Clinical trial NCT04542057
Conditions: Chronic Obstructive Pulmonary Disease
Keywords: COPD
Sponsor: Verona Pharma plc
Start date: 2020-09-22; Completion date: 2022-07-06
Enrollment: 790 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if ensifentrine is safe and effective for the treatment of patients with moderate to severe Chronic Obstructive Pulmonary Disease (COPD).

Detailed description:

Arms: arm 1: Ensifentrine Nebulized Suspension; 3 mg twice daily for 24 weeks arm 2: Ensifentrine Placebo Nebulized Solution; twice daily for 24 weeks
Interventions: intervention 1: Ensifentrine intervention 2: Placebo
Intervention descriptions: intervention 1: Dosage Formulation:

Ensifentrine Nebulizer suspension Dosage 3mg Frequency: Twice Daily for 24 weeks intervention 2: Dosage Formulation:

Ensifentrine Placebo Nebulizer solution Frequency: Twice Daily for 24 weeks

Protocol documents:
Prot_000.pdf: 
Protocol RPL554-CO-302  
 
Version 5.0; 30 Apr 2021 
 
CONFIDENTIAL 
 
 
 
 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Phase III Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of 
Ensifentrine over 24 Weeks in Patients with Moderate to 
Severe Chronic Obstructive Pulmonary Disease. 
Protocol Number: 
RPL554-CO-302 
Version: 
5.0 
Amendment Number: 
4.0 
Investigational Product: 
Ensifentrine 
Short Title: 
A Phase III randomized, placebo-controlled study to 
evaluate the efficacy and safety of ensifentrine over 
24 weeks in patients with chronic obstructive pulmonary 
disease. 
Study Phase: 
III 
Sponsor Name: 
Verona Pharma plc 
 
Legal Registered Address 
3 More London Riverside 
London, SE1 2RE 
UK 
Regulatory Agency 
Identifying Number(s): 
EudraCT Number: 2020-002069-32 
US IND Number: 133146 
Date of Protocol: 
30 April 2021 (replaces Version 4.0, dated 17 July 2020)  
 
 




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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
TABLE 
Table 1 Document History 
Protocol 
Version 
Amendment 
Date 
Substantial - timings 
Region 
Version 1.0 Original Protocol 28-May-2020 
Original Protocol 
Global 
Version 2.0 Amendment 1.0 
22-June-2020
Yes – prior to initial 
regulatory submissions 
Global 
Version 3.0 Amendment 2.0 
26-Jun-2020
Yes– prior to initial 
regulatory submissions 
Global 
Version 4.0 Amendment 3.0 
17-Jul-2020
Yes– prior to initial 
regulatory submissions 
Global 
Version 5.0 Amendment 4.0 
30-Apr-2021
Yes – during enrollment 
Global 
Protocol Version 2.0, Amendment 1.0: 22June-2020 
Overall Rationale for the Amendment: 
The protocol is amended to address minor administrative items (spelling, punctuation, 
spaces and Table numbering), clarifications, and substantial changes to add an ECG 
exclusion criteria, spirometry at Week 24, optional rather than mandatory COVID-19 
testing, and adding a section on Treatment After the End of Study. 
Table 2 Description of Changes in the Amendment 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3, Schedule of 
Activities, Register Visit 
in IRT 
Section 8.5.2, Interactive 
Response Technology 
Registration in IRT will not be 
required at Week 18. This is 
revised to “Register in IRT” with 
the word “visit” removed. 
Section 8.5.2 revised to note that 
information would only be 
entered into the IRT at specified 
visits. 
Administrative 
change to align with 
IRT system. 
Section 1.3, Screening 
Spirometry 
The timing of pre-and post-
bronchodilator spirometry testing 
was revised. Pre-bronchodilator 
testing will be conducted prior to 
dosing with albuterol/salbutamol. 
Administrative 
change to allow an 
appropriate window 


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Post-bronchodilator testing 
should be conducted between 15 
and 30 minutes following 
administration of 
albuterol/salbutamol 
within to collect the 
assessments. 
Section 1.3, eDiary Site 
Activation Activities 
Assessments deleted. 
Administrative 
change. Assessments 
not necessary. 
Section 1.3, Footnote 4 
Added to the X for the Early 
Termination visit for Blinded 
Study Medication Dosing in the 
Clinic. Added language to 
indicate that dosing should be 
performed “if possible”. 
Administrative 
change. 
Section 1.3, Patient 
Contact Day Prior to 
Spirometry Visits and 
Footnote 8 
Week 24 assessment added.  
Footnote 8 was amended to note 
additional detail regarding the 
expected timing of the contact 
“Either 3 or 4 days”, study 
medication, and other medication 
withholding prior to the clinic 
visit. This was also amended to 
note that patients would be 
reminded to fill out their paper 
diary during the Patient Contact 
prior to the spirometry visits. 
Substantial change. 
Additional patient 
contact required to 
align with added 
spirometry at Week 
24. 
Section 1.3, Patient 
Contact Day Prior to 
Pharmacokinetic 
Assessments and Footnote 
19 
Patient contact and Footnote 19 
deleted and combined with 
Footnote 8. 
Substantial change. 
Only one patient 
contact is needed. 
Section 1.3, Spirometry 
Inhalation Observation & 
Training 
Week 24 assessment added. 
Substantial change. 
Additional assessment 
required to align with 
added spirometry at 
Week 24. 
Section 5.2, Exclusion #8 
Sleep apnea was changed to 
“unstable” sleep apnea. 
Administrative 
change. Clarification. 


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Section 1.3, Chest X-ray 
and Footnote 6 
Section 5.2, Exclusion #22 
Section 8.1.7, Chest X-ray 
The language “unless restricted 
by local requirements” was 
changed to “For subjects in 
Germany, if a CXR or CT scan 
is not available in the 12 months 
prior to Screening, the subject is 
not eligible for the study”. 
Administrative 
change. To clarify 
requirements for 
Germany regarding 
chest X-ray. 
Section 1.3, Schedule of 
Activities, Spirometry 
(pre-dose); Spirometry 0-4 
hours post-dose 
Synopsis 
Section 1.4, Schedule of 
Spirometry and In-Clinic 
Dosing 
Section 2.1, Study 
Rationale 
Section 4.2, Scientific 
Rationale for Study 
Design 
Pre-dose and 0-4 hour post-dose 
spirometry assessments added at 
Week 24. 
Synopsis and study rationale 
revised to note that spirometry 
would be collected over 24 
weeks rather than 12. 
Footnote 1 added to Week 24. 
Substantial change. 
Additional duration of 
effect desired.  
Section 1.3, Footnote 14 
Section 6.7.2, Table 7 
Section 8.1.16, Dispense 
Rescue Medication 
Section 8.4.2, 
Electrocardiogram 
It was noted that 
albuterol/salbutamol should be 
withheld for at least 4 hours prior 
to ECG assessments. 
Administrative 
change for clarify 
intent. 
Section 1.3, Laboratory 
Tests 
Amended to clarify that serum 
pregnancy testing was included 
in laboratory testing. 
Footnote 15 linking to pregnancy 
testing information added. 
Administrative 
change to clarify 
when serum and urine 
pregnancy testing 
would be conducted. 
Section 1.3, Pregnancy 
Test for Women and 
Footnote 15 
Amended to clarify that only 
urine testing would be conducted 
at specified assessments. 
Footnote 15: the following 
language was added “A urine test 
Administrative 
change to clarify 
when serum and urine 
pregnancy testing 
would be conducted, 


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Section 11.3, Clinical 
Laboratory Tests 
Section 11.8, 
Contraceptive Guidance 
and Collection of 
Pregnancy Information 
will be conducted on all women 
prior to dosing at Visit 1.” 
Section 11.3: the following 
language was deleted “Pregnancy 
testing will be performed and 
assayed in the central 
laboratory.”  
The language “WOCBP should 
only be included after a 
confirmed menstrual period and a 
negative highly sensitive 
pregnancy test.” was revised to 
“WOCBP should only be 
included after a negative highly 
sensitive pregnancy test.” 
and to clarify other 
potentially ambiguous 
language. 
Section 1.3, Dispense 
Rescue albuterol/ 
salbutamol 
Dispensing of rescue 
albuterol/salbutamol was deleted 
at Week 24 
Administrative 
change to correct an 
error. 
Section 1.3, COVID-19 
Test and Footnote 16 
Section 8.1.10.2, 
COVID-19 
Section 8.4.3.1, 
COVID-19 
Changed COVID-19 testing 
requirement to optional and 
based on local requirements. 
Substantial change. 
Sites have indicated 
that COVID site risk 
is managed locally. 
Section 5.3, 
Randomization Criteria #4 
Section 7.1.3, 
Electrocardiogram 
Withdrawal Criteria 
Section 11.5, ECG 
Withdrawal Criteria 
In this statement, “In the event 
that the central ECG reviewer 
discovers a clinically significant 
ECG abnormality on the Visit 1 
ECG, the patient will be 
discontinued from the study.” 
The words “clinically” and “from 
the study” were deleted from the 
sentence. 
Clarifications were made to note 
that the central reviewer would 
make a determination on 
significant abnormalities, while 
clinically significant 
abnormalities would be 
Administrative 
change to clarify 
significant and 
clinically significant 
abnormalities, and 
allow flexibility for 
patients to withdraw 
from treatment and 
stay in the study. 


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determined per Investigator’s 
discretion. 
Section 6.1.2, Dosing at 
Home, Blinded Study 
Medication 
Administration, 4th bullet. 
Section 1.3, Patient 
Contact Day Prior to 
Spirometry Visits and 
Footnote 8 
Section 1.4, Schedule of 
Spirometry and In-Clinic 
Dosing 
 
The bullet originally stated, “The 
date, start time, and the end time 
of blinded study medication 
nebulization should be recorded 
in the patient diary.” 
The 4th bullet has been revised to 
state, “One the evening Prior to 
the Week 6,Week 12, and Week 
24 Visits: On a patient paper 
diary, the patient will record the 
date, the start time of 
nebulization, and the end time of 
nebulization for the evening dose 
of blinded study medication”. 
Footnote 8 was amended to note 
that patients would be reminded 
to fill out their paper diary during 
the Patient Contact prior to the 
spirometry visits.  
The following language was 
added in Table 4 as a Note: “For 
pre-dose spirometry conducted 
between 11.5 and 12 hours after 
the patients evening dose the day 
prior to the visit, the paper diary 
with the evening dosing 
completion time should be 
consulted.” 
Clarification change 
to more accurately 
reflect the dosing 
information required 
just prior to the Week 
6, Week 12, and 
Week 24 (or Early 
Term/Withdrawal 
visits where 12-hour 
spirometry will be 
performed).  
Synopsis, Overall Design 
Section 4.1, Overall 
Design 
Section 6.2, Section 6.7.2, 
Section 6.7.3, Section 8.2, 
Section 11.2, Section 11.3, 
Tables 5 to 14. 
In reference to ‘long-acting ȕ2 
agonist,’ the word ‘agonist’ was 
misspelled.  
Tables 3 to 12 were updated to 
numbers 5 to 14. 
 
Administrative 
change to correct a 
spelling error and 
Table numbering due 
to Amendment.  


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Section 6.7.1, Rescue 
Medication 
6.7.1.1, Documentation of 
Rescue Medication Use 
The sentence “Rescue 
medication will be sourced by 
the study center and dispensed at 
each visit as needed.” Was 
deleted, and the word “study” 
was added prior to 
albuterol/salbutamol. 
The following language was 
added “After Screening, use of 
Rescue Medication will not be 
recorded in the concomitant 
medication page of the eCRF.” 
The example was also updated to 
include number of puffs and to 
delete “route” in bullet 2. 
Administrative 
change to allow for 
flexible sourcing of 
rescue medication. 
6.7.3, Table 8 
“Systemic” and “parenteral” 
were added to “Oral steroid 
therapies”. Footnote 1 was 
inserted “Except for the 
treatment of COPD 
exacerbations during the study 
(Section 11.6). Localized 
corticosteroid injections are 
permitted”. 
Administrative 
change. Clarification. 
Section 6.7.4.1, Recording 
of Rescue Medication 
and/or LAMA or LABA 
Medications 
3rd bullet: removed descriptive 
text in the parenthesis “(eg, 
morning dose and evening dose, 
[both if on a twice-daily 
regimen]).” 
Administrative 
change.  
Section 6.8, Treatment 
After the End of Study 
This section was added along 
with the following language: 
“There are no plans to provide 
post-study treatment, including 
study medication for 
compassionate use following 
study completion. 
At the end of the treatment 
period (Visit 5 or Visit 9 or early 
termination), patients may 
resume conventional COPD 
therapy as prescribed by the 
investigator or other physician. 
Substantial change. 
Missing section was 
in error. 


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Medications initiated after the 
end of study treatment should not 
be entered into the eCRF except 
for those given for a serious 
adverse event (SAE).” 
Section 8.3.1, Spirometry 
The word “judgement” was 
replaced by “determination”. 
Administrative 
change. 
Section 8.3.2, COPD 
Exacerbation Assessment 
The language stating that 
exacerbations would be based on 
symptoms reported in the eDiary 
was removed. 
Administrative 
change to correct an 
error. 
Section 8.3.3.6, 
Evaluating-Respiratory 
Symptoms Questionnaire 
Section 1.3 and Footnote 
12 
Section 8.1.13, Electronic 
Diary Activities 
Section 8.5.4, Electronic 
Diary Activities 
Clarified that the E-RS is derived 
from the EXACT-PRO. 
This assessment is clarified as 
E-RS/EXACT-PRO.
Administrative 
change. Clarification. 
Section 8.4.2, 
Electrocardiogram 
The following language 
“determination of an acceptable 
endpoint measurement(s) will 
override judgement by the 
investigative site.” was revised 
to: “interpretation of the 
measurement(s) will override the 
interpretation by the investigative 
site, if consensus is not reached.” 
Administrative 
change. Clarification. 
Section 8.5.8, 
Dispense/Collect Rescue 
Albuterol/Salbutamol 
Corrected to note that rescue 
medication would be dispensed 
at specified visits rather than 
each study visit. 
Administrative 
change. Corrected 
inconsistency. 
8.5.10.2, Recording of 
Medications and 
Information Specific to the 
Pharmacokinetic 
Recording of the nebulization 
end time was added. 
Collection of Medication name, 
dose (eg. Dose unit, route, 
schedule/frequency) was added 
Administrative 
change to correct 
omissions and clarify 
language. 


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Procedures and Sample 
Analysis and Table 10 
to Table 10, along with other 
administrative edits. 
Section 8.6.1, Site Level 
Disaster Plan 
The text was revised to indicate it 
is ‘recommended’ that 
investigative sites prepare a 
written disaster plan for this 
study.  
The requirement for a written 
disaster plan to be prepared 
“before the site initiation visit is 
conducted” has been deleted. 
Administrative 
change to recommend 
rather than require  
investigative sites to 
prepare a Disaster 
Plan for the study. 
Section 9.4.3, Other 
Analyses 
The text “The outcome of 
COVID-19 tests will be 
summarized by treatment group 
and occasion” was removed. 
Administrative 
change to reflect 
optional COVID-19 
testing. 
Section 11.4, ECG 
Exclusion Criteria 
Added “QTcF  480 msec when 
RBBB is present” 
Substantial change 
recommended by a  
Cardiology 
consultant. 
Section 11.11, Country 
Specific Requirements 
The following language was 
added: “Germany: a CXR or CT 
scan must be available in the 12 
months prior to Screening for 
eligibility.” 
Administrative 
change to align with 
Eligibility language 
clarification. 
Protocol Version 3.0, Amendment 2.0: 26-June-2020 
Overall Rationale for the Amendment: 
The protocol is amended to remove the requirement for pregnancy testing in all women 
and to only perform pregnancy testing on women of childbearing potential. 
Description of Changes in the Amendment 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3, Footnote 15 
The current instruction ‘Pregnancy 
testing will be conducted on all 
women’ will be changed to 
‘Pregnancy testing will be 
To remove the 
requirement for 
pregnancy testing in 
all women. 


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conducted on women of 
childbearing potential.’ 
Section 7.1.5, Positive 
pregnancy test in females 
Changed ‘all women’ to ‘women 
of childbearing potential.’ 
To remove the 
requirement for 
pregnancy testing in 
all women. 
Section 11.3, Table 13 
Changed the first footnote to state  
women ‘of childbearing potential.’  
To remove the 
requirement for 
pregnancy testing in 
all women. 
Section 11.8, Contraceptive 
guidance and collection of 
pregnancy information 
The definition of non-childbearing 
potential in post-menopausal 
women was clarified: 
Additional detail was added to the 
text in 3.(a) to indicate that 
‘postmenopausal females are 
defined as amenorrhoeic for 
greater than 1 year with an 
appropriate clinical profile, eg, age 
appropriate, > 45 years, in the 
absence of hormone replacement 
therapy.’  
Language indicating FSH testing 
or hormonal birth control 
withdrawal was deleted. 
To clearly define 
the definition of 
post-menopausal 
women. 
11.12, Signature of 
Investigator 
Version number and version date 
updated to reflect version 3.0 and 
version date 26Jun2020. 
To match the 
version number and 
version date for this 
amendment. 
Protocol Version 4.0, Amendment 3.0: 17-July-2020 
Overall Rationale for the Amendment: 
The protocol is amended to reorder the secondary endpoint testing hierarchy, to remove 
an evening dosing requirement at early termination visits with 12-hour spirometry, to 
revise ‘Events Meeting the AE Definition’, to clarify COVID-19 testing as optional, to 
make minor clarifications to the pharmacokinetic section, to correct a minor document 
formatting issue, and to clarify the protocol version and amendment numbers.  


