of double-blind study treatment. Safety analysis will be by actual treatment 
received. 
The PK analysis set (PKAS) will consist of all randomized subjects with blood sampling 
performed after at least one dose of glycopyrrolate and have at least 1 quantifiable 
glycopyrronium free base concentrations without important protocol deviations and/or 
events with the potential to affect the PK concentrations. 
The PK parameter analysis set (PKPAS) will consist of all subjects in the PK analysis set 
with data sufficient to calculate at least 1 PK parameter without important protocol 
deviations and/or events with the potential to affect the PK results. 
9.4 
Statistical Methods 
In general, unless stated otherwise, continuous variables will be summarized using 
descriptive statistics (number of subjects, mean, standard deviation [SD], median, 
minimum, and maximum values) and for categorical (nominal) variables, the number and 
percentage of subjects will be used. 
All hypothesis testing will be done using two-sided alternative hypotheses. P-values less 
than 5% will be considered statistically significant. 
9.5 
Statistical Analyses 
Treatments will be characterized and, when compared, comparisons will be made using 
estimates obtained from analysis of covariance models.   
Spirometry parameters will be analyzed as change from average baseline FEV1 on study 
Day 1 and, separately, on Day 7, and will not be transformed prior to analysis.  Models 
will include terms for treatment, period, and subject as fixed effects, and baseline as a 
covariate. A separate model will be fit for each efficacy parameter from Day 1 and from 
Day 7.    
9.5.1 
Efficacy Analyses 
Primary efficacy analysis will be based on the FAS.  Analyses will be repeated for the 
CAS and the PPS set. 
Each efficacy parameter will be summarized both for the absolute value and for change 
from baseline using descriptive statistics (N, mean, median, SD, minimum, and 
maximum) for each treatment, generated separately for each Period as well as overall. 
Average baseline will represent the average of the two pre-treatment FEV1 values prior to 
the first dose of double-blind medication in each Treatment Period. 
Results will provide the number of subjects included in each analysis, estimated least 
square means and corresponding standard errors and 95% confidence intervals (CIs).  CIs 

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will not be adjusted for multiplicity.  Least square mean differences between each dose 
and placebo will be provided along with standard errors, 95% CIs, and p-values.  CIs and 
p-values will not be adjusted for multiplicity.  
Exploratory efficacy analyses will assess the incremental relationship between the 
glycopyrrolate dose and the corresponding difference in the least square means.  
Additional details will be provided in the Statistical Analysis Plan.   
9.5.2 
Safety Analyses 
Safety analysis will be descriptive and based on the SAS including all randomized and 
treated subjects. Safety analyses will be by actual treatment received. 
AEs will be analyzed using quantitative and qualitative measures. Treatment emergent 
adverse events (TEAEs) will be summarized by treatment for all AEs, related AEs, SAEs, 
deaths, AEs leading to discontinuation of blinded study medication and, separately, to 
withdrawal from study, AEs of different severity and AEs of different chronicity.  
TEAEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and summarized by system organ class (SOC) and preferred term (PT) for each treatment. 
Laboratory data will be summarized by each dose including change from baseline by 
treatment.  Changes which are markedly abnormal for each parameter will be summarized 
by treatment.  The number of normal and markedly abnormal for each parameter will be 
summarized for each treatment using shift tables. 
Vital signs and continuous parameters from the ECGs will be summarized for each dose, 
including change from baseline. Values outside pre-specified ranges (low, high) or 
changes exceeding pre-specified limits will be summarized as change from baseline 
values and using shift tables for each treatment and each parameter. 
The number of normal, abnormal not clinically significant and abnormal clinically 
significant values on the ECG overall evaluation will be summarized for each dose using 
shift tables.  
All laboratory, vital sign, and ECG data will be listed and values outside reference ranges 
will be highlighted in the listings. 
9.5.3 
Pharmacokinetic Analyses 
The following PK parameters will be calculated from plasma concentrations of 
glycopyrronium on Day 7. 
• AUC0-12h denotes the area under the plasma concentration curve versus time over 
the 12-hour dosing interval following the morning dose. 
• Cmax denotes the highest plasma concentration measured over the dosing interval. 
• Ctrough denotes the plasma concentration measured prior to dose administration. 

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• Cavg denotes the plasma average concentration measured over the dosing interval, 
calculated as AUC0-12h divided by the dosing interval. 
•  tmax denotes the time point corresponding to Cmax 
• CL/F denotes the apparent clearance from plasma following glycopyrrolate 
inhalation. 
All final PK parameter calculations will be performed by using actual elapsed time from 
the start of the inhalation.  Dose-normalized (DN) exposure parameters (DN-Cmax and 
DN-AUC0-12h) will also be calculated. Additional PK parameters may be calculated as 
warranted by the data. 
Glycopyrronium free base concentrations will be summarized by treatment using the 
PKAS.  
Subject and arithmetic mean (± standard deviation [SD]) profiles of glycopyrronium 
concentrations at each timepoint over 12 hours will be generated for each glycopyrrolate 
dose on both original and semi-logarithmic scales.   
PK parameters will be analyzed using the PKPAS.  Glycopyrronium free base PK 
parameters will be summarized using descriptive statistics (N, mean, median, SD, 
geometric mean, geometric CV%, minimum, and maximum) for each treatment, 
generated separately for each Treatment Period as well as overall for Treatment Periods 1 
and 2 combined. Only median, minimum, and maximum will be presented for tmax. 
Scatter plots of individual and geometric mean PK parameters [Cmax, AUC0-12h, Ctrough] 
versus glycopyrrolate will be presented with data for both treatment periods combined. A 
similar presentation will be prepared for DN-Cmax and DN-AUC0-12h.   
The dose proportionality of the exposure parameters, Cmax, AUC0-12h, over the 
administered dose range will be investigated using the following power model: 
 