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Description of Changes in the Amendment 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Secondary 
Endpoints 
Section 3.2.2, Secondary 
Endpoints 
Section 9.0, Statistical 
Considerations: 
 - Sections 9.1 Statistical 
Hypotheses 
 - Section 9.4.1 Efficacy 
Analysis 
The order of the secondary 
endpoints has changed to raise the 
testing hierarchy of ‘SGRQ total 
score at Week 24 (change from 
baseline)’ and to lower the testing 
hierarchy of ‘The proportion of St. 
George’s Respiratory 
Questionnaire (SGRQ) responders 
at Week 24’.   
To elevate the 
continuous variable 
in the testing 
hierarchy. 
Section 1.4 Schedule of 
Spirometry and In-Clinic 
Dosing 
Evening blinded study medication 
dosing in the Clinic at the Early 
Term/Withdrawal Visit has been 
removed. 
An evening dose of 
blinded study 
medication at the 
Early 
Term/Withdrawal 
Visit is not 
required. 
Appendix 7, Adverse 
Events: Definition and 
Procedures for Recording, 
Evaluating, Follow-up and 
Reporting.  
Events Meeting the AE 
Definition, last bullet. 
Removed the last bullet: “The 
signs, symptoms, and/or clinical 
sequelae resulting from lack of 
efficacy will be reported as AE or 
SAE if they fulfil the definition of 
an AE or SAE. Also, ‘lack of 
efficacy’ or ‘failure of expected 
pharmacological action’ also 
constitutes and AE or SAE.” 
This text 
contradicted the text 
in the bullet above. 
“Lack of efficacy” 
or “failure of 
expected 
pharmacological 
action” are not to be 
reported as adverse 
events in this study. 
Section 1.3, Schedule of 
Activities (SoA). 
COVID-19 Test. 
COVID-19 testing was made 
optional at any time during the 
study in Protocol Version 2.0.  The 
SoA has been updated to state 
Optional COVID-19 TEST in the 
line item and the term “Optional” 
Clarification 


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has been added to each potential 
testing timepoint in the SoA.   
Section 8.5.10 
Pharmacokinetics. Section 
8.5.10.1 Collection of 
Samples 
The volume of whole blood was 
reduced from ‘approximately 
8 ml’ to ‘approximately 4 ml.’ 
A clarification 
based on current 
blood volume 
requirements. 
Section 8.5.10 
Pharmacokinetics. Section 
8.5.10.2 Recording of 
Medications and 
Information Specific to the 
Pharmacokinetic 
Procedures and Sample 
Analysis, Pharmacokinetic 
(PK) eCRF module 
Pharmacokinetic (PK) eCRF: The 
title of this paragraph was changed 
from “Pharmacokinetic (PK) 
eCRF module” to “Collection of 
medication and associated 
information in the eCRF.”  
The 2nd bullet, sub-bullet 3 was 
deleted. 
A clarification to 
more accurately 
reflect that the 
information will be 
captured in more 
than one eCRF 
module. 
Sub-bullet 3 is not 
required. 
Section 8.1.8 Spirometry 
Assessment 
A formatting issue in the previous 
amendment caused the text 
associated with Section 8.1.7 to 
become part of the header for 
Section 8.1.8 Spirometry 
Assessment. This formatting issue 
has been corrected. 
Formatting 
correction 
Protocol Amendment 
Summary of Changes 
Table 1 Document History 
and the description of each 
amendment. 
In previous changes to the 
protocol, the term Protocol 
Amendment was used to describe 
the updated Protocol Version 
number. The text references to 
protocol version and amendment 
has been updated and corrected. 
Clarification 
Protocol Version 5.0, Amendment 4.0: 30-Apr-2021 
Overall Rationale for the Amendment: 
The protocol is amended to allow some patients with stable use of inhaled corticosteroids, 
reorder the secondary endpoint testing hierarchy and add additional endpoints, to update 
the handling of missing data in the statistical analysis, to incorporate contents of Protocol 
clarification letters dated 29Sep2020 and 5Nov2020, to revise exclusion criteria relating 
to hepatitis B and C, and to revise and clarify prohibited medication requirements 
regarding chronic use of antibiotics and beta-blockers, and to update and clarify 


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requirements for stable use of maintenance therapy in Inclusion #8. Minor spelling errors, 
formatting corrections were also made. 
Description of Changes in the Amendment 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities 
8.5.6 Inhalation and 
Observation and Training 
for Spirometry 
“Inhalation Observation” deleted 
Footnotes 4 and 19: Clarified that 
PK sampling should only be 
drawn at early termination and 
visits for patients who took 
blinded study medication within 
48 hours of the visit. 
Footnote 8: Added ICS to 
withholding 
Footnote 17: Added “rescue 
medication may be dispensed at 
the time of signing the Informed 
Consent, if this occurs prior to 
commencement of screening 
assessments.” 
Footnote 18: Added “if allowed 
per local site practices, otherwise 
the study supplied compressors 
will not be retrieved and 
collected.” 
Clarification. 
To eliminate 
unnecessary 
collection of PK 
samples in patients 
not taking study 
medication. 
To note allowance 
of ICS requires the 
same withholding 
as LAMA and 
LABA 
To ensure patients 
who require rescue 
medication prior to 
screening 
procedures have 
access to it. 
To note that due to 
COVID, sites may 
not be able to 
collect study 
compressors. 
1.4 Schedule of Spirometry 
and In-Clinic Dosing with 
Blinded Study Medication 
Footnote 1 added for Evening 
Dosing: “Patients may be 
discharged from the clinic after 
Week 12 assessments are complete 
to self-administer their evening 
dose of study medication. If 
administered in the clinic, the 
Week 12 evening dose must be 
administered by unblinded site 
staff.” 
To clarify that 
patients may be 
discharged for their 
evening dose at 
home at the Week 
12 visit. 


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2.2 Background 
Updated IB version from 19 to 20, 
2021 (or more current version, if 
applicable) 
IB version update. 
2.3 Benefit/Risk 
Assessment 
Updated with results from 
completed pre- and post-natal 
development definitive study 
“There were no effects of 
ensifentrine on fertility and 
reproductive performance in 
female rats and no effects on pre- 
and post-natal development in 
female rats or offspring (Study 
8438109).” 
Updated IB version from 19 to 20, 
2021 (or more current version, if 
applicable) 
Updated with recent 
results from the 
completed pre- and 
post-natal 
development study. 
IB version update. 
3.2.2 Secondary Endpoints 
9.1 Statistical Hypothesis 
1.1 Synopsis 
Average FEV1 AUC (0-4h) at 
week 12 was demoted to 
secondary endpoint #5. 
Endpoint reordering 
results in morning 
trough FEV1 at 
week 12 to be 
promoted to 
secondary endpoint 
#4. 
3.2.3 Other Endpoints  
1.1 Synopsis 
Average FEV1 AUC (6-12h) at 
week 12 was added 
Endpoint added to 
evaluate the effects 
in the second half of 
the dosing interval. 
4.1 Overall Design 
4.2 Scientific Rationale for 
Study Design 
1.1 Synopsis 
Allowance and withholding 
periods for ICS were added: “Up 
to 20% of patients are allowed to 
take inhaled corticosteroids during 
the study under certain provisions 
(see Sections 6.7.2 and 6.7.3).” 
LABA and LAMA monotherapy 
was changed to LABA and LAMA 
therapy. Withholding periods were 
updated to include LAMA/ICS 
and LABA/ICS. 
Updated to note 
allowance of ICS 
under certain 
provisions. Stable 
ICS use in a 
subgroup is not 
expected to impact 
study endpoints or 
safety assessment of 
ensifentrine. 
5.1 Inclusion Criteria 
#8: Statement clarified: Patients 
taking maintenance LAMA or 
Duration prior to 
screening updated 


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LABA therapy must demonstrate 
“stable regular use of the 
maintenance LAMA or LABA 
therapy, in any form, for at least 2 
3 months prior to Screening and 
agree to continue use of their 
current permitted LAMA or 
LABA medication for the duration 
of the study.” 
from 3 to 2 months, 
which still allows 3 
months stable use 
prior to baseline. 
Clarifies “in any 
form” to note that 
the exact same 
background 
medication is not 
required during this 
interval. 
5.2 Exclusion Criteria 
#12: Added: “Note: Chronic stable 
hepatitis B and C is not 
exclusionary if the patient 
otherwise meets study entry 
criteria.” 
#19 and #20 relating to specific 
exclusion of Hepatitis B and C 
were deleted. 
Language changed 
to allow for stable 
chronic hepatitis B 
and C to be allowed 
if the subject meets 
other study criteria. 
5.2 Exclusion Criteria 
#25: added nebulized: “blinded 
nebulized study medication” 
To clarify that 
patients that have 
received nebulized 
blinded study 
medication in a 
prior study are 
excluded. 
5.3 Randomization Criteria 
Inclusion #1: added “at Visit 1” 
Clarification. 
5.3 Randomization Criteria 
Exclusion #4: Reworded to 
include: “assessed before the 
patient is randomized.” “After a 
patient has been randomized, ECG 
withdrawal criteria (Section 11.5) 
will apply. In the event that the 
central ECG reviewer discovers a 
significant ECG abnormality 
meeting ECG withdrawal criteria 
on the Visit 1 ECG in 2 of 3 
triplicate measurements, the 
patient willmay be discontinued. 
To clarify that 
ECGs assessed 
prior to 
randomization are 
subject to ECG 
Exclusion Criteria, 
while ECGs 
assessed after 
randomization 
(even if they were 
conducted prior) are 
subject to ECG 
withdrawal criteria. 


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Abnormalities 
should be 
confirmed in 2 of 3 
triplicates. 
5.3 Randomization Criteria 
Exclusion #5: Added: “as assessed 
at Screening Visit 0 (e.g. including 
overreads or lab values obtained 
after the day of Screening).” 
Clarification. 
6.1.1 Dosing in the Clinic 
Deleted: this includes morning and 
evening doses on the 12 hour 
clinic day (week 12). Added: 
Patients may be discharged from 
the clinic after Week 12 
assessments are complete to self-
administer their evening dose of 
study medication. If administered 
in the clinic, the Week 12 evening 
dose must be administered by 
unblinded site staff. 
Updated to allow 
patient dosing at 
home the evening 
of the Week 12 
visit. 
6.1.2 Dosing at Home 
Added “(and ICS, if applicable)” 
To clarify order of 
dosing at home in 
patients on ICS. 
6.7.2 Permitted Rescue and 
Background Medications 
Added: “Any vaccine that is 
recommended by the patient’s 
healthcare provider is permitted 
during the study (e.g. COVID, 
influenza, pneumonia), and should 
be recorded in the eCRF. 
Clarification. 
6.7.2 Permitted Rescue and 
Background Medications 
Table 7: The table was updated to 
include ICS use, and the following 
language “Stable use of ICS is 
permitted IF the patient has been 
taking the ICS at least 4 weeks 
prior to Screening (Visit 0) AND 
the patient is also taking 
maintenance LAMA or LABA. 
ICS should not be initiated or 
discontinued during the study.  
ICS monotherapy and high dose 
ICS (e.g. >1000 mcg of 
Updated to note 
allowance of ICS 
under certain 
provisions. Stable 
ICS use in a 
subgroup is not 
expected to impact 
study endpoints or 
safety assessment of 
ensifentrine. 


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fluticasone propionate or 
equivalent) is not allowed.”  
“Dual LAMA/LABA therapy is not 
allowed”  
Language to clarify that ICS is 
subject to withholding prior to 
spirometry also added. 
6.7.3 Prohibited 
Medication/Therapy 
Table 8: 
Oral systemic or parenteral  
steroid therapies for COPD 
Added: Antibiotics for lower 
respiratory tract infection: 6 weeks 
prior to screening and prohibited 
during the study1. Chronic use of 
antibiotics is not allowed 6 weeks 
prior to or during the study. 
Added: ICS (e.g. ICS 
monotherapy and patients in the 
no background therapy stratum). 
High dose ICS (e.g. >1000 mcg 
fluticasone propionate or 
equivalent) 
Added: Ipratropium (including 
combinations with 
albuterol/salbutamol) 
Added: Nebulized LAMA or 
LABA or ICS. For patients in the 
no maintenance therapy stratum: 4 
weeks prior to screening and 
prohibited during the study. 
For patients in the LAMA/LAMA 
stratum: 1 week prior to screening 
and prohibited during the study 
(e.g. patient should switch from 
nebulizer to dry powder or 
metered dose inhaler therapy). 
Edits to clarify 
prohibited 
medications, certain 
ICS use in certain 
groups, nebulized 
therapy restrictions 
and to add 
exclusion for oral 
beta agonists, which 
can cause 
bronchodilation. 
The exclusion of 
oral beta blockers 
was deleted as it 
was determined that 
this would not 
impact safety of 
patients or efficacy 
endpoints. 


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Added: Oral beta2-agonists: one 
week prior to screening and 
prohibited during the study. 
Deleted: non selective oral beta 
blockers: 1 week prior to 
screening and prohibited during 
the study. 
6.7.4 Recording Use of 
Concomitant Medication 
8.5.4 Electronic Diary 
Activities 
Clarified recording of ICS use. 
Clarification. 
7.1.3 Electrocardiogram 
Withdrawal Criteria 
8.4.2.2 Clinically 
Significant Abnormality 
11.5 Appendix 5 
Electrocardiogram 
Withdrawal Criteria 
Added in 7.1.3: “All ECGs 
conducted or overread after a 
patient has been randomized will 
be subject to ECG Withdrawal 
Criteria (Section 11.5). Patients 
will may be discontinued” “and in 
consideration with the patients 
medical history and baseline ECG 
measurements” “The intent of the 
triplicate ECG measurement is to 
differentiate abnormalities from 
artifact. Abnormalities should be 
confirmed in 2 of 3 
measurements.” 
Language added for consistency in 
8.4.2.2 and 11.5. 
To clarify that 
ECGs assessed after 
randomization 
(even if they were 
conducted prior) are 
subject to ECG 
withdrawal criteria. 
The decision to 
withdraw a patient 
should be informed 
by the patients 
medical history and 
baseline ECGs. 
Abnormalities 
should be 
confirmed in 2 of 3 
triplicates. 
7.3.1 Early 
Termination/Withdrawal 
Procedures 
Added: and ICS 
To clarify patients 
should continue ICS 
if possible and 
follow withholding 
procedures. 
8.1.10.1 Viral Serology 
Added: “Chronic stable hepatitis B 
and C is not exclusionary if the 
patient otherwise meets study 
entry criteria.” Deleted: and 
evaluated per Exclusion criteria 19 
Clarified to align 
with Exclusion #12. 


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and 20. Viral serology may not be 
repeated. 
8.1.15 Nebulizer 
Equipment Training 
8.5.5 Nebulizer Equipment 
Training 
Language added to clarify that 
Instructions for Use will constitute 
nebulizer equipment training at 
Screening and hands on training 
will occur at Visit 1. 
Clarification. 
8.3.1 Spirometry 
Withholding periods were updated 
to include LAMA/ICS and 
LABA/ICS. 
Clarification. 
8.3.3 Health Outcomes 
Clarified that the healthcare 
utilization assessment can be done 
at any time during the visit. 
Clarification. 
8.4.1 Vital Signs 
Added: The mode of temperature 
collection should be noted in the 
source (e.g. oral, forehead, etc). 
Deleted: Oral 
Clarification. 
8.4.2 Electrocardiogram 
Added: It is recommended that 
ECG assessments should be 
obtained after patients have rested 
for approximately 5 minutes. 
Clarification. 
8.5.11 
Genotyping/Phenotyping 
Edit: “will be” changed to “may 
be” stored for up to 1 year. 
Deleted: However, genetic 
research may be extended to other 
genes that might affect 
ensifentrine PK (eg, other drug 
metabolizing enzymes, drug 
transporters) if the results from the 
clinical study cannot be explained 
by the current level of drug 
metabolism and PK understanding, 
or if patients with outlying PK 
behavior are observed. Therefore, 
a blood sample will be collected 
for deoxyribonucleic acid (DNA) 
analysis for genotyping. 
Clarification. 
Language deleted as 
additional 
genotyping will not 
be conducted. 


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9.4.1 Efficacy Analysis 
9.4.4 Missing Data 
Missing data handling approach 
was clarified: All data collected 
after treatment withdrawal will be 
used in the analysis. Remaining 
missing data will primarily be 
imputed using multiple imputation 
based on baseline characteristics 
and data collected at post-
randomization visits. A sensitivity 
analysis will also be conducted. 
Revised approach 
following FDA 
feedback. 
9.4.1 Efficacy Analysis 
ICS use added as a subgroup 
Alignment with ICS 
allowance. 
11.9 Appendix 9 Liver 
Safety 
Added: “Investigators may at their 
discretion refer patients 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).” 
Deleted “Liver imaging 
(ultrasound, magnetic resonance, 
or computerized tomography) to 
evaluate liver disease.” 
Clarification. 
 