 
log (parameter) = a + b * log (dose) 
 
 
where ‘a’ is the intercept and ‘b’ is the slope. 
The analysis will be performed by including all available exposure parameters for both 
periods combined. If warranted, this analysis may be repeated utilizing Treatment 
Period 1 data only.   
Further details regarding the pharmacokinetic analysis will be provided in the SAP. 
9.5.4 
Other Analyses 
The subject flow including total number of screened subjects, number of randomized 
subjects, completers, withdrawn subjects (including reason for withdrawal) and subjects 
included in each of the analysis sets will be summarized by sequence and overall, and by 
treatment and overall. 

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The number of subjects with major protocol deviations will be summarized by category 
of violation by sequence and overall, and by dose and overall including subset of major 
protocol deviation leading to exclusion from the per-protocol set.   
Demographic and baseline characteristics will be summarized using descriptive statistics 
for by sequence and overall, and by treatment and overall.  
Medical history will be coded using MedDRA and summarized by SOC and PT for each 
sequence and overall.  
Prior medications will denote medications used prior to the first dose of study drug 
independent of whether the medication was stopped at randomization or not.  Prior 
medications will be summarized by sequence and provided in subject listings.  
Concomitant medications will denote medications started prior to but continuing after 
randomization or medications with a start date at or after the randomization date. 
Concomitant medications will be summarized separately by Anatomical Therapeutic 
Chemical (ATC) levels 2 and 4.  Concomitant medication will be summarized by 
sequence and by treatment. 
Compliance to blinded study medication will be computed based on the number of 
ampules/foil pouch count dispensed and unused ampules/foil pouches returned. Non-
compliance will be defined as a compliance value less than 70% over the full study 
period.  Compliance will be summarized by sequence and overall and by treatment and 
overall.   
9.5.5 
Missing Data 
As discontinuation of study medication will result in subject withdrawal, data collected 
after treatment withdrawal will not be included in the analyses, and missing data will not 
be imputed. 
9.6 
Interim Analyses 
No interim analysis is planned. 
 

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10.0 REFERENCE LIST 
 
Anzueto A, Barjaktarevic IZ, Siler TM, Rheault T, Bengtsson T, Rickard K, et al. 
Ensifentrine, a Novel Phosphodiesterase 3 and 4 Inhibitor for the Treatment of 
Chronic Obstructive Pulmonary Disease: Randomized, Double-Blind, Placebo-
controlled, Multicenter Phase III Trials (the ENHANCE Trials). Am J Respir Crit Care 
Med. 2023;208(4):406–16.  
Calverley PMA, Sanchez-Toril F, McIvor A, Teichmann P, Bredenbroeker D, Fabbri LM. 
Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary 
disease. American Journal of Respiratory and Critical Care Medicine. 2007 
Jul;176:154–61.  
Celli BR, MacNee W, Agusti A, Anzueto A, Berg B, Buist AS, et al. Standards for the 
diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position 
paper. European Respiratory Journal. 2004;23:932–46.  
Chabicovsky M, Winkler S, Soeberdt M, Kilic A, Masur C, Abels C. Pharmacology, 
toxicology and clinical safety of glycopyrrolate. Toxicol Appl Pharmacol. 
2019;370:154–69.  
Dijk L, Kerkhof M, Driessen M, Gerritsma YH, Bosnic-Anticevich S, Correia-de-Sousa 
J, et al. Does mixing inhaler devices lead to unchecked inhaler technique errors in 
patients with COPD? Findings from the cross-sectional observational MISMATCH 
study. BMJ Open Respir Res. 2023;10(1):e001821.  
Gal FL, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, et al. Quantification of 
hepatitis delta virus RNA in serum by consensus real-time PCR indicates different 
patterns of virological response to interferon therapy in chronically infected patients. 
Journal of Clinical Microbiology. 2005 May;43:2363–9.  
GOLD. 2024 Global Strategy for Prevention, Diagnosis and Management of COPD 
[Internet]. 2024. Available from: https://goldcopd.org/2024-gold-report/ 
Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et al. 
Standardization of Spirometry 2019 Update. An Official American Thoracic Society 
and European Respiratory Society Technical Statement. Am J Resp Crit Care. 
2019;200(8):e70–88.  
Hanania NA, Sharafkhaneh A, Celli B, Decramer M, Lystig T, Kesten S, et al. Acute 
bronchodilator responsiveness and health outcomes in COPD patients in the UPLIFT 
trial. 2011; Available from: http://respiratory-research.com/content/12/1/6 
Inker LA, Eneanya ND, Coresh J, Tighiouart H, Wang D, Sang Y, et al. New Creatinine- 
and Cystatin C–Based Equations to Estimate GFR without Race. N Engl J Med. 
2021;385(19):1737–49.  
Karimi-Shah BA. Lonhala Magnair Clinical Review NDA 208437. 2017; Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208437Orig1s000MedR.pd
f 

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Mannino D, Siddall J, Small M, Haq A, Stiegler M, Bogart M. Treatment Patterns for 
Chronic Obstructive Pulmonary Disease (COPD) in the United States: Results from an 
Observational Cross-Sectional Physician and Patient Survey. Int J Chronic Obstr Pulm 
Dis. 2022;17:749–61.  
Pleasants RA, II. Glycopyrrolate/eFlow CS: The First Nebulized Long-Acting Muscarinic 
Antagonist Approved to Treat Chronic Obstructive Pulmonary Disease. The Annals of 
pharmacotherapy [Internet]. 2019 Mar;53:285–93. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/30175596 
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC6357169 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: The global lung function 
2012 equations. European Respiratory Journal. 2012 Dec;40:1324–43.  
Rabe KF, Bateman ED, O’Donnell D, Witte S, Bredenbröker D, Bethke TD. 
Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary 
disease: a randomised controlled trial. Lancet. 2005;366(9485):563–71.  
Rennard SI, Calverley PMA, Goehring UM, Bredenbröker D, Martinez FJ. Reduction of 
exacerbations by the PDE4 inhibitor roflumilast - the importance of defining different 
subsets of patients with COPD. Respiratory Research. 2011 Jan;12.  
Saluja B, Marathe A, Liu C, Yu J. Lonhala Magnair Clinical Pharmacology Review NDA 
208437. 2017; Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208437Orig1s000ClinPhar
mR.pdf 
Singh D. New combination bronchodilators for chronic obstructive pulmonary disease: 
Current evidence and future perspectives. British Journal of Clinical Pharmacology. 
2015 May;79:695–708.  
STUCKLER D. Population Causes and Consequences of Leading Chronic Diseases: A 
Comparative Analysis of Prevailing Explanations. Milbank Q. 2008;86(2):273–326.  
Sunovion. Lonhala Magnair Full Prescribing Information. 2019; Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208437s003lbl.pdf 
  
 

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Appendix 1 
Abbreviations 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ATC  
Anatomical Therapeutic Chemical 
ATS 
American Thoracic Society 
AUC0-4h 
Area under the curve versus time from time 0 to 4 hours 
AUC0-12h 
Area under the curve versus time from time 0 to 12 hours 
BID 
Twice daily 
CAS 
Completers analysis set 
CI 
Confidence interval 
COPD 
Chronic obstructive pulmonary disease 
Cmax 
Maximum plasma drug concentration 
CPAP 
Continuous positive airway pressure 
CXR 
Chest x-ray 
CT 
Computed tomography 
CV 
Coefficient of variation 
DAC 
Data Assessment Committee 
DN 
Dose normalized 
DPI 
Dry powder inhaler 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ERS 
European Respiratory Society 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FDC 
Fixed dose combination 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICS 
Inhaled corticosteroid(s) 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LABA 
Long-acting β2-agonist 

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LAMA 
Long-acting muscarinic antagonist 
LDPE 
Low-density polyethylene 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCFBE 
Non-cystic fibrosis bronchiectasis 
NYHA 
New York Heart Association 
PD 
Pharmacodynamic(s) 
PDE 
Phosphodiesterase 
PK 
Pharmacokinetic(s) 
PKAS 
Pharmacokinetic analysis set 
PKPAS 
Pharmacokinetic parameter analysis set 
pMDI 
Pressurized metered dose inhaler 
PPS 
Per-protocol set 
PT 
Preferred term 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Safety analysis set 
SD 
Standard deviation 
SoA 
Schedule of Activities 
SOC 
System organ class 
Study CO-211 
RPL554-CO-211 
Study CO-212 
RPL554-CO-212 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
tmax 
Time to maximum plasma drug concentration 
ULN 
Upper limit of normal 
US 
United States 
Verona 
Verona Pharma plc. 
WOCBP 
Women of Childbearing Potential 
 
DEFINITION OF TERMS 
QT interval 
The portion of an electrocardiogram between the onset of the 
Q wave and the end of the T wave. 

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Appendix 2 
Regulatory, Ethical, and Study Oversight 
Consideration 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
­ Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
­ Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
­ Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the Investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC and regulatory authority 
approval, when applicable, before implementation of changes made to the study 
design, except for changes necessary to eliminate an immediate hazard to subjects. 
• The Investigator will be responsible for the following: 
­ Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
­ Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
­ Providing oversight of the conduct of the study at the study center and adherence 
to requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, EU Clinical Trials Directive 2001/20/EC (if applicable), and all other 
applicable local regulations. 
• After reading the protocol, the Principal Investigator will sign the protocol signature 
page and send a copy of the signed page to the Sponsor or designee (Appendix 9). 
The study will not start at any study center at which the Investigator has not signed 
the protocol. 
Adequate Resources 
The Investigator is responsible for supervising any individual or party to whom the 
Investigator delegates study-related duties and functions conducted at the study center. 