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TABLE OF CONTENTS 
TITLE PAGE .................................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ....... 3
TABLE OF CONTENTS ............................................................................. 22
1.0
PROTOCOL SUMMARY ............................................................... 30
1.1
Synopsis .................................................................................. 30
1.2
Schema ................................................................................... 36
1.3
Schedule of Activities ............................................................ 37
1.4
Schedule of Spirometry and In-Clinic Dosing with Blinded 
Study Medication .................................................................. 43
2.0
INTRODUCTION............................................................................. 44
2.1
Study Rationale ..................................................................... 44
2.2
Background ........................................................................... 44
2.3
Benefit/Risk Assessment ....................................................... 46
3.0
OBJECTIVES AND ENDPOINTS ................................................. 48
3.1
Objectives............................................................................... 48
3.1.1
Primary Objective ..................................................... 48
3.1.2
Secondary Objectives ............................................... 48
3.1.3
Other Objectives ....................................................... 48
3.1.4
Safety Objective ....................................................... 48
3.2
Endpoints ............................................................................... 48
3.2.1
Primary Endpoint ...................................................... 48
3.2.2
Secondary Endpoints ................................................ 48
3.2.3
Other Endpoints ........................................................ 49
3.2.4
Safety Endpoints ....................................................... 49
4.0
STUDY DESIGN ............................................................................... 50
4.1
Overall Design ....................................................................... 50
4.2
Scientific Rationale for Study Design .................................. 51
4.3
Justification for Dose ............................................................ 52
4.4
End of Study Definition ........................................................ 52
5.0
STUDY POPULATION ................................................................... 53
5.1
Inclusion Criteria .................................................................. 53
5.2
Exclusion Criteria ................................................................. 54
5.3
Randomization Criteria........................................................ 57
5.4
Lifestyle Considerations ....................................................... 57
5.4.1
Caffeine and Tobacco ............................................... 57
5.4.1.1
Prior to Spirometry and prior to ECG: ... 57
5.5
Rescreening ............................................................................ 58
5.5.1
Rescreening Prohibited ............................................. 58


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5.5.2
Rescreening Permitted if Medical Monitor Approves
 .................................................................................. 58
5.6
Screen Failures ...................................................................... 58
6.0
STUDY TREATMENT .................................................................... 59
6.1
Administration of Blinded Study Medication .................... 59
6.1.1
Dosing in the Clinic .................................................. 59
6.1.2
Dosing at Home ........................................................ 60
6.2
Investigational Product/Blinded Study Medication ........... 61
6.2.1
Blinded Study Medication Dispensing and 
Formulation Information .......................................... 62
6.2.2
Medical Devices ....................................................... 62
6.3
Preparation/Handling/Storage/Accountability .................. 63
6.4
Measures to Minimize Bias: Randomization and Blinding
................................................................................................. 63
6.5
Emergency Unblinding ......................................................... 64
6.6
Blinded Study Medication Compliance .............................. 64
6.7
Concomitant Therapy ........................................................... 64
6.7.1
Rescue Medication ................................................... 65
6.7.1.1
Documentation of Rescue Medication Use
 ................................................................ 65
6.7.2
Permitted Rescue and Background Medications ...... 65
6.7.3
Prohibited Medications/Therapy .............................. 66
6.7.4
Recording Use of Concomitant Medications ........... 68
6.7.4.1
Recording of Rescue Medication and/or 
LAMA or LABA Medications, and ICS (if 
applicable) .............................................. 68
6.7.4.2
Recording of Medications other than 
Rescue Medication and/or LAMA or 
LABA or ICS Medications ..................... 68
6.7.4.3
Recording of Medications and Information 
Specific to the Pharmacokinetic 
Procedures and Sample Analysis: .......... 68
6.8
Treatment After the End of Study ...................................... 68
7.0
DISCONTINUATION OF BLINDED STUDY MEDICATION 
AND PATIENT DISCONTINUATION/ WITHDRAWAL .......... 70
7.1
Discontinuation of Blinded Study Medication ................... 70
7.1.1
Does Not Meet Criteria for Randomization ............. 70
7.1.2
Liver Chemistry Stopping Criteria ........................... 70
7.1.3
Electrocardiogram Withdrawal Criteria ................... 70
7.1.4
COPD Exacerbation Withdrawal Criteria ................ 71
7.1.5
Positive Pregnancy Test in Females ......................... 71
7.1.6
Positive COVID-19 Test Indicating an Active 
Infection .................................................................... 71
7.1.7
Other Criteria ............................................................ 71
7.2
Study Participation After Discontinuation of Blinded Study 
Medication ............................................................................. 71
7.2.1
Reduced Assessments ............................................... 72


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7.2.2
Combination of Phone Contact and Reduced 
Assessments .............................................................. 72
7.2.3
Phone Contact Only .................................................. 72
7.3
Patient Discontinuation/Withdrawal from the Study ........ 73
7.3.1
Early Termination/Withdrawal Procedures .............. 73
7.3.1.1
12-Hour Spirometry and 1.5 Hour ECG 
Procedures .............................................. 73
7.3.1.2
Single 12-Lead ECG ............................... 74
7.4
Lost to Follow-up .................................................................. 74
8.0
STUDY ASSESSMENTS AND PROCEDURES ........................... 76
8.1
Screening Assessments and Procedures .............................. 76
8.1.1
Informed Consent ..................................................... 76
8.1.2
Demographic Variables ............................................ 76
8.1.3
Medical/Surgical/ COPD/ and Smoking History ..... 77
8.1.4
Prior/Concomitant Medications/Therapies ............... 77
8.1.5
Vital Signs ................................................................ 77
8.1.6
Electrocardiogram .................................................... 77
8.1.7
Chest X-Ray ............................................................. 77
8.1.8
Spirometry Assessment ............................................ 78
8.1.9
Modified Medical Research Council Dyspnea Scale 78
8.1.10
Clinical Laboratory Assessments ............................. 78
8.1.10.1
Viral Serology ........................................ 78
8.1.10.2
COVID-19 .............................................. 78
8.1.11
Physical Examination ............................................... 78
8.1.12
Inclusion/Exclusion Criteria ..................................... 78
8.1.13
Electronic Diary Activities ....................................... 78
8.1.14
Interactive Response Technology ............................. 79
8.1.15
Nebulizer Equipment Training ................................. 79
8.1.16
Dispense Rescue Medication .................................... 79
8.2
Randomization Criteria Assessment– Day 1 ...................... 79
8.3
Efficacy Assessments ............................................................ 79
8.3.1
Spirometry ................................................................ 79
8.3.1.1
Spirometry Training ............................... 80
8.3.1.2
Spirometry must be performed as follows:
 ................................................................ 80
8.3.2
COPD Exacerbation Assessment ............................. 80
8.3.3
Health Outcomes ...................................................... 80
8.3.3.1
St. George’s Respiratory Questionnaire . 81
8.3.3.2
EuroQol-5-Domain Questionnaire ......... 81
8.3.3.3
Baseline Dyspnea Index/Transitional 
Dyspnea Index ........................................ 81
8.3.3.4
Healthcare Utilization ............................. 81
Patient Perception Survey ....................... 81
8.3.3.6
Evaluating-Respiratory Symptoms 
Questionnaire .......................................... 81
8.4
Safety Assessments ................................................................ 81
8.4.1
Vital Signs ................................................................ 82
8.3.3.


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8.4.2
Electrocardiogram .................................................... 82
8.4.2.1
Day 1/Randomization/Visit 1: Triplicate 
ECGs at Pre-Dose ................................... 82
8.4.2.2
Clinically Significant Abnormality ........ 82
8.4.2.3
Recommendation/ Request ..................... 82
8.4.3
Clinical Laboratory Assessments ............................. 82
8.4.3.1
COVID-19 .............................................. 83
8.4.4
Adverse Event Assessment ....................................... 83
8.5
Other Assessments and Procedures .................................... 83
8.5.1
Concomitant Medication Assessment ...................... 83
8.5.2
Interactive Response Technology ............................. 83
8.5.3
Randomization .......................................................... 83
8.5.4
Electronic Diary Activities ....................................... 83
8.5.5
Nebulizer Equipment Training ................................. 84
8.5.6
Training for Spirometry ............................................ 84
8.5.7
Blinded Study Medication Dosing in the Clinic ....... 84
8.5.8
Dispense/Collect Rescue Albuterol/Salbutamol ....... 84
8.5.9
Dispense/Collect Blinded Study Medication ............ 84
8.5.10
Pharmacokinetics ...................................................... 84
8.5.10.1
Collection of Samples ............................. 84
8.5.10.2
Recording of Medications and Information 
Specific to the Pharmacokinetic 
Procedures and Sample Analysis ............ 85
8.5.10.3
Determination of Drug Concentration .... 87
8.5.11
Genotyping/ Phenotyping ......................................... 87
8.5.12
Biomarker Collection ............................................... 88
8.6
Disaster Contingencies.......................................................... 88
8.6.1
Site-Level Disaster Plan ........................................... 88
8.6.2
Unscheduled Visit .................................................... 89
8.6.2.1
Blinded Study Medication and/or Rescue 
Medication .............................................. 89
8.6.2.2
Study Supplied Nebulizer Replacement . 89
8.6.2.3
Other Contingencies ............................... 89
8.7
Adverse Events ...................................................................... 89
8.7.1
Time Period and Frequency for Collecting AE and 
SAE Information ...................................................... 90
8.7.2
Method of Detecting AEs and SAEs ........................ 90
8.7.3
Follow-up of AEs and SAEs .................................... 90
8.7.4
Regulatory Reporting Requirements for SAEs ........ 90
8.7.5
Pregnancy ................................................................. 91
8.7.6
Adverse Events of Special Interest ........................... 91
8.7.7
Disease-related Events and/or Disease-related 
Outcomes Not Qualifying as AEs or SAEs .............. 91
8.7.8
Medical Device Incidents (Including Malfunctions) 91
8.7.8.1
Time Period for Detecting Medical Device 
Incidents ................................................. 92
8.7.8.2
Follow-up of Medical Device Incidents . 92
8.7.8.3
Prompt Reporting of Medical Device 
Incidents to Sponsor/Sponsor 
Representative ........................................ 92


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8.7.8.4
Regulatory Reporting Requirements for 
Medical Device Incidents ....................... 92
8.7.9
COVID-19 Positive for Active Disease ................... 93
8.8
Treatment of Overdose ......................................................... 93
9.0
STATISTICAL CONSIDERATIONS ............................................ 94
9.1
Statistical Hypotheses ........................................................... 94
9.2
Sample Size Determination .................................................. 94
9.3
Populations for Analyses ...................................................... 94
9.4
Statistical Analyses................................................................ 95
9.4.1
Efficacy Analyses ..................................................... 95
9.4.2
Safety Analyses ........................................................ 96
9.4.3
Other Analyses ......................................................... 96
9.4.4
Missing Data ............................................................. 97
9.4.5
Pharmacokinetics ...................................................... 97
9.5
Interim Analyses ................................................................... 98
10.0
REFERENCE LIST .......................................................................... 99
11.0
APPENDICES ................................................................................. 101
11.1
Appendix 1: Abbreviations ................................................ 102
11.2
Appendix 2: Regulatory, Ethical, and Study Oversight 
Consideration ...................................................................... 105
11.3
Appendix 3: Clinical Laboratory Tests............................. 111
11.4
Appendix 4: ECG Exclusion Criteria ............................... 114
11.5
Appendix 5: ECG Withdrawal Criteria ........................... 115
11.6
Appendix 6: Guidelines for Identifying COPD 
Exacerbation ........................................................................ 116
11.6.1
COPD Exacerbation Signs and Symptoms ............. 116
11.6.2
COPD Symptom Verification ................................. 116
11.6.3
COPD Exacerbation Severity: ................................ 117
11.6.3.1
Moderate ............................................... 117
11.6.3.2
Severe ................................................... 117
11.6.3.3
Guideline for assessing exacerbations that 
increase in severity ............................... 117
11.6.4
Onset and Resolution of COPD Exacerbations: ..... 117
11.6.5
Treatment of COPD Exacerbations ........................ 117
11.6.5.1
Guidelines for Treatment with 
Corticosteroids ...................................... 117
11.6.5.2
Guidelines for Treatment with Antibiotics
 .............................................................. 117
11.6.6
Recording COPD Exacerbations ............................ 118
11.6.7
Study Continuation or Withdrawal Due to COPD 
Exacerbation ........................................................... 118
11.7
Appendix 7: Adverse Events: Definitions and Procedures 
for Recording, Evaluating, Follow-up and Reporting ..... 119
11.8
Appendix 8: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................... 125
11.9
Appendix 9: Liver Safety ................................................... 129


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11.10 Appendix 10: Medical Device Information....................... 133
11.11 Appendix 11: Country Specific Requirements ................. 135
11.12 Appendix 12: Signature of Investigator ............................ 136


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LIST OF IN-TEXT TABLES 
Table 1 Document History ................................................................................ 3
Table 2 Description of Changes in the Amendment ......................................... 3
Table 3: Schedule of Activities ....................................................................... 37
Table 4: Schedule of Spirometry and In-Clinic Dosing with Blinded Study 
Medication .............................................................................. 43
Table 5: Investigational Product/Blinded Study Medication Details ............. 61
Table 6: Blinded Study Medication Formulation Constituents and 
Concentrations ........................................................................ 62
Table 7: Permitted Rescue and Background Medications .............................. 66
Table 8: Prohibited Medications/Therapy ...................................................... 67
Table 9: PK Collection Timepoints and Window Relative to Ensifentrine 
Dosing ..................................................................................... 85
Table 10: Recording of Medications and Information Specific to 
Pharmacokinetics .................................................................... 86
Table 11: Study Administrative Structure .................................................... 108
Table 12: Medical Monitor ........................................................................... 108
Table 13: Protocol Required Safety Laboratory Assessments ...................... 112
Table 14: Highly Effective Contraceptive Methods ..................................... 126
 


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LIST OF IN-TEXT FIGURES 
Figure 1: Study Schematic .............................................................................. 36


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1.0 PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: 
A Phase III Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Ensifentrine over 24 Weeks in Patients with Moderate to Severe 
Chronic Obstructive Pulmonary Disease. 
Short Title: 
A Phase III randomized, placebo-controlled study to evaluate the efficacy and safety of 
ensifentrine over 24 weeks in patients with chronic obstructive pulmonary disease. 
Rationale 
Verona Pharma plc. is developing inhaled nebulized ensifentrine for the maintenance 
treatment of chronic obstructive pulmonary disease (COPD). RPL554-CO-302 is one of 
the two Phase III confirmatory studies for the inhaled nebulized ensifentrine suspension 
formulation in patients with COPD. 
The two confirmatory studies RPL554-CO-301 and RPL554-CO-302 are planned as 
randomized, double-blind, parallel-group, placebo-controlled studies intended to provide 
replicate evidence of efficacy in terms of improvements in lung function, symptoms and 
quality of life and the safety of ensifentrine compared to placebo in patients with 
moderate to severe COPD.  
Ensifentrine is a dual inhibitor of phosphodiesterase (PDE)3 and PDE4 which has 
demonstrated both bronchodilator and anti-inflammatory effects in clinical studies  
(Singh 2018, 2020 and Franciosi 2013). No dual inhibitors of PDE3 and PDE4 are 
currently approved for the treatment of COPD. As such, both studies are placebo-
controlled to assess the treatment effect of ensifentrine as a novel treatment for patients 
with COPD. The dose of 3 mg twice daily was informed by two Phase IIb studies in 
patients with COPD. The first study evaluated ensifentrine as monotherapy and the 
second study assessed ensifentrine as an add-on to tiotropium. Both studies showed that 
the 3 mg dose had an optimal benefit:risk profile. Because ensifentrine provides 
bronchodilation via its inhibition of PDE3 and PDE4, lung function endpoints are key 
endpoints for the evaluation of efficacy in patients with COPD. Additional endpoints 
validated in patients with COPD will inform on effects of ensifentrine on symptoms and 
quality of life from this dual mechanism of action. A treatment duration of 12 weeks is 
considered sufficient to demonstrate the bronchodilator effects, while a duration of 24 
weeks will inform on symptom improvement. Ensifentrine has demonstrated in Phase II 
studies additional meaningful bronchodilation when added on to current standard of care 
beta-agonist and muscarinic antagonist therapies.  


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RPL554-CO-301 will enroll approximately 800 patients with moderate to severe COPD 
in 2 subsets. The 24-week subset will enroll approximately 400 patients randomized 1:1 
ensifentrine (3 mg): placebo and the 48-week subset will enroll approximately 400 
patients randomized 3:1 in order to minimize the number of patients assigned to placebo 
over 48 weeks. The assessments in each subset are identical over the first 24 weeks. The 
48-week subset will continue to assess long-term safety in this subset of patients.
Study RPL554-CO-302 is planned as a 24-week study that will enroll 800 patients and be 
randomized 5:3 to ensifentrine (3 mg): placebo and is otherwise identical to the first 24 
weeks of RPL554-CO-301. This study will assess population pharmacokinetic (PK) via 
sparse sampling in all patients.  
Both studies will assess lung function, symptoms, and quality of life over 24 weeks. 
Safety and tolerability will be assessed over 24 or 48 weeks. 
Objectives and Endpoints  
Objectives  
Primary Objective 
The primary objective of this study is to evaluate the efficacy of ensifentrine on lung 
function compared to placebo over a 12-hour dosing interval in patients with moderate to 
severe chronic obstructive pulmonary disease (COPD). 
Secondary Objectives 
x
To evaluate the effect of ensifentrine on other lung function parameters.
x
To evaluate the effect of ensifentrine on COPD symptoms.
x
To evaluate the effect of ensifentrine on health-related quality of life.
Other Objectives 
x
To evaluate the effect of ensifentrine on moderate/severe COPD exacerbations.
x
To evaluate the effect of ensifentrine on health utility and healthcare resource
utilization. (HRU)
x
To characterize the pharmacokinetics of ensifentrine in patients with COPD.
x
To evaluate the effect of ensifentrine on inflammatory biomarkers
Safety Objective 
To evaluate the safety and tolerability of ensifentrine over 24 Weeks. 


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Endpoints 
Primary Endpoint 
Average forced expiratory volume in 1 second (FEV1) area under the curve (AUC)0-12h 
post-dose at Week 12 (change from baseline). 
Secondary Endpoints 
x
Peak FEV1 over 4 hours post-dose at Week 12 (change from baseline).
x
Evaluating-Respiratory Symptoms (E-RS) Total Score at Week 24 (change from
baseline as a weekly average).
x
SGRQ total score at Week 24 (change from baseline).
x
Morning trough FEV1 at Week 12 (change from baseline).
x
Average FEV1 AUC0-4h post-dose at Week 12 (change from baseline).
x
The proportion of St. George’s Respiratory Questionnaire (SGRQ) responders at
Week 24.
x
Rescue medication use at Week 24 (change from baseline).
x
Transitional Dyspnea Index (TDI) at Week 24.
x
Evening trough FEV1 at Week 12 (change from baseline).
x
Peak FEV1, morning and evening trough FEV1, FEV1 AUC0-4h, E-RS Total Score,
SGRQ responder analysis, and TDI at other Study Visits (change from baseline).
x
SGRQ total score at Weeks 6 and 12 (change from baseline).
x
Rescue medication use at Weeks 6 and 12 (change from baseline).
Other Endpoints 
x
Moderate/severe COPD exacerbation frequency over 24 Weeks (this individual
study and pooled with data from study RPL554-CO-301).
x
Time to first moderate/severe COPD exacerbation over 24 Weeks (this individual
study and pooled with data from study RPL554-CO-301).
x
Study withdrawal before 24 Weeks.
x
EuroQol-5-Domain Questionnaire (EQ-5D-5L) at Week 12 (change from baseline).
x
Healthcare Resource Utilization (HRU) over 24 Weeks.
x
Average FEV1 AUC6-12h post-dose at Week 12 (change from baseline).


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x
Ensifentrine concentrations following sparse sample collection at Weeks 6, 12, and
24.
x
Patient genotype/phenotype including but not limited to cytochrome P-450
(CYP)2C9 and CYP2D6 metabolic activity.
x
Interleukin (IL)-6, IL-8, and C-reactive protein at Weeks 12 and 24.
Safety Endpoints 
x
Incidence of adverse events (AEs)
x
Vital signs
x
Electrocardiogram (ECG)
x
Laboratory tests
Overall Design 
RPL554-CO-302 is a multicenter, randomized, double blind, parallel group, placebo 
controlled study to determine the efficacy and safety of ensifentrine 3 mg twice daily 
(BID) for 24 weeks, administered via nebulizer vs. placebo in patients 40 to 80 years of 
age with moderate to severe COPD (FEV1 30% – 70% of predicted, FEV1/forced vital 
capacity [FVC] ratio <0.7, with documented COPD symptoms).  
Up to 50% of patients recruited will be using stable background maintenance as either 
long-acting muscarinic antagonist (LAMA) or long-acting ȕ2 agonist (LABA) 
maintenance therapy for 24 weeks and all patients will be provided with rescue 
albuterol/salbutamol for use as needed during the study. Up to 20% of patients are 
allowed to take inhaled corticosteroids during the study under certain provisions (see 
Sections 6.7.2 and 6.7.3). Washout of patients on stable background maintenance LAMA 
or LABA monotherapy for the sole purpose of study eligibility is not recommended. 
Randomization will be stratified by two different factors: stable background maintenance 
LAMA or LABA therapy use (yes or no) and cigarette smoking (current or former). 
Patients will be randomized 5:3 to receive ensifentrine (3 mg):placebo for 24 weeks. 
Patients in the stable background maintenance LAMA or LABA therapy stratum must 
withhold Twice-Daily LAMA or LABA (or LAMA/ICS or LABA/ICS) for 24 hours and 
Once-Daily LAMA or LABA (or LAMA/ICS or LABA/ICS) for 48 hours prior to 
initiation of any spirometry. All patients must withhold short acting bronchodilator 
(SABA) rescue medication for at least 4 hours prior to initiation of any spirometry.  
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.  
Patients will be screened for eligibility before entering a 28-day run-in period to ensure a 
stable COPD treatment regimen and to collect baseline information on symptoms and 


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rescue medication use. Permitted rescue and background medications and the condition of 
their use during the study are described in Section 6.7.2. Prohibited medications and the 
prohibited time intervals prior to Screening are described in Section 6.7.3. 
Patients completing the run-in period and meeting all entry and Randomization Criteria 
will be randomized. The two different stratification factors will be applied at 
randomization. Details on blinded study medication and administration are provided in 
Section 6. The Study Schematic is shown in Section 1.2. 
During the treatment period, patients will complete all assessments and procedures as 
outlined in the Schedule of Activities (SoA, Section 1.3) for 24 weeks. Patients 
completing treatment will complete a Follow-up within 4 to 10 days of the last scheduled 
study visit. 
Patients 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 within 4 to 10 days of the Early 
Termination/Withdrawal Visit. 
Patients who permanently discontinue double blind study medication may remain in the 
study and follow the assessments and procedures as noted in Section 7.2. 
Number of Investigators and Study Centers 
Approximately 151 Investigators and study centers are expected to participate in this 
study. 
Number of Patients 
Approximately 800 randomized patients are planned. 
Treatment Groups and Duration 
Randomization will be stratified by two different factors: background maintenance 
LAMA or LABA therapy use (yes or no) and cigarette smoking (current or former). 
Patients will be randomized active to placebo 5:3 for 24 weeks. The background therapy 
stratum will be capped at 50%. Patients in the background therapy stratum are expected to 
continue their background maintenance LAMA or LABA therapy daily throughout the 
duration of the study, with the exception of withholding 24 or 48 hours prior to 
spirometry as previously described.  
The approximately 800 patients meeting the Randomization Criteria will be randomized 
to receive the following treatments in a 5:3 ratio: 
Treatment Arm 1: Ensifentrine Nebulized Suspension; 3 mg BID 
Treatment Arm 2: Ensifentrine Placebo Nebulized BID 


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Overall, 500 patients will be randomized to ensifentrine and 300 patients will be 
randomized to placebo. 
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 minutes but no longer than 10 minutes. 
Statistical Methods 
Efficacy analysis will primarily be performed on the modified intent-to-treat (mITT) 
population including all patients randomized and treated in the study. All tests will be 
two-sided at a 5% significance level. Secondary efficacy endpoints intended for label 
claims will be tested in a strict hierarchical order to preserve the alpha level. 
Primary endpoint, change from baseline in FEV1 AUC0-12h at Week 12, will be compared 
between treatments using an analysis of covariance (ANCOVA) model adjusting for 
treatment, region, background medication strata, smoking status, and baseline FEV1. 
Patients will be included in analysis as randomized. Missing data will be imputed to get 
as close to the mITT population as possible. Primary choice of imputation will be based 
on data collected at early termination visits or at visits performed after treatment 
withdrawal and, when no such data available, by the average change in the opposite 
treatment group as randomized to. 
Safety analysis will be descriptive and based on the safety set including all randomized 
and treated patients. Safety analysis will be by actual treatment received. 
The pharmacokinetics of ensifentrine will be characterized by nonlinear mixed effects 
modeling based on sparse sampling. The population PK (and population PK-PD, if 
performed) analyses will be performed in accordance with a separate modeling data 
analysis plan and will be reported outside of the clinical study report. 
Sample Size 
Approximately 800 patients will be randomized. The standard deviation for the change in 
peak FEV1 is estimated to be 250 mL. With a 2-sided test at a 5% significance level and 
500 vs. 300 evaluable patients in the two groups, there will be an 90% power to detect a 
true difference of 59 mL between the treatments. 
 


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1.2 
Schema 
Figure 1: Study Schematic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 










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12. The E-RS/EXACT-PRO will be completed by the patient each evening in the eDiary (see details in Section 8.5.4). eDiary compliance will be visually reviewed by site staff at each on-
site clinic visit and via discussion with the patient during phone contact and/or flexible visits when patients are unable come into the clinic. Patients with poor compliance should be
instructed by the site staff to  improve compliance.
13.
Vital signs: See Section 8.1.5 and Section 8.4.1 for details.
14. At Day 1/Randomization/Visit 1 prior to dosing (pre-dose), triplicate ECGs must be performed. Patients should refrain from caffeine, smoking and albuterol/salbutamol prior to ECGs for
the withholding periods described in Section 5.4.1 and Section 8.4.2. See Section 8.4.2 for instructions on ECG. See Section 7.3.1.1 and Section 7.3.1.2 for ECG procedures at Early Term/ 
Withdrawal.
15. Pregnancy Testing: Pregnancy testing will be conducted on women of childbearing potential. A urine test will be conducted prior to dosing at Visit 1. Instructions in Section 7.1.5,
Section 8.7.5 and Section 11.8 should be followed for Women with a positive pregnancy test after randomization.
16.
A COVID-19 test for active disease is optional. COVID-19 testing should follow local requirements (Section 11.3). If conducted, the test may be done within 7 days of the visit or at the
visit.  In addition, a COVID-19 test may be conducted anytime a patient is suspected/exhibiting signs of active disease. If a COVID-19 test is positive for active disease, see Section 7.1.6  
17. Information on blinded study medication, dosing and compliance, rescue medication, nebulizers and compressor can be found in Section 6.0. 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 (Section 6.1.1).
Rescue medication may be dispensed at the time of signing the Informed Consent, if this occurs prior to commencement of screening assessments.
18. Collect study supplied compressor if allowed per local site practices, otherwise study supplied compressors will not be returned and collected.
19. Pharmacokinetic Sampling: Pharmacokinetic (PK) sample collection schedule will be different between even and odd numbered sites as described in Section 8.5.10.1, and should only be
drawn for patients who have taken blinded study medication at least 48 hours prior to the visit
20. Patients will be invited to participate in optional genetic research. The pharmacogenomic sample should be collected on Day 1 but may be collected at any time during the study. See
Section 8.5.11.
21. The biomarker samples should be collected from all patients pre-dose. See Section 8.5.12 and Section 11.3.
Abbreviations: AE=Adverse Event; BDI=Baseline Dyspnea Index; COPD=Chronic Obstructive Pulmonary Disease; CT=Computed Tomography; COVID=Corona Virus Disease; 
CXR=Chest X-Ray; eDiary=Electronic Diary; ECG=Electrocardiogram; EQ-5D-5L=EuroQol Questionnaire; E-RS=Exact-Respiratory Symptoms; ET=Early Term; IEC=Independent Ethics 
Committee; IRB=Institutional Review Board; IRT=Interactive Response Technology; LABA= Long-acting ȕ2 agonist; LAMA= Long-acting muscarinic antagonist; IL=Interleukin; 
mMRC=Modified Medical Research Council Dyspnoea Scale; PK=Pharmacokinetic; Rand=Randomization; SGRQ=St. George Respiratory Questionnaire; TDI=Transitional Dyspnea Index; 
V=Visit. 




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2.0 INTRODUCTION 
2.1 
Study Rationale 
Verona Pharma plc. is developing inhaled nebulized ensifentrine for the maintenance 
treatment of chronic obstructive pulmonary disease (COPD). RPL554-CO-302 is one of 
the two Phase III confirmatory studies for the inhaled nebulized ensifentrine suspension 
formulation in patients with COPD. 
The two confirmatory studies RPL554-CO-301 and RPL554-CO-302 are planned as 
randomized, double-blind, parallel-group, placebo-controlled studies intended to provide 
replicate evidence of efficacy in terms of improvements in lung function, symptoms and 
quality of life and the safety of ensifentrine compared to placebo in patients with 
moderate to severe COPD.  
RPL554-CO-301 will enroll approximately 800 patients with moderate to severe COPD 
in 2 subsets. The 24-week subset will enroll approximately 400 patients randomized 1:1 
ensifentrine (3 mg): placebo and the 48-week subset will enroll approximately 400 
patients randomized 3:1 in order to minimize the number of patients assigned to placebo 
over 48 weeks. The assessments in each subset are identical over the first 24 weeks. The 
48-week subset will continue to provide long-term safety data in this subset of patients.
Study RPL554-CO-302 is planned as a 24-week study that will enroll 800 patients and be 
randomized 5:3 to ensifentrine (3 mg): placebo and is otherwise identical to the first 24 
weeks of RPL554-CO-301. This study will assess population PK via sparse sampling in 
all patients.  
Both studies will assess lung function, symptoms, and quality of life over 24 weeks. 
Safety and tolerability will be assessed over 24 or 48 weeks. 
2.2 
Background 
Ensifentrine is a selective dual phosphodiesterase (PDE)3 and PDE4 inhibitor which has 
clinically demonstrated bronchodilation and anti-inflammatory activity following inhaled 
dosing. This novel mechanism of action represents an important potential additional 
treatment option for patients with moderate to severe COPD, and other respiratory 
indications such as asthma and cystic fibrosis whose disease is manifest by airways 
obstruction and inflammation. As a potential new treatment for COPD, this new 
mechanism of action can be used as a monotherapy or added to current inhaled standard 
of care bronchodilator and anti-inflammatory therapies, producing complementary effects 
in patients needing additional therapeutic options. Ensifentrine is first being developed as 
an inhaled suspension formulation for delivery via a nebulizer for patients with COPD. 


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Ensifentrine has been studied in the nebulizer formulation in 15 clinical trials involving 
more than 1250 subjects. The initial nebulizer solution formulation was used in the first 
five clinical trials between 2009 and 2014.  
Ten clinical studies have been completed with ensifentrine delivered in a nebulized 
suspension format. The two most recent of the ten studies, 4-week Phase IIb study 
RPL554-CO-205 and Phase 1 study RPL554-PK-102, were performed using an optimized 
variant of the suspension formulation in which the phosphate buffer loading in the vehicle 
was reduced ten-fold. This optimized formulation, referred to as the ‘low phosphate’ 
formulation, is the proposed Phase III and to-be-marketed formulation. 
In the clinical studies performed to date, ensifentrine has demonstrated pronounced 
bronchodilator effects in healthy subjects and in patients with COPD or asthma. In single-
dose studies, ensifentrine alone was as effective as albuterol or ipratropium as a 
bronchodilator in patients with COPD (RPL554-009-2015; Singh 2018). Ensifentrine has 
also demonstrated anti-inflammatory effects in a model of COPD-like inflammation in 
healthy subjects (Franciosi 2013).  
A 3-day study was conducted where nebulized ensifentrine or placebo was administered 
twice daily to patients with COPD as an add-on treatment to tiotropium (Spiriva®; 
RPL554-CO-202). In this study, statistically significant and clinically meaningful 
improvements in bronchodilation were seen compared to placebo. In addition, 
ensifentrine significantly reduced residual lung volumes and increased the speed of onset 
of the bronchodilator effect to under 5 minutes.  
In the first completed 4 week dose-ranging, 403-patient Phase IIb study, 
RPL554-CO-203, four dose levels of nebulized ensifentrine (0.75, 1.5, 3, and 6 mg) were 
administered twice daily to patients with moderate to severe COPD not taking additional 
maintenance bronchodilator therapies. All doses of ensifentrine met the primary endpoint, 
showing a statistically significant increase in peak FEV1 vs placebo (p<0.001) with 
placebo-corrected changes from baseline >200 mL in peak FEV1 after 4 weeks of dosing. 
In addition, statistically significant improvements in average FEV1 over 12 hours were 
observed at all doses after the first administration, and this effect was sustained over 4 
weeks. Notably, statistically significant and clinically meaningful improvements in total 
COPD symptoms were shown using the Evaluating Respiratory Symptoms in COPD 
(E-RS™: COPD) measure, a validated daily assessment of stable COPD symptoms. 
Ensifentrine showed a meaningful reduction in symptoms on the total score and all 
subscales of the E-RS at or near the minimal clinically important difference (MCID) of 
each. 
In a second recently completed 4 week dose-ranging, 413-patient Phase IIb study, 
RPL554-CO-205, with ensifentrine or placebo added on to maintenance tiotropium, 
4 dose levels (0.375, 0.75, 1.5, and 3 mg) of ensifentrine or placebo were administered 
twice daily to patients with moderate to severe COPD who remained symptomatic and 
with impaired lung function following a 2 week tiotropium run-in. All doses of 