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If the Investigator/institution retains the services of any individual or party to perform 
study related duties and functions, the Investigator/institution should ensure this 
individual or party is qualified to perform those study-related duties and functions and 
should implement procedures to ensure the integrity of the study-related duties and 
functions performed and any data generated. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
Insurance 
Financial arrangements are detailed in the Investigator Agreement between the Sponsor 
and Investigator. 
The Sponsor will arrange clinical study insurance to compensate subjects for any 
potential injury or death caused by the study. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the 
subject and/or the subject’s legally authorized representative and answer all questions 
regarding the study. 
• Subjects must be informed that their participation is voluntary. Subjects will be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study center. 
• The medical record must include a statement that written informed consent was 
obtained before the subject was entered in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign 
the ICF. 
• A copy of the original ICF(s) must be provided to the subject or the subject’s legally 
authorized representative. 
• ICF New Information: New information since the time of the original consent can be 
presented to subjects in format(s) or method(s) including, but not limited to those 
listed below unless excluded by local requirements: 
­ Revised consent document 

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­ Addendum to consent 
­ Memo or other communication to subjects 
­ Orally by phone or in person 
Documentation of the method the new information was presented to the subject along 
with the name of the site staff member and date the new information was presented to the 
subject must be documented in the subject’s source document. 
Data Protection 
• Subjects will be assigned a unique identifier by the Sponsor. Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be 
transferred. 
• The subject must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the subject. 
• The subject must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
• The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy 
legislation. 
Administrative Structure 
The study administration structure is in Table 9 and the Medical Monitor and 24-hour 
urgent medical contact information is in Table 10. 

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Table 9: Study Administrative Structure 
Function 
Responsible Organization 
Study Operations Management  
PPD 
929 North Front Street 
Wilmington, NC 28401-3331, US 
 
Medical Monitoring 
Study Master File 
Randomization Code 
Data Management 
Quality Assurance Auditing 
Verona Pharma plc 
3 More London Riverside; London, SE1 2RE; UK 
Biostatistics 
Verona Pharma plc and PPD  
Clinical Supply Management 
Medical Writing 
Safety Reporting 
Laboratory Assessments 
PPD and 
Q2 Solutions  
2400 Ellis Road; Durham NC 27703, US 
Spirometry and Electrocardiogram 
Collection, Review, and Analysis 
Clario 
818 Market St; Suite 2600; Philadelphia, PA 19103, US 
 
Table 10: Medical Monitor  
Primary Medical Monitor: 
 
 
Secondary Medical Monitor: 
 
 
24-hour Urgent Medical 
Contact 
Please use this number below and you will be directed to one of the 
PPD Medical Monitors.   
PPD Medical Monitoring Hotline: 
    US Number: + 1-888-483-7729 
 
Dissemination of Clinical Study Data 
For studies conducted in the United States, the results of the study are required to be 
reported on clinicaltrials.gov no later than 1 year after the primary completion date of the 
clinical study, which is defined as the date of final data collection for the primary 
outcome measure. 
Data Quality Assurance 
• All subject data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 

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Investigator is responsible for verifying that data entries are accurate and correct and 
will need to confirm that the blinding procedures have or have not been maintained 
for each subject by physically or electronically signing the eCRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered into the eCRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized study center personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the Sponsor. 
No records may be transferred to another location or party without written notification 
to the Sponsor. 
Source Documents 
The Investigator/institution should maintain adequate and accurate source documents and 
study records that include all pertinent observations on each of the study center’s subjects. 
Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete. Changes to source data should be traceable, should not obscure the original 
entry, and should be explained if necessary (e.g., via an audit trail). 
• Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s 
study center. 
• Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in ICH E6(R2) Section 1.51. 

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Study and Study Center Closure 
The Sponsor reserves the right to close the study center or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study centers will be closed upon 
study completion. A study center is considered closed when all required documents and 
study supplies have been collected and a study center closure visit has been performed. 
The Investigator may initiate study center closure at any time, provided there is 
reasonable cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study center by the Sponsor or Investigator may include 
but are not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
• Inadequate recruitment of subjects by the Investigator. 
• Discontinuation of further study medication development. 
Publication Policy 
The data generated by this study are the confidential information of the Sponsor. 

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Appendix 3 
Clinical Laboratory Tests 
The tests detailed in Table 11 will be performed by the central laboratory. 
• Fasting is not required prior to laboratory testing. 
• Laboratory tests should be collected prior to dosing with blinded study 
medication. 
Table 11: Protocol Required Laboratory Assessments 
Chemistry  
Hematology  
Viral Serology 
Albumin 
Hemoglobin 
Hepatitis B Serology (Markers 
include HBsAg, anti-HBs, anti-
HBc, and others) 
Alkaline phosphatase 
Hematocrit 
Hepatitis C virus antibody 
Alanine amino transferase (ALT or 
SGPT) 
Platelet count 
 
Aspartate amino transferase (AST or 
SGOT) 
WBC count 
Other Laboratory Tests 
Bilirubin, direct 
Leukocyte differential count 
Pregnancy test for WOCBP1 
Bilirubin, indirect 
Neutrophils, absolute 
 
Bilirubin, total 
Neutrophils, segs (%) 
 
Calcium 
Neutrophils, bands (%) 
 
Chloride 
Basophils (%) 
 
CO2 content/Bicarbonate 
Eosinophils (%) 
 
Creatinine 
Eosinophils, absolute 
 
Creatine phosphokinase (CPK), total 
Lymphocytes (%) 
 
Gamma glutamyl transferase (GGT) 
Monocytes (%) 
 
Glucose 
RBC count 
 
Phosphorus 
 
 
Potassium 
 
 
Protein, total serum 
 
 
Sodium 
 
 
Urea nitrogen (BUN) 
 
 
Uric Acid 
 
 
1 Pregnancy test for women of childbearing potential. A serum pregnancy test will be conducted at 
Visit 1. A urine pregnancy test will be conducted at the Day 1 visit for each of the Treatment Periods. 
Abbreviations: anti-HBc = total hepatitis B core antibody; anti-HBs = hepatitis B surface antibody; 
HBsAg = hepatitis B surface antigen; WOCBP = women of child-bearing potential (Appendix 7). 
 