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ensifentrine met the primary endpoint, showing a statistically significant increase in peak 
FEV1 (all p<0.05) which was sustained over 4 weeks. For the two highest doses, 1.5 and 
3 mg, increases in peak FEV1 were observed >100 mL compared to placebo after 4 weeks 
of dosing. In addition, a statistically significant and meaningful improvement in average 
FEV1 over 12 hours was shown with the 3 mg dose at Week 4 (87 mL, p=0.0111). 
Notably, statistically significant and clinically meaningful improvements in health-related 
quality of life as measured by St. George’s Respiratory Questionnaire (SGRQ)-COPD 
(Meguro, 2007) were observed at Week 4 with the 1.5 and 3 mg doses of ensifentrine 
added onto tiotropium (placebo-corrected; both p<0.05), which exceeded the MCID for 
both doses. 
Overall, ensifentrine was well tolerated in the 15 clinical studies conducted to date, with 
adverse event (AE) incidence and severity generally similar to those in the placebo-
treated group. Serious adverse events (SAEs) have been uncommon and there is no 
apparent pattern in the SAEs reported to date.  
Verona Pharma is developing nebulized ensifentrine as a maintenance therapy for patients 
with COPD. Information on the background of ensifentrine as described in this section 
can be found in the Verona Pharma plc. Ensifentrine Clinical Investigators Brochure 
(IB) v. 20.0, 2021 (or more current version, if applicable), unless otherwise cited. 
2.3 
Benefit/Risk Assessment 
No significant medical risks to patients have been identified from studies conducted thus 
far with ensifentrine administered in the solution formulation, suspension formulation, or 
dry powder formulation. A slight increase in mean heart rate (up to 12 beats per minute 
[bpm]) without reported medical significance at a 6 mg supratherapeutic doses has been 
reported in healthy volunteers (RPL554-PK-101). In patients with COPD, transient 
increases in peak heart rate of 3 bpm vs placebo have been observed with the 6 mg twice 
daily dose only over 4 weeks. Otherwise, non-clinical and clinical data to date do not 
indicate any areas of particular medical safety concern.  
Effects on reproductive performance in male rats given the highest dose of 15.5 
mg/kg/day included lower number of pairings of dosed males resulting in pregnancy in 
undosed females, higher pre and post implantation loss resulting in lower mean litter size, 
and lower sperm motility and higher abnormal sperm. No ensifentrine-related adverse 
effects were observed at 5.75 mg/kg/day (20.5 times the maximum recommended human 
dose based on area under the curve [AUC]). There were no effects on embryo-fetal 
survival and development in either rats or rabbits in the main embryo-fetal development 
studies. Ensifentrine had no effects on fertility or reproductive performance in female 
rats. 
Ensifentrine has statistically and clinically significant bronchodilator as well as 
anti-inflammatory effects. As such, the clinical development of ensifentrine is focused on 
the treatment of obstructive and inflammatory lung diseases, including COPD. 


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Considering the consistent improvements in lung function, symptoms, and health-related 
quality of life across multiple studies in patients with COPD and the overall favorable 
safety profile in studies to date, the benefit/risk profile of ensifentrine is considered 
positive.  
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of ensifentrine can be found in the Verona Pharma plc. 
Ensifentrine Clinical IB v. 20.0, 2021 (or more current version, if applicable).  


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3.0 OBJECTIVES AND ENDPOINTS 
3.1 Objectives 
3.1.1 Primary Objective 
The primary objective of this study is to evaluate the efficacy of ensifentrine on lung 
function compared to placebo over a 12-hour dosing interval in patients with moderate to 
severe COPD. 
3.1.2 Secondary Objectives 
x
To evaluate the effect of ensifentrine on other lung function parameters.
x
To evaluate the effect of ensifentrine on COPD symptoms.
x
To evaluate the effect of ensifentrine on health-related quality of life.
3.1.3 Other Objectives 
x
To evaluate the effect of ensifentrine on moderate/severe COPD exacerbations.
x
To evaluate the effect of ensifentrine on health utility and healthcare resource
utilization (HRU).
x
To characterize the pharmacokinetics of ensifentrine in patients with COPD.
x
To evaluate the effect of ensifentrine on inflammatory biomarkers.
3.1.4 Safety Objective 
To evaluate the safety and tolerability of ensifentrine over 24 Weeks. 
3.2 Endpoints 
3.2.1 Primary Endpoint 
Average forced expiratory volume in 1 second (FEV1) area under the curve (AUC)0-12h 
post-dose at Week 12 (change from baseline).  
3.2.2 Secondary Endpoints 
x
Peak FEV1 over 4 hours post-dose at Week 12 (change from baseline).
x
Evaluating-Respiratory Symptoms (E-RS) Total Score at Week 24 (change from
baseline as a weekly average).
x
SGRQ total score at Week 24 (change from baseline).


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x Morning trough FEV1 at Week 12 (change from baseline).  
x Average FEV1 AUC0-4h post-dose at Week 12 (change from baseline). 
x The proportion of St. George’s Respiratory Questionnaire (SGRQ) responders at 
Week 24.  
x Rescue medication use at Week 24 (change from baseline). 
x Transitional Dyspnea Index (TDI) at Week 24. 
x Evening trough FEV1 at Week 12 (change from baseline). 
x Peak FEV1, morning and evening trough FEV1, FEV1 AUC0-4h, E-RS Total Score, 
SGRQ responder analysis, and TDI at other Study Visits (change from baseline). 
x SGRQ total score at Weeks 6 and 12 (change from baseline).  
x Rescue medication use at Weeks 6 and 12 (change from baseline). 
3.2.3 Other Endpoints 
x Moderate/severe COPD exacerbation frequency over 24 Weeks (this individual 
study and pooled with data from study RPL554-CO-301). 
x Time to first moderate/severe COPD exacerbation over 24 Weeks (this individual 
study and pooled with data from study RPL554-CO-301). 
x Study withdrawal before 24 Weeks. 
x EuroQol-5-Domain Questionnaire (EQ-5D-5L) at Week 12 (change from baseline). 
x Healthcare Resource Utilization (HRU) over 24 Weeks. 
x Average FEV1 AUC6-12h post-dose at Week 12 (change from baseline). 
x Ensifentrine concentrations (sparse sample collection) at Weeks 6, 12, and 24. 
x Patient genotype/phenotype including but not limited to cytochrome P-450 
(CYP)2C9 and CYP2D6 metabolic activity. 
x Interleukin (IL)-6, IL-8, and C-reactive protein at Weeks 12 and 24. 
3.2.4 Safety Endpoints 
x Incidence of AEs 
x Vital signs 
x Electrocardiogram (ECG) 
x Laboratory tests 


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4.0 STUDY DESIGN 
4.1 
Overall Design 
RPL554-CO-302 is a multicenter, randomized, double blind, parallel group, placebo 
controlled study to determine the efficacy and safety of ensifentrine 3 mg twice daily 
(BID) for 24 weeks administered via nebulizer vs. placebo in patients 40 to 80 years of 
age with moderate to severe COPD (FEV1 30% – 70% of predicted, FEV1/forced vital 
capacity (FVC) ratio <0.7, with documented COPD symptoms).  
Up to 50% of patients recruited will be using stable background maintenance as either 
long-acting muscarinic antagonist (LAMA) or long-acting ȕ2 agonist (LABA) 
maintenance therapy for 24 weeks and all patients will be provided with rescue 
albuterol/salbutamol for use as needed during the study. Up to 20% of patients are 
allowed to take inhaled corticosteroids during the study under certain provisions (see 
Sections 6.7.2 and 6.7.3). Washout of patients on stable background maintenance LAMA 
or LABA monotherapy for the sole purpose of study eligibility is not recommended. 
Randomization will be stratified by two different factors: stable background maintenance 
LAMA or LABA therapy use (yes or no) and cigarette smoking (current or former). 
Patients will be randomized 5:3 to receive ensifentrine (3 mg):placebo for 24 weeks. 
Patients in the background maintenance LAMA or LABA therapy stratum must withhold 
Twice-Daily maintenance LAMA or LABA (or LAMA/ICS or LABA/ICS) for 24 hours 
and Once-Daily maintenance LAMA or LABA (or LAMA/ICS or LABA/ICS) for 48 
hours prior to initiation of any spirometry. All patients must withhold short acting 
bronchodilator (SABA) rescue medication for at least 4 hours prior to initiation of any 
spirometry.  
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.  
Patients will be screened for eligibility before entering a 28-day run-in period to ensure a 
stable background maintenance LAMA or LABA bronchodilator medication regimen and 
to collect baseline information on symptoms and rescue medication use. Permitted rescue 
and background medications and the condition of their use during the study are described 
in Section 6.7.2. Prohibited medications and the prohibited time intervals prior to 
Screening are described in Section 6.7.3 
Patients completing the run-in period and meeting all entry and Randomization Criteria 
will be randomized. The two different stratification factors will be applied at 
randomization. Details on blinded study medication and administration are provided in 
Section 6.0. The Study Schematic is shown in Section 1.2. 
During the treatment period, patients will complete all assessments and procedures as 
outlined in the Schedule of Activities (Section 1.3) for 24 weeks. Patients completing 
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Patients 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 within 4 to 10 days of the Early 
Termination/ Withdrawal Visit. 
Patients who permanently discontinue double blind study medication may remain in the 
study and follow the assessments and procedures as noted in Section 7.2. 
4.2 
Scientific Rationale for Study Design 
Verona Pharma plc is developing inhaled nebulized ensifentrine for the maintenance 
treatment of COPD. RPL554-CO-301 is one of the two Phase III confirmatory studies for 
the inhaled nebulized ensifentrine suspension formulation in patients with COPD. 
The two confirmatory studies RPL554-CO-301 and RPL554-CO-302 are planned as 
randomized, double-blind, parallel-group, placebo-controlled studies intended to provide 
replicate evidence of efficacy in terms of improvements in lung function symptoms and 
quality of life and safety of ensifentrine compared to placebo in patients with moderate to 
severe COPD.  
Ensifentrine is a dual inhibitor of PDE3 and PDE4 which has demonstrated both 
bronchodilator and anti-inflammatory effects in clinical studies (Singh 2018, 2020 and 
Franciosi 2013). No dual inhibitors of PDE3 and PDE4 are currently approved for the 
treatment of COPD. As such, both studies are placebo-controlled to assess the treatment 
effect of ensifentrine as a novel treatment for patients with COPD. The dose of 3 mg 
twice daily was informed by two Phase IIb studies in patients with COPD. The first 
evaluated ensifentrine as monotherapy and the other added on to tiotropium which 
showed that the 3 mg dose had an optimal benefit:risk profile. Because ensifentrine 
provides bronchodilation via its inhibition of PDE3 and PDE4, lung function endpoints 
are key endpoints for the evaluation of efficacy in patients with COPD. Additional 
endpoints validated in patients with COPD will inform on effects on symptoms and 
quality of life from this dual mechanism of action. A treatment duration of 12 weeks is 
considered sufficient to inform on bronchodilator effects, while a duration of 24 weeks 
will inform on symptom improvement. 
Ensifentrine has demonstrated in Phase II studies additional meaningful bronchodilation 
alone or when added on to current standard of care beta-agonist and muscarinic 
antagonist therapies. Symptom and quality of life improvement has been shown over 4 
weeks as monotherapy or added on to tiotropium. 
In RPL554-CO-301 and RPL554-CO-302, up to 50% of patients recruited will be using 
stable background maintenance as either LAMA or LABA maintenance therapy and all 
patients will be provided with rescue albuterol/salbutamol for use as needed during the 
study. Up to 20% of patients are allowed to take inhaled corticosteroids during the study 
under certain provisions (see Sections 6.7.2 and 6.7.3).  Washout of patients on stable 


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background maintenance LAMA or LABA monotherapy for the sole purpose of study 
eligibility is not recommended to ensure a population with stable COPD is enrolled. 
Randomization in RPL554-CO-301 will be stratified by three different factors: treatment 
duration (48 or 24 weeks), stable background maintenance LAMA or LABA therapy use 
(yes or no), and cigarette smoking (current or former). The 48 weeks strata will be 
randomized active to placebo 3:1, and the 24 weeks strata will be randomized active to 
placebo 1:1. The 48-week subset is intended to inform on the long-term safety of 
ensifentrine vs placebo and the 3:1 randomization in this subset is intended to minimize 
the number of patients randomized to placebo for 48 weeks. 
Study RPL554-CO-302 is planned as a 24-week study that will enroll 800 patients and be 
randomized 5:3 to ensifentrine (3 mg): placebo and is otherwise identical to the first 24 
weeks of RPL554-CO-301. This study will assess population PK via sparse sampling in 
all patients.  
Both studies will assess lung function, symptoms, and quality of life over 24 weeks. 
Safety and tolerability will be assessed over 24 or 48 weeks. 
4.3 
Justification for Dose 
A 3 mg twice daily dose was selected as the Phase 3 dose based on data from two 4-week 
Phase IIb studies RPL554-CO-203 and RPL554-CO-205 which show clinically 
meaningful and statistically significant improvements in pulmonary function with the 3 
mg dose over the 12-hour dosing interval, in patients with or without additional 
bronchodilator background therapy.  
A review of safety and tolerability across all COPD studies has shown a safety profile 
similar to placebo, even when added on top of other bronchodilator therapies: 
x
No dose-related trends in AEs (including those related to cardiovascular or
gastrointestinal systems) have been observed up to and including 6 mg twice daily
ensifentrine in patients with COPD.
x
Changes in electrocardiogram (ECG) parameters and vital signs (blood pressure and
pulse) have not been observed at any dose (except for a small and transient increase in
peak heart rate [~3 bpm] with the 6 mg BID dose in COPD patients after 4 weeks.
x
24-hour Holter monitoring in 324 patients after 4 weeks (RPL554-CO-203) has not
shown any data trends suggesting arrhythmogenic potential or difference compared to
placebo including 6 mg twice daily ensifentrine.
4.4 
End of Study Definition 
A patient is considered to have completed the study if he/she has successfully completed 
all on-treatment randomized visits and completed the follow-up contact.  
The end of the study is defined as the date of the last follow-up contact of the last patient 
in the study. 


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5.0 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is 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: Patient must be 40 to 80 years of age inclusive, at the time of Screening.
3. Sex:
x
Males are eligible to participate if they agree to use contraception as described
in the contraceptive guidance (Section 11.8) from Screening and throughout the
study and for at least 30 days after the last dose of blinded study medication.
x
Females are eligible to participate if they are not pregnant, not breastfeeding,
and at least one of the following conditions apply:
a) Not a woman of childbearing potential (WOCBP) as defined in
Section 11.8.
Or
b) A WOCBP who agrees to follow the contraceptive guidance in
Section 11.8 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 (Visit 0) [number of pack years = (number of
cigarettes per day / 20) × number of years smoked (eg, 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 Visit 0. Smoking cessation programs are
permitted during the study.
COPD Diagnosis, Symptoms, Severity and Maintenance Therapy 
5. COPD Diagnosis: Patients with an established clinical history of COPD as defined by
the American Thoracic Society (ATS)/European Respiratory Society (ERS)
guidelines (Celli BR, 2004) with symptoms compatible with COPD.
6. COPD Symptoms: A score of 2 on the Modified Medical Research Council
(mMRC) Dyspnea Scale.


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7. COPD Severity:
a.
Pre- and Post-albuterol/salbutamol FEV1/FVC ratio of <0.70.
b. Post-albuterol/salbutamol FEV1 30 % and 70% of predicted normal
calculated using the National Health and Nutrition Examination Survey III
(Hankinson, 1999).
8. Maintenance Therapy: Patients on no maintenance/background therapy or patients on
stable maintenance as either LAMA or LABA therapy are eligible. Patients taking
maintenance LAMA or LABA therapy must demonstrate regular use of maintenance
LAMA or LABA therapy, in any form, for at least 2 months prior to Screening and
agree to continue use of their current permitted LAMA or LABA medication for the
duration of the study. Section 6.7.3 lists the medications that are prohibited during the
study and the prohibited time intervals prior to Screening. Background maintenance
LAMA or LABA bronchodilator therapy will be capped at 50% of patients.
Other Requirements for Inclusion 
9. Capable of withholding SABAs for 4 hours prior to initiation of any spirometry.
Patients in the maintenance LAMA or LABA therapy stratum must be capable of
withholding Twice-Daily maintenance LAMA or LABA for 24 hours and Once-Daily
maintenance LAMA or LABA for 48 hours prior to initiation of any spirometry.
10. Capable of using the study nebulizer correctly and complying with all study
restrictions and procedures.
11. Ability to perform acceptable spirometry in accordance with ATS/ERS guidelines
(Miller 2005).
5.2 Exclusion Criteria 
Current Condition or Medical History 
1. History of life-threatening COPD including Intensive Care Unit admission and/or
requiring intubation.
2. Hospitalizations for COPD, pneumonia, or Corona Virus Disease 2019 (COVID-19)
in the 12 weeks prior to Screening and/or a positive COVID-19 test result indicating
an active infection at Screening. Patients with COVID-19 antibodies from a previous
exposure with no active infection are not excluded.
3. COPD exacerbation requiring oral or parenteral steroids within 3 months of
Screening.
4. Previous lung resection or lung reduction surgery within 1-year of Screening.
5. 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.
6. Pulmonary rehabilitation, unless such treatment has been in a stable maintenance
phase for 4 weeks prior to Visit 1 and remains stable during the study.


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7. Lower respiratory tract infection within 6 weeks of Screening.
8. Other respiratory disorders including, but not limited to, a current diagnosis of
asthma, active tuberculosis, lung cancer, sarcoidosis, lung fibrosis, interstitial lung
diseases, unstable sleep apnea, known alpha-1 antitrypsin deficiency, core pulmonale,
clinically significant pulmonary hypertension, clinically significant bronchiectasis, or
other active pulmonary diseases.
9. 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.
10. Historical or current evidence of clinically significant cardiovascular disease defined
as any disease that in the opinion of the Investigator would put the safety of the
patient at risk through participation or which could affect the efficacy or safety
analysis if the disease/condition were to exacerbate during the study, including, but
not limited to:
x
Myocardial infarction or unstable angina within 6 months prior to Screening.
x
Unstable or life-threatening cardiac arrhythmia requiring intervention within 3
months prior to Screening.
x
Diagnosis of New York Heart Association (Dolgin 1994) Class III and
Class IV heart failure.
11. Chronic uncontrolled disease including, but not limited to, endocrine, active
hyperthyroidism, neurological, hepatic, gastrointestinal, renal, hematological,
urological, immunological, psychiatric, or ophthalmic diseases that the Investigator
believes are clinically significant.
12. Unstable liver disease defined by the presence of ascites, encephalopathy,
coagulopathy, hypoalbuminemia, esophageal or gastric varices or persistent jaundice,
cirrhosis, known biliary abnormalities (except for Gilbert’s syndrome or
asymptomatic gallstones). Note: Chronic stable hepatitis B and C is not exclusionary
if the patient otherwise meets study entry criteria.
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. Findings on physical examination that an investigator considers to be clinically
significant at Screening.
Prior/Concomitant Therapy 
15. Use of prohibited medications within the time intervals defined in Section 6.7.3.
History or Suspicion of Drug or Alcohol Abuse
16. Current or history of past drug or alcohol abuse within the past 5 years.


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Laboratory and Other Diagnostic Parameters 
17. Glomerular Filtration Rate (eGFR) <30 mL/min. The Chronic Kidney Disease 
Epidemiology Collaboration Creatinine (2009) calculation will be used  
(Levey, 2009). 
18. Alanine aminotransferase (ALT)  2 x upper limit of normal (ULN), alkaline 
phosphatase and/or bilirubin > 1.5 x ULN (isolated bilirubin >1.5 x ULN is 
acceptable if bilirubin is fractionated and direct bilirubin <35%). 
19. Any other abnormal hematology, biochemistry, or viral serology deemed by an 
investigator to be clinically significantly abnormal. Abnormal chemistry and/or 
hematology may be repeated during Screening. 
20. Chest X-ray (CXR; posterior-anterior) at Screening, or in the 12 months prior to 
Screening with clinically significant abnormalities not attributable to COPD. If a CXR 
within the past 12 months is not available but a computerized tomography (CT) scan 
within the same time period is available, the CT scan may be reviewed in place of a 
CXR. For subjects in Germany, if a CXR or CT scan is not available in the 12 
months prior to Screening, the subject is not eligible for the study. 
21. Electrocardiogram (ECG) finding that is significantly abnormal as defined in 
Section 11.4 on the 12-lead ECG obtained at Screening.  
Other Exclusions 
22. 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 trial 
within 30 days prior to Screening. 
23. Use of an experimental medical device or participation in a follow-up phase of an 
experimental medical device clinical trial within 30 days prior to Screening.  
24. Intolerance or hypersensitivity to albuterol/salbutamol or ensifentrine (RPL554) or 
any of its excipients/components. 
25. Prior receipt of blinded nebulized study medication in an ensifentrine (RPL554) 
study. 
26. 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. 
27. Inability to read, understand, and/or complete questionnaires (in the opinion of the 
Investigator). 
28. A disclosed history or one known to the Investigator of significant non-compliance in 
previous investigational studies or with prescribed medications. 
29. Any other reason that the Investigator considers makes the patient unsuitable to 
participate. 


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5.3 Randomization Criteria 
Criteria for Inclusion at Randomization 
1. Symptoms of COPD: A score of 2 on the mMRC Dyspnea Scale at Visit 1.
2. Completion of the e-Diary at least 5 of the last 7 days of the Run-in period.
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).
Patients with a severe COPD exacerbation that requires hospitalization may not be
rescreened.
2. Positive COVID-19 result at Screening or between Screening and Randomization.
3. Prohibited medication use between Screening Visit 0 and Visit 1.
4. Significantly abnormal ECG finding as defined in Section 11.4 on the 12-lead ECG
obtained at 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 patient is
randomized. After a patient has been randomized, ECG withdrawal criteria
(Section 11.5) will apply. In the event that the central ECG reviewer discovers a
significant ECG abnormality meeting ECG withdrawal criteria on the Visit 1 ECG in
2 of 3 triplicate measurements, the patient may be discontinued.
5. Did not meet one or more of the Inclusion Criteria (Section 5.1) or met one or more of
the Exclusion Criteria (Section 5.2) as assessed at Screening Visit 0 (e.g. including
overreads or lab values obtained after the day of Screening).
5.4 Lifestyle Considerations 
5.4.1 Caffeine and Tobacco 
5.4.1.1 
Prior to Spirometry and prior to ECG:  
Recommendation/request: Patients 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 beverages with high levels
of caffeine (eg, tea, coffee) for 2 hours prior to each spirometry and ECG
assessment.


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5.5 Rescreening 
5.5.1 
Rescreening Prohibited 
Patients who do not meet the following Inclusion Criteria may not be rescreened under 
any circumstances: 
x
Inclusion Criteria #5: COPD Diagnosis
x
Inclusion Criteria #6: COPD Symptoms
x
Inclusion Criteria #7: COPD Severity
5.5.2 
Rescreening Permitted if Medical Monitor Approves 
Approval from the Medical Monitor must be obtained to rescreen patients other than 
those for whom rescreening is prohibited (Section 5.5.1). Rescreened patients should be 
assigned the same patient number as for the initial screening. 
5.6 Screen Failures 
Screen failures are defined as patients 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 patients 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 patients to meet the Consolidated Standards of Reporting Trials publishing 
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 
Patients will be randomly assigned to receive double-blind study medication (either 
ensifentrine or placebo) administered using the inhaled route via a standard jet nebulizer 
(Section 6.2.2) supplied by the Sponsor. 
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. 
6.1 
Administration of Blinded Study Medication 
6.1.1 Dosing in the Clinic 
The Clinic Visit MUST BE RESCHEDULED within 3 days of the scheduled visit if 
any of the following apply: 
x
If the rescue medication or maintenance LAMA or LABA medication are not
withheld for the time intervals defined in Section 6.7.2.
x
If the morning dose of blinded study medication is not withheld.
Dosing Environment 
x
To avoid cross-contamination, blinded study medication dosing must be
conducted in a shielded and well-ventilated environment.
x
Patients may be in the same room as other patients who are being dosed on the
same day if separated by a partial partition or curtain and if other patients and
other staff members cannot visualize the study medication administration by the
blinded study site staff member. These measures are in place to protect study
medication blinding.
Designated Unblinded Site Staff Member 
To maintain the treatment blind, each site will designate an unblinded site staff member 
not associated with study conduct to administer in-clinic doses. 
Dosing Visit Schedule and Time(s) of Day 
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 new PARI LC Sprint® jet nebulizer (study supplied nebulizer), with a PARI Vios® 
PRO Aerosol Delivery System PARI BOY® compressor or equivalent (study supplied 


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compressor) will be dispensed to the patient and used to dose the blinded study 
medication in the clinic and at home.  
x Blinded study medication will be administered by inhalation of an aerosol 
generated by the reusable study supplied nebulizer attached to a study supplied 
compressor.  
x The unblinded site staff member should follow the nebulizer Set-Up instructions 
provided with the nebulizer and the Pharmacy Manual to prepare and administer 
the blinded study medication.  
x Administration of nebulized blinded study medication will be observed by the 
unblinded site staff member from start of nebulization until end time of 
nebulization. The unblinded site staff member MUST administer blinded study 
medication at all in-clinic dosing times. Patients may be discharged from the 
clinic after Week 12 assessments are complete to self-administer their evening 
dose of study medication. If administered in the clinic, the Week 12 evening dose 
must be administered by unblinded site staff. 
x Blinded study medication nebulization time should be approximately 5 minutes 
and may not exceed 10 minutes.  
x 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.  
x The date, the start time, and the end time of blinded study medication nebulization 
will be recorded by the unblinded site staff member in the patient source 
document and the electronic case report form (eCRF).  
x Patients will take their study supplied nebulizer study supplied compressor and 
instructions home for use during the study. A new study supplied nebulizer(s) will 
be issued periodically. Only a study supplied nebulizer and a study supplied 
compressor may be used to administer blinded study medication during the study. 
6.1.2 Dosing at Home 
Following Visit 1, patients 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 study, except for specific clinic visit days when patients will have their 
doses administered in the clinic.  
Prior to Dosing at Home 
x Patients in the maintenance LAMA or LABA stratum should take their maintenance 
LAMA or LABA (and ICS, if applicable) prior to taking blinded study medication. 
Blinded Study Medication Administration 
x Each patient 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. 


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x
Blinded study medication nebulization time should be approximately 5 minutes
and may not exceed 10 minutes.
x
The end time of blinded study medication nebulization is considered to be 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.
x
On the evening Prior to the Week 6, Week 12 and Week 24 Visits (or Early
Term/Withdrawal visits where 12-hour spirometry will be performed): On a
patient paper diary, the patient will record the date, the start time of nebulization,
and the end time of nebulization for the evening dose of blinded study medication.
Used Blinded Study Medication 
x
Patients will be instructed to discard all used ampules of blinded study medication
and the open foil pouches that contained the used ampules at home.
Unused Blinded Study Medication 
x
Patients should be instructed to bring all unused blinded study medication to the
clinic at each clinic visit for collection and assessment of medication compliance
by the unblinded site staff member.
x
If a foil pouch is opened but the blinded study medication is not opened/not used,
the patient should seal the opened foil pouch (eg, tape) before returning it to the
clinic.
6.2 Investigational Product/Blinded Study Medication 
Investigational product/blinded study medication is described in Table 5. 
Table 5: Investigational Product/Blinded Study Medication Details 
Name:
Ensifentrine
Placebo
Dosage Formulation: 
Nebulizer suspension 
Nebulizer solution 
Unit Dose: 
3 mg 
0 mg 
Concentration (mg/mL) 
1.2 mg/mL 
0 mg/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 ensifentrine formulation is a sterile suspension of micronized ensifentrine 
 
 and supplied 
as a 2.5 mL nominal fill in single unit-dose low density polyethylene (LDPE) translucent 
ampule overwrapped in a foil pouch.  
The placebo is the same as the ensifentrine suspension except that the active ensifentrine 
ingredient is omitted, 
 




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6.3 Preparation/Handling/Storage/Accountability 
1. Blinded study medication should be stored below 25°C (77°F) and should not be 
frozen. 
2. 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. 
3. 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. 
4. 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. 
5. Only patients 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.  
6. 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). 
7. 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 site 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 
Measures to Minimize Bias: Randomization and Blinding 
1. Both ensifentrine and placebo pouches and packaging are identical in appearance. 
2. Packaging of both ensifentrine and placebo will have a blinded description applied 
and all packs will have a unique kit number applied for identification. 
3. Deliveries of both ensifentrine and placebo will not indicate the actual product but 
will instead indicate a blinded description. 
4. Patients will be randomized to receive either ensifentrine or placebo using an 
electronic Interactive Response Technology (IRT). The IRT will not indicate the 
treatment arm during the randomization process but will indicate the unique kit 
numbers to be dispensed to the patient. 
5. Site staff (both blinded and unblinded) will only have access to blinded reports 
within the IRT. 
6. An unblinded site staff member not associated with study conduct will administer in-
clinic doses. 
7. If more than one patient will be at the clinic at the same time, they will be shielded 
from each other to prevent cross-contamination or observance of treatment. 


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Note: Patients may be aware of the appearance when pouring blinded study medication 
into the nebulizer. Therefore, they should be instructed not to inform site personnel of the 
appearance of their blinded study medication. Similarly, study personnel are not to 
discuss the appearance with patients or other site personnel. Patients will be instructed to 
return unused blinded study medication (ie, unopened or unused blinded study medication 
in taped foil pouches) only to the unblinded site staff at their next visit. The investigator 
will need to confirm and document that the blinding procedures have/have not been 
maintained for each patient throughout the study. See Data Quality Assurance in 
Section 11.2).  
6.5 
Emergency Unblinding 
The blind will be broken only if specific emergency treatment would require knowing the 
treatment status of the patient. 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. 
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 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 each visit, prior to dispensing blinded study medication, previously dispensed unused 
blinded study medication (ie, unopened or unused blinded study medication in taped foil 
pouches) will be retrieved by the unblinded site staff member and compliance assessed. 
Patients 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 patient 
source document.  
Noncompliance is defined as taking less than 70% of blinded study medication during 
any evaluation period (visit to visit). 
6.7 Concomitant Therapy 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 


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6.7.1 Rescue Medication 
Study albuterol/salbutamol should be used for rescue use. If study rescue 
albuterol/salbutamol cannot be dispensed at a scheduled clinic visit, the medication may 
be dispensed alternatively according to local requirements (Section 8.6). If at any time 
during the study albuterol/salbutamol is unavailable in a given country or region, the 
Medical Monitor must be contacted to discuss and approve alternative rescue medication 
(Section 8.6). 
6.7.1.1 
Documentation of Rescue Medication Use 
x Documentation of albuterol/salbutamol during the 3 months prior to Screening 
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.” 
x Rescue albuterol/salbutamol 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 (eg, dose (number of puffs), date, and time of 
administration) will be recorded.  
x Rescue albuterol/salbutamol used at all other times after Screening will be 
documented in the eDiary (eg, number of puffs per day). 
x After Screening, use of Rescue Medication will not be recorded in the 
concomitant medication page of the eCRF. 
6.7.2 Permitted Rescue and Background Medications 
Permitted rescue and background medications are provided in Table 7. 
Any vaccine that is recommended by the patient’s healthcare provider is permitted during 
the study (e.g. COVID, influenza, pneumonia), and should be recorded in the eCRF. 


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Table 7: Permitted Rescue and Background Medications 
Medication 
Condition 
Albuterol/salbutamol 
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. 
Either LAMA or LABA 
Patients entering the study on a maintenance regimen of either LAMA or 
LABA therapy will be required to remain on that regimen at a stable dose 
for the duration of the study. Dual LAMA/LABA therapy is not allowed. 
Stable ICS use is allowed along with a LAMA or LABA maintenance 
regimen if it was initiated at least 4 weeks prior to Screening. ICS 
monotherapy is not allowed. 
Must withhold prior to spirometry: Twice-Daily maintenance LAMA or 
LABA (or LAMA/ICS or LABA/ICS) for 24 hours, and Once-Daily 
maintenance LAMA or LABA (or LAMA/ICS or LABA/ICS) for 48 hours, 
including at Visit 1.1 
The maintenance LAMA or LABA (or LAMA/ICS or LABA/ICS) therapy 
should resume once all spirometry for a given visit has been completed.  
No maintenance or 
background therapy 
Patients entering the study on no maintenance background therapy will not 
be allowed to initiate background maintenance therapy for COPD (ie, 
maintenance LAMA or LABA therapy, or ICS therapy) for the duration of 
the study. 
Inhaled corticosteroids 
(ICS) 
Stable use of ICS is permitted IF the patient has been taking the ICS at least 
4 weeks prior to Screening (Visit 0) AND the patient is also taking 
maintenance LAMA or LABA. ICS should not be initiated or discontinued 
during the study.  
ICS monotherapy and high dose ICS (e.g. >1000 mcg of fluticasone 
propionate or equivalent) is not allowed. 
1If the withholding periods are not met the visit should be rescheduled to be held within 3 days of the 
scheduled visit.  
Abbreviations: COPD=chronic obstructive pulmonary disease; LAMA= long-acting muscarinic 
antagonist; LABA= long-acting ȕ2 agonist 
6.7.3 Prohibited Medications/Therapy 
Prohibited medications and therapies are provided in Table 8. 


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Table 8: Prohibited Medications/Therapy 
Medication 
Time Interval 
Oral, Systemic or Parenteral Steroid Therapies  
3 months prior to Screening Visit and prohibited 
during the study.1 
Antibiotics for lower respiratory tract infection 
6 weeks prior to Screening Visit and prohibited during 
the study.1 Chronic use of antibiotics is not allowed 6 
weeks prior to or during the study. 
Inhaled Corticosteroids (ICS) (e.g. ICS 
monotherapy and patients in the no 
maintenance therapy stratum) 
High dose ICS (e.g. >1000 mcg of fluticasone 
propionate or equivalent) 
4 weeks prior to Screening Visit and prohibited during 
the study. 
 