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Additional Instructions: 
• The Investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. 
• If additional tests are required to be completed urgently by a local lab to assess an AE 
or for any other reason, these labs should also be completed by the central laboratory 
for this study using the unscheduled laboratory forms and procedures provided in the 
laboratory manual. The values obtained by the central laboratory will override the 
values obtained by the local laboratory. 
• The laboratory reports must be signed by the investigator who reviewed the report and 
filed with the source documents. 
• Clinically significant abnormal laboratory findings are those that are not associated 
with the subject’s health status and judged by the Investigator to be more severe than 
expected. 
• All abnormal laboratory tests with values considered clinically significant after 
randomization should be repeated until the values return to normal or baseline or are 
no longer considered clinically significant by the Investigator or Medical Monitor. 
­ If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the 
Sponsor notified. 
­ All protocol-required laboratory assessments must be conducted in accordance 
with the laboratory manual that will be developed by the central laboratory 
vendor and per the timelines outlined in the SoA (Section 1.3). 
­ If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in subject 
management or are considered clinically significant by the Investigator (e.g., 
SAE or AE), then the results must be recorded in the eCRF. 

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Appendix 4 
ECG Exclusion Criteria 
A 12-lead ECG recording at Screening showing any of the following abnormalities: 
• Sinus tachycardia ≥ 110 bpm (Sinus tachycardia ≥ 110 bpm should be confirmed by 
2 additional readings at least 5 minutes apart.). 
• Sinus bradycardia < 45 bpm (Sinus bradycardia < 45 bpm should be confirmed by 
2 additional readings at least 5 minutes apart). 
• Multifocal atrial tachycardia 
• Junctional (heart rate > 100 bpm) 
• Supraventricular tachycardia (> 100 bpm) 
• Ventricular tachycardia 
• Atrial fibrillation with rapid ventricular response (rate > 100 bpm). 
• Atrial flutter 
• Frequent VPCs (> 2 on a 10 sec ECG) 
• Ventricular flutter 
• Ventricular fibrillation 
• Torsades de Pointes 
• Wide QRS tachycardia (diagnosis unknown) 
• Electrical alternans 
• Pacemaker or ICD 
• Idioventricular rhythm – heart rate < 100 bpm 
• Mobitz type II second degree or third degree atrioventricular (AV) block. 
• AV dissociation 
• Bifascicular Block (RBBB plus LAHB or RBBB plus LPHB) 
• Left bundle branch block 
• Wolff Parkinson White Syndrome 
• Brugada Syndrome pattern 
• QTcF ≥ 480 msec when RBBB is present 
• Subjects without complete right bundle branch block: QTc(F) ≥ 450 msec or an ECG 
that is unsuitable for QT measurements (e.g., poorly defined termination of the T 
wave). 

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Appendix 5 
ECG Withdrawal Criteria 
All ECGs conducted or overread after a subject has been randomized will be subject to 
ECG Withdrawal Criteria (including the pre-dose ECGs at Visit 2 and subsequent visits). 
A subject may be withdrawn from study medication if the 12-lead ECG recording during 
the study shows any of the following abnormalities: 
The Investigator may withdraw subjects from study treatment for any other clinically 
significant finding (Section 7.0). Triplicate ECGs (over a brief period of time) should be 
performed on subjects experiencing any of the following or a clinically significant 
abnormality on their ECG per the Investigator’s discretion, in order to confirm the 
abnormality in 2 of 3 measurements. The decision to withdraw a subject should also take 
into consideration the subject’s medical history and prior/baseline ECGs. 
• Sinus tachycardia ≥ 120 bpm (Sinus tachycardia ≥ 120 bpm should be confirmed by 
2 additional readings at least 5 minutes apart.). 
• Sinus bradycardia < 37 bpm (Sinus bradycardia < 37 bpm should be confirmed by 
2 additional readings at least 5 minutes apart). 
• Increase in heart rate ≥ 40 bpm relative to baseline. 
• Multifocal atrial tachycardia 
• Supraventricular tachycardia (> 100 bpm) 
• Atrial fibrillation with rapid ventricular response (rate > 120 bpm). 
• Atrial flutter with rapid ventricular response (rate > 120 bpm). 
• Ventricular tachycardia (non-sustained, sustained, polymorphic or monomorphic) 
• Ventricular flutter 
• Ventricular fibrillation 
• Torsades de Pointes 
• Evidence of Mobitz type II second degree or third degree atrioventricular (AV) block. 
• AV dissociation 
• 2:1 AV block 
• Bifascicular Block (RBBB plus LAHB or RBBB plus LPHB) 
• An increase in QTcF > 60 msec from baseline ECG 
• Uncorrected QT > 600 msec 
• For subjects with QRS duration < 120 msec: QTc(F) ≥ 500 msec or an ECG that is 
unsuitable for QT measurements (e.g., poor defined termination of the T wave). 
• For subjects with QRS duration ≥ 120 msec: QTc(F) ≥ 530 msec or an ECG that is 
unsuitable for QT measurements (e.g., poor defined termination of the T wave). 
• Myocardial infarction (acute or recent) Note: Evidence of an old resolved Myocardial 
infarction is not exclusionary. 
 

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Appendix 6 
Adverse Events: Definitions and Procedures 
for Recording, Evaluating, Follow-up and 
Reporting 
Definition of AE 
• An AE is any untoward medical occurrence in a subject or subject, temporally 
associated with the use of blinded study medication, whether or not considered related 
to the blinded study medication. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of blinded study medication. 
• COPD exacerbations are an expected disease-related outcome. COPD exacerbations 
including daily expected COPD symptoms (e.g., dyspnea, chest tightness, wheezing, 
cough, sputum, that are not associated with the dosing event) will not be collected as 
an AE unless they meet the definition of an SAE. 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (e.g., hematology, clinical chemistry) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the Investigator (i.e., not related to progression of 
underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition other than COPD 
including either an increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after blinded study medication administration 
even though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either blinded 
study medication or a concomitant medication. Overdose per se will not be reported 
as an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms and/or clinical sequelae resulting from 
lack of efficacy will be reported as an AE or SAE if they fulfil the definition of an AE 
or SAE. 

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Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the Investigator to be more severe than expected for the subject’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
subject’s condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure should be assessed using the AE/SAE definitions. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death. 
b) Is life-threatening. 
The term ‘life-threatening’ in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization. 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 

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d) Results in persistent disability/incapacity. 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the subject or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
Recording and Follow-up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The Investigator will then record all relevant AE/SAE information in the eCRF. 
Each event must be recorded separately. 
• It is not acceptable for the Investigator to send photocopies of the subject’s 
medical records to Sponsor/Sponsor’s designee in lieu of completion of the 
Verona Pharma /AE/SAE eCRF page. 
• There may be instances when copies of medical records for certain cases are 
requested by groups such as the Sponsor/Sponsor’s designee, Health Authority, or 
Ethics Committee. In this case, all subject identifiers, with the exception of the 
subject/patient number, will be redacted on the copies of the medical records 
before submission to records to the Sponsor/Sponsor’s designee. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE; however, 
the signs and symptoms should be described in the narrative of the SAE form.  

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Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to one of the following categories: 
• Mild: An event that is easily tolerated by the subject, causing minimal discomfort, and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Chronicity 
• Single occasion: Single event with limited duration. 
• Intermittent: Several episodes of an event, each of limited duration 
• Persistent: Event which remained indefinitely. 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between blinded study 
medication and each occurrence of each AE/SAE. The AE must be characterized 
as either 1) a reasonable possibility of causality or 2) no reasonable possibility of 
causality: 
o Reasonable possibility:  There is a clear temporal relationship between the 
study intervention and the event onset; and the event is known to occur 
with the study intervention or there is a reasonable possibility that the 
study intervention caused the event.  Reasonable possibility means that 
there is evidence to suggest a causal relationship between the study 
intervention and the event. 
o No reasonable possibility:  There is no evidence suggesting that the study 
intervention caused the event, there is no temporal relationship between 
the study intervention and event onset, or an alternate etiology has been 
established (e.g. event is consistent with medical history). 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to blinded study 
medication administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure (IB) in his/her 
assessment. 

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• For each AE/SAE, the Investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the Investigator has 
minimal information to include in the initial report to the Sponsor/Sponsor’s 
designee. However, it is very important that the Investigator always make an 
assessment of causality for every event before the initial transmission of the SAE 
data to the Sponsor/Sponsor’s designee. 
• The Investigator may change his/her opinion of causality considering follow-up 
information and send a SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Action and Outcome 
• Action taken with blinded study medication (none, blinded study medication 
stopped, blinded study medication temporarily interrupted) 
• Other actions (none, concomitant medication, study discontinuation, 
hospitalization, other) 
• The outcome and date of outcome according to the following definitions: 
­ Recovered or resolved (adverse event disappeared) 
­ Recovering or resolving (subject is recovering) 
­ Not recovered or not resolved (adverse event remains without signs of 
improvement) 
­ Recovered or resolved with sequelae (adverse event has resulted in 
permanent disability or incapacity) 
­ Fatal 
­ Unknown (only applicable if subject has been lost to follow-up) 
• Seriousness (yes or no) 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor/Sponsor’s designee to elucidate the nature and/or causality of the AE or SAE 
as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• If a subject dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor/Sponsor’s designee with a copy of 
any postmortem findings including histopathology, as applicable local regulatory 
requirements will allow. 
• New or updated information will be recorded in the originally completed eCRF. 
• The Investigator will submit any updated SAE data to the Sponsor/Sponsor’s 
Designee within 24 hours of receipt of the information. 

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Reporting of SAEs 
SAE Reporting to the Sponsor/Sponsor’s designee via an Electronic Data Collection 
Tool 
• The primary mechanism for reporting an SAE to the Sponsor/Sponsor’s designee 
will be the electronic data collection tool. 
• If the electronic system is unavailable, then the study center will use the paper 
SAE data collection tool (see next section). 
• The study center will enter the SAE data into the electronic system as soon as it 
becomes available. 
• After the study is completed at a given study center, the electronic data collection 
tool will be taken off-line to prevent the entry of new data or changes to existing 
data. 
• If a study center receives a report of a new SAE from a subject or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the study center can report this information on a 
paper SAE form (see next section) or to the Medical Monitor by telephone. 
• Contacts for SAE reporting can be found in Appendix 2 on the Medical Monitor 
Contact Information page. 
SAE Reporting to Sponsor/ Sponsor’s Designee via Paper CRF if eCRF is not 
Available 
• If the eCRF is not available, facsimile transmission of the SAE paper CRF may be 
used to transmit this information to the Medical Monitor. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection forms sent by 
overnight mail or courier service to the Medical Monitor. 
• Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in Appendix 2 on the Medical Monitor 
Contact Information page. 
Device Incidents 
The Investigator, or responsible person according to local requirements (e.g., the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of device incidents. 
A device incident is defined as an incident related to the failure of a medical device, 
deterioration in its effectiveness, or inadequacy in its labeling or directions that led to the 
death or serious deterioration in health of a patient, user, or other person, or could do so 
were it to recur. 
 