Oral leukotriene inhibitors (i.e. montelukast, 
zafirlukast, zileuton) 
48 hours prior to Screening Visit and prohibited 
during the study. 
Theophylline and PDE4 inhibitor (e.g. 
roflumilast, apremilast, crisaborole) 
48 hours prior to Screening Visit and prohibited 
during the study. 
Terbutaline 
1-day prior to Screening Visit and prohibited during 
the study. 
Ipratropium (including combinations with 
albuterol/salbutamol) 
6 hours prior to Screening Visit and prohibited during 
the study. 
LAMA/LABA combination products 
4 weeks prior to Screening Visit and prohibited during 
the study. 
Nebulized LAMA or LABA or ICS 
For patients in the no maintenance therapy 
stratum: 
For patients in the LAMA or LABA stratum: 
 
4 weeks prior to Screening Visit and prohibited during 
the study. 
1-week prior to Screening Visit and prohibited during 
the study (e.g. patient should switch from nebulized to 
dry powder or metered dose therapy) 
LAMA Excluded ONLY for patients in the no 
maintenance therapy stratum 
4 weeks prior to Screening Visit and prohibited during 
the study.2 
LABA Excluded ONLY for patients in the no 
maintenance therapy stratum 
4 weeks prior to Screening Visit and prohibited during 
the study.2 
Oral beta2-agonists 
1-week prior to Screening Visit and prohibited during 
the study. 
1Except for the treatment of COPD exacerbations during the study (Section 11.6). Localized 
corticosteroid injections (eg, intra-articular and epidural), intranasal and topical corticosteroids are 
permitted. 
2Washout of patients on stable background maintenance LAMA or LABA monotherapy for the sole 
purpose of study eligibility is not recommended. 
Abbreviations: COPD=chronic obstructive pulmonary disease; ICS=inhaled corticosteroids; LAMA= 
long-acting muscarinic antagonist; LABA= long-acting ȕ2 agonist; PDE4= phosphodiesterase 4 
 
 


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6.7.4 Recording Use of Concomitant Medications  
6.7.4.1 
Recording of Rescue Medication and/or LAMA or LABA Medications, and 
ICS (if applicable) 
x Rescue medication (albuterol/salbutamol) use during the study should be recorded 
as described in Section 6.7.1.  
x Use of LAMA or LABA medications, and ICS (if applicable) during the 3 months 
prior to Screening 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).  
- For patients in the maintenance LAMA or LABA therapy stratum, the end 
date for LAMA or LABA, and ICS (if applicable) should be documented 
as “Ongoing.” 
- For patients not in the maintenance LAMA or LABA therapy stratum, the 
actual end date should be documented, if applicable.  
x For patients in the maintenance LAMA or LABA therapy stratum, the LAMA or 
LABA (or LAMA/ICS or LABA/ICS) medication used during the study should be 
recorded in the eDiary only.   
x See Section 8.5.10.2 for information to be collected for PK. 
6.7.4.2 
Recording of Medications other than Rescue Medication and/or LAMA or 
LABA or ICS Medications 
All COPD medications used within 3 months prior to Screening will be recorded in the 
eCRF. 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:  
x Reason for use. 
x Dates of administration including start and end dates. 
x Dosage information including route, dose, and frequency. 
6.7.4.3 
Recording of Medications and Information Specific to the Pharmacokinetic 
Procedures and Sample Analysis:  
See Section 8.5.10.2 for recording of medications and information specific to the PK 
procedures and sample analysis. 
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. 


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At the end of the blinded study medication treatment period (Visit 5 or Visit 9 or early 
termination), patients may resume conventional COPD therapy as prescribed by the 
investigator or other physician. 
Medications initiated after the end of study treatment should not be entered into the eCRF 
except for those given for a serious adverse event (SAE).  
 
 


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7.0 DISCONTINUATION OF BLINDED STUDY 
MEDICATION AND PATIENT DISCONTINUATION/ 
WITHDRAWAL 
7.1 
Discontinuation of Blinded Study Medication 
Patients who permanently discontinue blinded study medication are not required to 
withdraw from the study unless they test positive for COVID-19 active disease. If a 
patient must permanently discontinue blinded study medication for reason(s) other than 
testing positive for COVID-19 active disease, the patient should complete the “Patient 
Discontinuation/Withdrawal from the Study” assessments described in Section 7.3 as 
soon as possible. In addition, every effort should be made by the investigator/staff to keep 
the patient in the study to collect important efficacy and safety data as detailed in 
Section  7.2. 
Circumstances potentially requiring or actually resulting in discontinuation of blinded 
study medication are described below.  
See the SoA (Section 1.3) for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that need to be completed. 
7.1.1 
Does Not Meet Criteria for Randomization 
If a patient who does not meet the Randomization Criteria is inadvertently randomized 
and receives blinded study medication, the Medical Monitor must be contacted and will 
consult with the Sponsor to determine if the patient may continue, must be discontinued 
from blinded study medication and/or discontinued from the study.  
7.1.2 
Liver Chemistry Stopping Criteria 
Discontinuation of blinded study medication for abnormal liver function should be 
considered by the Investigator when a patient meets one of the conditions outlined in 
Section 11.9 or if the Investigator believes that it is in best interest of the patient. 
7.1.3 
Electrocardiogram Withdrawal Criteria 
All ECGs conducted or overread after a patient has been randomized will be subject to 
ECG Withdrawal Criteria (Section 11.5). Patients 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, Section 11.5, 
and in consideration with the patient’s medical history and baseline ECG measurements. 
Clinically significant abnormalities as determined by the Investigator may also result in 
patient discontinuation from study medication per the Investigator’s judgement. Triplicate 
ECGs (over a brief period of time) should be performed on patients experiencing a 


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significant abnormality on their ECG or other clinically significant abnormality as 
determined by the Investigator. The intent of triplicate ECG measurements is to 
differentiate significant abnormalities from artifact. Abnormalities should be confirmed in 
2 of 3 triplicate ECG measurements. 
7.1.4 
COPD Exacerbation Withdrawal Criteria 
Guidelines for identifying COPD exacerbation in this study and conditions for study 
continuation or withdrawal due to COPD exacerbation can be found in Section 11.6. 
7.1.5 
Positive Pregnancy Test in Females 
Women who are pregnant or breastfeeding are not eligible to participate. Pregnancy 
testing is being conducted in women of childbearing potential at Screening and at other 
times specified in the SoA (Section 1.3). 
Women exhibiting a positive pregnancy test (Section 11.3) 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 Section 11.8. 
7.1.6 Positive COVID-19 Test Indicating an Active Infection 
Patients with a positive COVID-19 test result indicating an active infection will be 
required to discontinue blinded study medication and will be required to withdraw from 
the study. 
7.1.7 Other Criteria 
Other criteria that may or may not require permanent discontinuation of blinded study 
medication include but are not limited to adverse event, lack of efficacy, protocol 
deviation, non-compliance, study closed/terminated, investigator discretion or patient 
withdrawal of consent. 
7.2 
Study Participation After Discontinuation of Blinded Study 
Medication 
Patients may permanently discontinue blinded study medication before the end of the 
study if they choose to or at the investigator’s discretion.  
Patients who permanently discontinue blinded study medication are not required to 
withdraw from the study unless they test positive for COVID-19 active disease. Patients 
who have permanently discontinued blinded study medication but do not test positive for 
COVID-19 active disease and have not withdrawn consent may continue in the study and 
complete all remaining protocol specified visits. 
The Investigator must document the reason for discontinuation of blinded study 
medication in the eCRF.  


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Ideally, patients who have permanently discontinued blinded study medication will 
continue to attend scheduled clinic visits and complete important efficacy and safety 
assessments. However, if this is not possible then the investigator will encourage the 
patient to select one of the three options below to participate in as much of the study as 
they are willing (or able) to participate:  
7.2.1 
Reduced Assessments 
The patient continues to follow the SoA (Section 1.3) and completes only the following 
assessments: 
x Spirometry 
x SGRQ 
x COPD exacerbation 
x AE 
x Concomitant medication 
7.2.2 
Combination of Phone Contact and Reduced Assessments 
The site contacts the patient by phone per the SoA (Section 1.3) to complete the following 
assessments: 
x COPD exacerbation  
x SAE 
x Concomitant medication 
In addition, the patient returns to the clinic at Week 24 to complete the following 
assessments: 
x Spirometry 
x SGRQ 
x COPD exacerbation 
x SAE 
x Concomitant medication 
7.2.3 
Phone Contact Only 
The site contacts the patient by phone per the SoA (Section 1.3) to complete the following 
assessments: 


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x COPD exacerbation  
x SAE 
x Concomitant medication 
7.3 
Patient Discontinuation/Withdrawal from the Study  
A patient may withdraw from the study at any time at his/her own request, may 
permanently discontinue blinded study medication but wish to remain in the study, or 
may be withdrawn from administration of blinded study medication or from all study 
participation at the discretion of the Investigator at any time for safety, behavioral, 
compliance, or administrative reasons. See the SoA (Section 1.3) for data to be collected 
at the time of study discontinuation and follow-up and for any further evaluations that 
need to be completed. 
x If the patient withdraws consent for disclosure of future information, the Sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
x If a patient 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. 
7.3.1 Early Termination/Withdrawal Procedures 
If a patient is withdrawn prior to the Week 12 visit, every attempt should be made to have 
the patient complete the early termination/ withdrawal procedures in the SoA 
(Section 1.3) as soon as possible.  
x If possible, patients should remain on blinded study medication and their 
maintenance LAMA or LABA medication and ICS (if applicable), follow the 
withholding procedures prior to Spirometry in Section 8.3.1.2, and should refrain 
from smoking or caffeinated beverages as recommended in Section 5.4.1.1. 
x Patients unable to remain on blinded study medication and/or their maintenance 
LAMA or LABA medications and ICS (if applicable) should still complete the 
early termination/ withdrawal visit as soon as possible. 
7.3.1.1 
12-Hour Spirometry and 1.5 Hour ECG Procedures 
For patients who are withdrawn prior to completing the Week 12 visit only, every attempt 
should be made to have the patient complete the 12-hour spirometry procedures and the 
ECG procedures at the early termination/withdrawal visit unless consent is withdrawn or 
the patient is being withdrawn for safety reasons precluding this assessment.  


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Patients who Continued Blinded Study Medication 
Patients who have continued administration of their blinded study medication should 
complete the spirometry and ECG procedures as follows: 
x Spirometry: Pre-dose and 0-12-hour post-dose assessments as per Section 1.4 and 
Section 8.3.1.  
x ECG: Pre-dose and 1.5-hour post-dose ECG procedures as per Section 8.4.2. 
Patients who Discontinued Blinded Study Medication 
Patients who have discontinued blinded study medication prior to the early termination/ 
withdrawal visit may optionally complete spirometry and ECG assessments at the early 
termination visit if they have not already completed the Week 12 assessments. These 
patients will not be dosed with blinded study medication. If possible, patients should start 
spirometry between 6 am and 10am, withhold rescue medication and/or maintenance 
LAMA or LABA medications for the time period specified in Section 6.7.2, and refrain 
from caffeinated beverages and/or smoking for the time period specified in Section 5.4.1. 
The spirometry and ECG procedures should be completed as follows: 
x Spirometry: Serial spirometry at 0-hour, 30 min, and 1, 2, 4, 6, 8, and 12 hours.  
x ECG: 12-lead ECG at 0-hour and 1.5 hours. 
x Note: If a patient completed only one of the serial 12-hour spirometry or 1.5-hour 
ECG procedures at Week 12, they may optionally complete the other one (the one 
not completed at Week 12) at this visit.  
7.3.1.2 
Single 12-Lead ECG  
Patients who early term/withdraw after Week 12 and are not completing either the pre-
dose and 1.5-hour or the 0-hour and 1.5-hour ECG assessments described in 
Section 7.3.1.1 will complete a single 12-lead ECG as per Section 8.4.2. 
7.4 
Lost to Follow-up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study center. 
The following actions must be taken if a patient fails to return to the clinic for a required 
study visit: 
x The study center must attempt to contact the patient and reschedule the missed 
visit as soon as possible and counsel the patient on the importance of maintaining 
the assigned visit schedule and ascertain whether the patient wishes to and/or 
should continue in the study. 


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x Before a patient is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the patient (where possible, 3 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
patient’s medical record. 
x Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
 


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8.0 STUDY ASSESSMENTS AND PROCEDURES 
x Patients may not complete any Screening Visit Procedures including the 
Spirometry Assessment unless all prohibited medications/therapy described in 
Section 6.7.3 have been withheld for the defined time interval.  
x Study procedures and their timing are summarized in the SoA (Section 1.3). 
x Protocol waivers or exemptions are not allowed. 
x Immediate safety concerns should be discussed with the Sponsor immediately 
upon occurrence or awareness to determine if the patient should continue or 
discontinue blinded study medication. 
x Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
x All Screening evaluations must be completed and reviewed to confirm that 
potential patients meet all eligibility criteria. The Investigator will maintain a 
screening log to record details of all patients screened and to confirm eligibility or 
record reasons for Screening failure, as applicable. 
x Procedures conducted as part of the patient’s routine clinical management (eg, 
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.  
x The maximum amount of blood collected from each patient 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. 
x 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 Section 11.2. 
8.1.2 Demographic Variables 
Demographic variables will include items such as age, sex, ethnicity, body mass index, 
and race. 


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8.1.8 Spirometry Assessment 
Spirometry at Screening will be completed per the instructions in Section 8.3.1. 
8.1.9 Modified Medical Research Council Dyspnea Scale 
The mMRC dyspnea scale is a questionnaire that measures COPD symptoms and defines 
symptom burden at Screening (Fletcher, 1960). Site staff will administer/interview the 
patient to complete the mMRC dyspnea scale questionnaire. 
8.1.10 Clinical Laboratory Assessments 
Clinical laboratory tests will be conducted per the instructions in Section 8.4.3. Abnormal 
chemistry and/or hematology may be repeated during Screening/Run-in. 
8.1.10.1 
Viral Serology 
Viral serology for HBsAg, anti-HBc, anti-HBs, and Hepatitis C Virus will be obtained at 
Screening. Chronic stable hepatitis B and C is not exclusionary if the patient otherwise 
meets study entry criteria. 
8.1.10.2 
COVID-19 
Testing for COVID-19 may optionally be completed (Section 11.3) prior to spirometry 
and following local requirements. Patients with a positive COVID-19 test result 
indicating an active infection at Screening or anytime between Screening and 
Randomization will be excluded.  
Patients with a positive COVID-19 antibody test from a past exposure who do not exhibit 
symptoms of an active COVID-19 infection are eligible to participate in the study. 
8.1.11 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 patients have had no 
previous serious illness(es). 
8.1.12 Inclusion/Exclusion Criteria 
Patient eligibility will be assessed using the inclusion criteria (Section 5.1) and exclusion 
criteria (Section 5.2). 
8.1.13 Electronic Diary Activities 
Electronic Diary training will be conducted and the eDiary will be issued for use during 
the study. Patients will be instructed to enter their daily symptoms (E-RS:COPD/EXACT-
PRO questionnaire), rescue medication (puffs per day), and maintenance LAMA or 
LABA medication (if applicable) into the eDiary each day. 


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8.1.14 Interactive Response Technology 
Patients will be registered in the IRT system (See Section 8.5.2). 
8.1.15 Nebulizer Equipment Training 
See Section 8.5.5 for details on nebulizer equipment training. At the Screening Visit, site 
staff will review the information and instructions provided by the manufacturer with the 
patient (e.g. Instructions for Use, located in the Pharmacy Manual). Hands-on training 
with the nebulizer equipment will not occur until the Randomization Visit. 
8.1.16 Dispense Rescue Medication  
Rescue medication (albuterol/salbutamol) 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 6.7.2 for additional details. 
8.2 Randomization Criteria Assessment– Day 1 
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 (Section 1.3). 
8.3.1 Spirometry  
Spirometry will be obtained using spirometry equipment provided by the central 
spirometry vendor that meets or exceeds the American Thoracic Society minimal 
performance recommendations [Miller, 2005].  
The central spirometry vendor will provide a spirometry manual with additional 
instructions and details. 
All Spirometry will be reviewed and over-read by the central spirometry vendor and the 
spirometry vendors determination of acceptable endpoint measurements will override 
determination by the investigative site. 
x
Acceptable spirometry efforts should have a satisfactory start of test and end of
test (plateau in the volume-time curve) and be free from artifacts due to cough,
early termination, poor effort, obstructed mouthpiece, equipment malfunction, or
other reason [Miller, 2005].
x
For FEV1 and FVC determinations, at least 3 but no more than 8 acceptable
spirometry efforts should be obtained.
x
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even
if they do not come from the same effort.