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Appendix 7 
Contraceptive Guidance and Collection of 
Pregnancy Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenopausal female with 1 of the following: 
a) Documented hysterectomy. 
b) Documented bilateral salpingectomy. 
c) Documented bilateral oophorectomy. Note: Documentation can come from the study 
center personnel’s: review of the subject’s medical records, medical examination, or 
medical history interview. 
2. Postmenopausal female: 
a) Postmenopausal females are defined as amenorrhoeic for greater than 1 year with an 
appropriate clinical profile, e.g., age appropriate, > 45 years, in the absence of hormone 
replacement therapy. 
Contraception Guidance 
Female subjects 
Female subjects of childbearing potential are eligible to participate if they are not 
breastfeeding and agree to use a highly effective method of contraception consistently and 
correctly as described in the table below, during the study starting at Visit 1 and for at 
least 30 days after the last dose of study treatment. 
Table 12: Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of < 1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulationb 
• Oral 
• Intravaginal 
• Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• Oral 
• Injectable 

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Table 12: Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Independent a 
Implantable progestogen only hormonal contraception associated with inhibition of 
ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
Bilateral tubal occlusion. 
Vasectomized partner 
A vasectomized partner is a highly effective birth control method provided that the 
partner is the sole male sexual partner of the WOCBP, and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception should be 
used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the subject. 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. 
Use should be consistent with local regulations regarding the use of contraceptive 
methods for subjects participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, 
which may reduce the efficacy of the contraceptive method. In this case, 2 highly 
effective methods of contraception should be utilized during the treatment period and 
for at least 30 days after the last dose of study treatment. 
 
Pregnancy Testing: 
• WOCBP should only be included after a negative highly sensitive pregnancy test 
at Screening (Visit 1). 
• Additional pregnancy testing should be performed at times specified in the SoA 
(Section 1.3). 
Pregnancy testing should be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
Collection of Pregnancy Information 
Female subjects who become pregnant 
• The Investigator will collect pregnancy information on any female subject who 
becomes pregnant while participating in this study. Information will be recorded on 

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the appropriate form and submitted to the Sponsor within 24 hours of learning of a 
subject’s pregnancy. 
• The subject will be approached and asked to consent to be followed to determine the 
outcome of the pregnancy. The Investigator will collect follow-up information on the 
subject and the neonate, and the information will be forwarded to the Sponsor. 
Generally, follow-up will be no longer than 6 to 8 weeks beyond the estimated 
delivery date. Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported 
as such. 
• Any post-study pregnancy related SAE considered reasonably related to the blinded 
study medication by the Investigator will be reported to the Sponsor as described in 
Section 8.7.5. While the Investigator is not obligated to actively seek this information 
in former subjects, he or she may learn of an SAE through spontaneous reporting. 
• Any female subject who becomes pregnant while participating in the study will 
discontinue blinded study medication and be withdrawn from the study. 
 

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Appendix 8 
Liver Safety 
Phase III-IV liver chemistry stopping criteria and follow-up criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). Phase III to IV liver chemistry stopping 
criteria 1 to 5 are defined below. Investigators may at their discretion refer subjects 
meeting liver safety criteria below to a specialist who may determine the appropriate or 
medically necessary additional or confirmatory laboratory tests or procedures as required 
by the protocol or otherwise deemed necessary (e.g., liver imaging). 
1. ALT ≥ 3 × ULN and bilirubin ≥ 2 × ULN (35% direct bilirubin) (or ALT ≥ 3 × ULN 
and INR > 1.5 if international normalize ratio (INR) measured. 
Note: if serum bilirubin fractionation is not immediately available, withdraw study 
drug for that subject if ALT ≥ 3 × ULN and bilirubin ≥ 2 × ULN. Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct 
bilirubin elevations and suggesting liver injury. 
2. ALT ≥ 8 × ULN. 
3. ALT ≥ 5 × ULN but < 8 × ULN persists for ≥ 2 weeks. 
4. ALT ≥ 3 × ULN if associated with symptoms (new or worsening) believed to be 
related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, or jaundice) or hypersensitivity (such as fever, rash, or eosinophilia). 
5. ALT ≥ 5 × ULN but < 8 × ULN and cannot be monitored weekly for ≥ 2 weeks. 
When any of the liver stopping criteria 1 to 5 is met do the following: 
• Immediately discontinue blinded study medication/investigational product for 
that subject. 
• Report the event to PPD within 24 hours of learning its occurrence. 
• Complete the liver event CRF and SAE data collection form if the event also 
meets the criteria for an SAE. All events of ALT ≥ 3 × ULN and bilirubin 
≥ 2 × ULN (35% direct bilirubin) (or ALT ≥ 3 × ULN and INR > 1.5, if INR 
measured; INR measurement is not required and the threshold value stated will 
not apply to subjects receiving anticoagulants), termed ‘Hy’s Law’ must be 
reported as an SAE (excluding studies of hepatic impairment or cirrhosis). 
Note: if serum bilirubin fractionation is not immediately available, discontinue blinded 
study medication/investigational product for that subject if ALT ≥ 3 × ULN and bilirubin 
≥ 2 × ULN. Serum bilirubin fractionation should be performed if testing is available. If 
testing is unavailable, record presence of detectable urinary bilirubin on dipstick, 
indicating direct bilirubin elevations and suggesting liver injury. 

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• Complete the liver imaging and/or liver biopsy CRFs if these tests are performed. 
• Perform liver event follow-up assessments and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below. 
• Discontinue blinded study medication/investigational product after completion of 
the liver chemistry monitoring as described below. 
• Do not restart investigational product. 
In addition, for criterion 1: 
• Make every reasonable attempt to have subjects return to clinic within 24 hours 
for repeat liver chemistries, liver event follow-up assessments (see below), and 
close monitoring. 
• A specialist or hepatology consultation is recommended. 
• Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values. 
For criteria 2, 3, 4, and 5: 
• Make every reasonable attempt to have subjects return to clinic within 
24 to 72 hours for repeat liver chemistries and liver event follow-up assessments 
(see below). 
• Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize, or return to within baseline values; criterion 5 subjects 
should be monitored as frequently as possible. 
Subjects with ALT ≥ 5 × ULN and < 8 × ULN which exhibit a decrease to 
ALT ≥ 3 × ULN, but < 5 × ULN and bilirubin < 2 × ULN without hepatitis symptoms or 
rash, and who can be monitored for 4 weeks: 
• Notify the Medical Monitor within 24 hours of learning of the abnormality to 
discuss subject safety. 
• Can continue investigational product. 
• Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize, or return to within baseline. 
• If at any time these subjects meet the liver chemistry stopping criteria, proceed as 
described above. 
• If, after 4 weeks of monitoring, ALT < 3 × ULN and bilirubin < 2 × ULN, 
monitor subjects twice monthly until live chemistries normalize or return to within 
baseline values. 

Protocol RPL554-CO-211 
 
Version 3.0; 14 October 2024 
Verona Pharma plc 
CONFIDENTIAL 
Page 108 of 110 
For criteria 1 to 5, make every attempt to carry out the liver event follow up assessments 
described below: 
• Viral hepatitis serology including 
­ Hepatitis A IgM antibody 
­ Hepatitis B surface antigen and Hepatitis B Core antibody (IgM) 
­ Hepatitis C RNA 
­ Cytomegalovirus IgM antibody 
­ Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing). 
­ Hepatitis E IgM antibody 
• Blood sample for PK analysis, obtained within 72 hours of the last dose. Record 
the date/time of the PK blood sample draw and the date/time of the last dose of 
blinded study medication/investigational product prior to blood sample draw on 
the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK 
sample cannot be collected in the time period indicated above, do not obtain a PK 
sample. Instructions for sample handling and shipping are in the SPM. 
• Serum creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• Fractionate bilirubin if total bilirubin ≥ 2 × ULN. 
• Obtain complete blood count with differential to assess eosinophilia. 
• Record the appearance or worsening of clinical symptoms of hepatitis or 
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia as relevant on the AE report form. 
• Record use of concomitant medications, acetaminophen, herbal remedies, or over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form. 
• Record alcohol use on the liver event alcohol intake case report form. 
The following are required for subjects with ALT ≥ 3 × ULN and bilirubin ≥ 2 × ULN 
(35% direct) but are optional for the other abnormal liver chemistries: 
• Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma 
globulins). 

Protocol RPL554-CO-211 
 
Version 3.0; 14 October 2024 
Verona Pharma plc 
CONFIDENTIAL 
Page 109 of 110 
• Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in 
the preceding week).  
• Only in those with underlying chronic hepatitis B at study entry (identified by 
positive hepatitis B surface antigen): quantitative hepatitis B DNA and hepatitis 
delta antibody. NOTE: if hepatitis delta antibody assay cannot be performed, it 
can be replaced with a PCR of hepatitis D RNA virus where needed 
(Gal et al. 2005). 
 
 

Protocol RPL554-CO-211 
 
Version 3.0; 14 October 2024 
Verona Pharma plc 
CONFIDENTIAL 
Page 110 of 110 
Appendix 9 
Signature of Investigator 
PROTOCOL TITLE: A Phase IIb, randomized, double-blind, placebo-controlled study to 
assess the efficacy, safety, and pharmacokinetics of glycopyrrolate inhalation solution 
over 1 week in subjects with COPD. 
PROTOCOL NO: RPL554-CO-211 
VERSION: 3.0 
Version Date: 14 October 2024 
This protocol is a confidential communication of Verona Pharma plc. I confirm that I 
have read this protocol, I understand it, and I will work according to this protocol. I will 
also work consistently with the ethical principles that have their origin in the Declaration 
of Helsinki and that are consistent with Good Clinical Practices and the applicable laws 
and regulations. Acceptance of this document constitutes my agreement that no 
unpublished information contained herein will be published or disclosed without prior 
written approval from the Sponsor.  
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT 
your name, title, and the name of the study center where the study will be conducted. 
Return the signed copy to the Sponsor. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
 
Signature of Investigator 
Date 
 
 
 
Printed Name 
 
Investigator Title 
 
Name/Address of Center