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8.3.1.1 
Spirometry Training 
Prior to the first spirometry measurement at each clinic visit requiring Spirometry, the site 
staff will train each patient 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: 
x 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. 
x Spirometry Start Time: between 06:00 am and 10:00 am. 
x Health Outcomes: Complete health outcome assessments as described in 
Section 8.3.3 prior to spirometry. 
x Withhold the Following or Reschedule the Visit*: 
- Blinded Study Medication: Blinded study medication must be withheld 
until pre-dose spirometry is completed. 
- Rescue Medication: Albuterol/salbutamol must be withheld for 4 hours. 
- Maintenance LAMA or LABA medications (or LAMA/ICS or LABA/ICS, if 
applicable): Must withhold Twice-Daily medications for 24 hours and 
Once-Daily medications for 48 hours prior to spirometry. 
*If the withholding periods above are not met, the visit should be 
rescheduled to be held within 3 days of the scheduled visit. 
x Recommendation/ Request: Patients 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 
assessment. 
- Caffeinated Beverages: Abstain from drinking beverages with high levels 
of caffeine (eg, tea, coffee) for 2 hours prior to each spirometry 
assessment.  
8.3.2 COPD Exacerbation Assessment 
Guidelines for Identifying COPD Exacerbations for this study are located in Section 11.6. 
8.3.3 Health Outcomes 
The schedule for all health outcomes assessments are provided in the SoA (Section 1.3). 
During Study Visits 
All patient reported outcomes administered during study visits should be administered at 
the beginning of a study visit before any physical activity or spirometry, except for 
Healthcare Utilization assessment, which can be done at any point during the visit. The 
following is the recommended order as applicable for a given visit: 


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x mMRC  
x SGRQ  
x EQ-5D-5L 
x Baseline/Transitional Dyspnea Index (BDI)/TDI 
8.3.3.1 
St. George’s Respiratory Questionnaire 
The SGRQ Patient Reported Outcome (PRO) measure is designed to assess health-related 
quality of life in patients with COPD in terms of symptoms, daily activity limitation, and 
psychosocial well-being (Jones, 1991). The SGRQ is completed by the patient. 
8.3.3.2 
EuroQol-5-Domain Questionnaire 
The EQ-5D-5L questionnaire is a standardized instrument designed to measure health 
utility in terms of mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression (Szende, 2014). The EQ-5D-5L questionnaire is completed by the 
patient. 
8.3.3.3 
Baseline Dyspnea Index/Transitional Dyspnea Index 
The BDI is used to measure the severity of dyspnea in patients at baseline (Mahler, 1984). 
Mahler also developed the TDI which measures changes in patient dyspnea from 
baseline. The instruments are scored based on ratings for functional impairment, 
magnitude of task, and magnitude of effort. The BDI and TDI are administered by site 
staff via patient interview. 
8.3.3.4 
Healthcare Utilization 
All unscheduled visits to a physician office, visits to urgent care, visits to emergency 
department, and hospitalizations for any cause and/or related to COPD will be recorded in 
the eCRF. In addition, visits and contacts that are due to a COPD exacerbation will be 
assessed at each clinic visit and recorded in the exacerbation form of the eCRF.  
8.3.3.5 
Patient Perception Survey 
At the Follow-up contact, the study site will survey each patient regarding patient 
perception of their study treatment assignment. 
At Home 
8.3.3.6 
Evaluating-Respiratory Symptoms Questionnaire 
The E-RS is a PRO instrument derived from the EXACT-PRO designed to collect data to 
quantify the severity of respiratory symptoms across domains of breathlessness, chest 
symptoms and cough/sputum in patients with COPD and evaluate treatment benefit 
(EXACT 2013). The E-RS is an electronic instrument to be completed by the patient in 
the form of the EXACT-PRO in the eDiary each evening before bedtime.  
8.4 Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA, Section 1.3. 


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8.4.1 Vital Signs 
x Vital signs should be obtained prior to blinded study medication dosing at all visits. 
x Temperature in Celsius, pulse rate, blood pressure, and respiratory rate will be 
assessed. The mode of temperature collection should be noted in the source (e.g. oral, 
forehead, etc). 
x 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.  
x Supine blood pressure, respiratory rate, and pulse measurements should be obtained 
after the patient has been at rest for at least 5 minutes in the supine position and 
located in a quiet setting without distractions (eg, television, cell phones).  
8.4.2 Electrocardiogram 
12-lead ECG will be obtained using standardized ECG equipment provided by the 
centralized vendor. Albuterol/salbutamol should be withheld for at least 4 hours prior to 
ECG assessments. It is recommended that ECG assessments should be obtained after 
patients have rested for approximately 5 minutes. 
x The central ECG vendor will provide an ECG manual with additional instructions 
and details. 
x All ECGs will be reviewed and over-read by the central ECG vendor and the ECG 
vendors interpretation of the measurement(s) will override the interpretation by 
the investigative site, if a consensus is not reached.  
8.4.2.1 
Day 1/Randomization/Visit 1: Triplicate ECGs at Pre-Dose 
At Day 1/Randomization/Visit 1 prior to dosing (pre-dose), triplicate ECGs (over a brief 
period of time) must be performed. 
8.4.2.2 
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 Section 11.5 should be reviewed and triplicate ECGs (over a brief period of 
time) should be performed to confirm the abnormality in 2 of 3 measurements. 
8.4.2.3 
Recommendation/ Request 
Patients should refrain from smoking and/or caffeinated beverages prior to ECGs for the 
withholding periods below:  
- Smoking: No smoking for at least 1-hour prior to each ECG assessment. 
- Caffeinated Beverages: Abstain from drinking beverages with high levels of caffeine 
(eg, tea, coffee) for 2 hours prior to each ECG assessment.  
8.4.3 Clinical Laboratory Assessments 
See Section 11.3 for the list of clinical laboratory tests to be performed and additional 
instructions. 


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8.4.3.1 
COVID-19 
Testing for COVID-19 may optionally be completed. Patients with a positive COVID-19 
test result indicating an active infection anytime during the study will be withdrawn.  
8.4.4 Adverse Event Assessment 
The method of detecting AE will be performed as described in Section 8.7 and 
Section 11.7. 
8.5 Other Assessments and Procedures 
Planned timepoints for all other assessments and procedures are provided in the SoA, 
Section 1.3. 
8.5.1 Concomitant Medication Assessment 
Patients 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 6.7. The list of permitted 
rescue and background medications is provided in Section 6.7.2. The list of prohibited 
medications/therapy is provided in Section 6.7.3. 
8.5.2 Interactive Response Technology 
Sites will enter information into the IRT at specified visits. All patients consented will be 
assigned a patient identification number upon signing of the informed consent. 
8.5.3 Randomization 
Patients meeting all inclusion criteria (Section 5.1) and all Randomization Criteria 
(Section 5.3) and meeting none of the exclusion criteria (Section 5.2) will be randomly 
assigned to blinded study medication via the IRT (Section 8.5.2) at Visit 1. 
8.5.4 Electronic Diary Activities 
Electronic Diary (eDiary) training will be conducted. Patients will be instructed to enter 
their daily symptoms (E-RS:COPD/EXACT-PRO questionnaire), administration of their 
blinded study medication (morning and evening), rescue medication (puffs per day), and 
maintenance LAMA or LABA medication, or LAMA/ICS or LABA/ICS (if applicable) 
into the eDiary each day. Electronic Diary compliance will be visually reviewed by the 
site staff at each clinic visit or discussed with the patient via phone contact and/or when 
patients are unable to come into the clinic. Patients with poor compliance should be 
instructed by the site staff to improve eDiary compliance. 


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8.5.5 Nebulizer Equipment Training 
Patients and site staff will be trained on use of the PARI LC Sprint nebulizer and PARI 
Vios PRO Aerosol Delivery System, and the PARI BOY compressor or equivalent which 
will be used for inhalation of blinded study medication during the study period. Once the 
site staff has been trained, they will review the information and instructions provided by 
the manufacturer with the patient (e.g. Instructions for Use, located in the Pharmacy 
Manual). Hands on training with the nebulizer will occur at randomization with 
administration of the first dose of blinded study medication. 
8.5.6 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. 
8.5.7 Blinded Study Medication Dosing in the Clinic 
Blinded study medication dosing in the clinic will be conducted as described in 
Section 6.1.1. 
8.5.8 Dispense/Collect Rescue Albuterol/Salbutamol 
Albuterol/salbutamol will be dispensed/collected at specified visit for use as needed. See 
Section 6.7.1 for additional detail. 
8.5.9 Dispense/Collect Blinded Study Medication 
Blinded study medication will be dispensed/collected at clinic visits that include 
Spirometry. 
8.5.10 Pharmacokinetics 
All randomized patients will participate in pharmacokinetics. 
8.5.10.1 
Collection of Samples 
A limited (sparse) sampling strategy to collect samples of whole blood will be 
implemented for the determination of ensifentrine in human plasma for PK assessment. 
Blood samples for the determination of plasma concentrations ensifentrine will be taken 
by venipuncture or indwelling catheter at the times specified in the SoA (Section 1.3). Up 
to 7 blood samples will be collected from each patient across visits at Weeks 6, 12, 24, 
and/or early termination visit. A sparse sampling collection scheme will be followed with 
sample collection times being different between even and odd numbered sites. The PK 
collection timepoints and associated windows are detailed by visit in Table 9 below: 


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Table 9: PK Collection Timepoints and Window Relative to Ensifentrine Dosing 
Visit 
Number 
Visit 
Week 
Odd Sites [a] 
Even Sites [a] 
2 
6 
1.5 hours[b] 
4 (± 1) hours 
1.0 (± 0.5) hours 
2.5 (± 0.5) hours 
3 
12 
0.5 (± 0.25) hours 
3 (± 0.5) hours 
6 to 8 hours 
Pre-dose (-0.5 hours) 
4 to 6 hours 
8 to 12 hours 
5 
24 
Pre-dose (-0.5 hours) 
1.0 (± 0.5) hours 
Pre-dose (-0.5 hours) 
1.5 hours[b] 
ET/ 
withdrawal 
 
At the time of visit [c] 
At the time of visit [c] 
a. Sample collection range is provided for samples scheduled on Week 12 at  4 hours to provide flexibility 
for collection at the later sampling time points. 
b. The samples scheduled at 1.5 hours post-dose should be collected immediately (within 10 minutes) 
following the simultaneously scheduled ECG collection. 
c. This sample should only be collected if the patient has received ensifentrine within the last 48 hours. 
Abbreviations: ET=early termination; ECG=electrocardiogram; PK=pharmacokinetic 
Approximately 4 mL of whole blood per time point for PK will be collected. The exact 
date/time of each blood sample collection will be recorded in the patient’s eCRF. Blood 
samples for PK analyses should be collected in appropriate blood collection tubes as 
defined in the PK laboratory manual. The Sponsor or designee will provide the 
Investigator with a manual containing details for the preparation of blood samples to be 
collected. Detailed sample collection, labeling, storage, and shipment information will be 
described in the Laboratory Manual. 
8.5.10.2 
Recording of Medications and Information Specific to the Pharmacokinetic 
Procedures and Sample Analysis 
Paper Diary 
In addition to the information on blinded study medication, LAMA and/or LABA 
medication, and rescue albuterol/salbutamol collected in the e-Diary (Section 8.5.4) and 
concomitant medication information collected as described in Section 6.7, the information 
in Table 10 will be collected by the patient on a paper diary for the two (2) full calendar 
days prior to each PK collection visit. This information will be transcribed into the PK 
eCRF module, the concomitant medication eCRF module, or both, as applicable: 


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Table 10: Recording of Medications and Information Specific to Pharmacokinetics 
Medication and Time Period 
Collect 
For all medications that are administered for the 
2 full calendar days immediately prior to each PK 
collection visit: 
Medication name, dose (eg. Dose unit, route, 
schedule/frequency) 
Start Date and Start Time 
Date and Time of all doses taken prior to 
collection of the PK Sample 
Blinded study medication administered the 
morning and the evening for the two full calendar 
days immediately prior to the PK collection visit: 
Date 
Nebulization Start Time 
Nebulization End Time  
Any missed or partially administered (eg, 
nebulization not complete) blinded study 
medication administration timepoints within 2 
days prior to a PK collection visit.  
Abbreviations: PK=pharmacokinetic 
Collection of medication and associated information in the eCRF 
Medication and associated information collected in eCRF modules will include, but not 
be limited to the following information: 
x Subject Number/Visit Number/Study Week 
x All medications administered for the 2 calendar days immediately prior to each 
PK collection visit and administered during the PK collection visit: 
- Medication information including but not limited to the medication name, 
dose, dose unit, route, schedule/frequency 
- The start date and start time or ‘continuing.’ ‘Continuing’ can be selected if: 
 1) the medication name, dose, dose unit, route, schedule/frequency are 
documented exactly the same as documented in the concomitant 
medication eCRF,  
 2) the start date is prior to the 2 days before the PK collection visit, and  
- The stop date(s) and stop time(s) of the last dose taken prior to collection of a 
PK sample at any PK collection sampling timepoint on the day of a PK 
collection visit. 
x Blinded study medication history for the 2 calendar days immediately prior to 
each PK collection visit which includes, but are not limited to the details below: 
- The start date, nebulization start time, and nebulization end time of blinded 
study medication each morning and each evening.  
- Response to the question at each dosing time “Was administration of the 
blinded study medication completed (yes/ no)?” If the response is “no,” the 
reason for interruption should be documented. 
- Response to the question “Were there any missed or partially administered 
(eg, nebulization not complete) blinded study medication administration 
timepoints (yes or no)?” If the response is “yes,” the length of the interruption 
should be recorded in minutes and the reason for the interruption should be 
documented. 


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x Dosing of blinded study medication during each PK collection visit must include 
the following information as applicable for a given PK collection visit:  
- Morning Dose:  
- The start date and nebulization start time of blinded study medication. 
- Response to the question “Was administration of the blinded study 
medication completed (yes/ no)?” If the response is “no,” the reason 
for interruption should be documented. 
x PK Sample Collection 
- The date and time of each PK blood sample collected for PK analysis must 
be recorded. 
8.5.10.3 
Determination of Drug Concentration 
Samples for the determination of plasma PK for ensifentrine will be analyzed on behalf of 
the Sponsor using appropriate validated analytical methods. Full details of the 
bioanalytical methods will be described in a separate Bioanalytical Report. All samples 
from patient assigned to treatment with ensifentrine during the study that are within the 
known stability of ensifentrine at the time of planned analysis by the bioanalytical 
laboratory will be analyzed; samples obtained from placebo patients will not be analyzed. 
Drug concentration information that may unblind the study will not be reported to study 
centers or blinded personnel until the study has been unblinded. Only the bioanalytical 
laboratory and unblinded biostatistician(s) who generate the randomization schedule may 
be unblinded to patient treatment assignment prior to database lock (DBL). 
8.5.11 
Genotyping/ Phenotyping 
Genetic variation may impact a patient’s response to study treatment, susceptibility to, 
and severity and progression of disease. Variable response to study treatment may be due 
to genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular subtype of 
the disease being treated.   
Since it is known that ensifentrine is metabolized by cytochrome P450 (CYP) isozymes 
2C9 (primary) and also 2D6, assessment of genetic variation will include the assessment 
of CYP2C9 phenotype and CYP2D6 phenotype of patients.  
The results of this pharmacogenetic research will be reported separately and will not form 
part of the Clinical Study Report (CSR). 
Approximately 8 mL of blood for DNA isolation will be collected from patients who have 
consented to participate in the genotyping/phenotyping analysis component of the study. 
Participation is optional. Patients who do not wish to participate in the genotyping/ 
phenotyping research may still participate in the study.  
In the event of DNA extraction failure, a replacement genotyping/phenotyping blood 
sample may be requested from the patient. Signed informed consent will be required to 


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obtain a replacement sample unless it was included in the original genotyping/ 
phenotyping consent. 
These samples may be stored for up to 1-year after the genotyping/ phenotyping analysis 
has been completed. 
Details on processes for collection and shipment and destruction of these samples can be 
found in the genotyping/phenotyping laboratory instructions. 
8.5.12 
Biomarker Collection 
Collection of samples for other biomarker research is also a part of this study. 
Approximately 10 mL of blood for biomarker research is required and will be collected 
from all patients in this study as specified in the SoA (Section 1.3). 
Analysis of interleukin (IL)-6, IL-8, and C-reactive protein (CRP) will be conducted to 
evaluate the effect of ensifentrine on inflammatory biomarkers (Section 11.3). 
8.6 
Disaster Contingencies 
Prospective planning is required for this study due to the increased risk of a regional or 
global disaster (eg pandemic, natural disaster, terrorism). 
8.6.1 
Site-Level Disaster Plan 
It is recommended that investigative sites prepare a written Disaster Plan for this study 
which describes how the site will manage patient activities and procedures in the event 
that site is not operating normally, site equipment is not available, and/or patient(s) 
cannot attend an in-clinic study visit. This written Disaster Plan could include but not be 
limited to a description of how the following activities and procedures will be conducted 
for remote visits or phone/video contact: 
x
Phlebotomy collection
x
Vital signs collection
x
Blinded study medication distribution
x
Rescue albuterol/salbutamol distribution


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8.6.2 
Unscheduled Visit 
8.6.2.1 
Blinded Study Medication and/or Rescue Medication 
If blinded study medication and/or rescue albuterol/salbutamol cannot be dispensed at a 
scheduled clinic visit or if a patient will likely run out before attending a scheduled clinic 
visit, the medication may be dispense alternatively in line with according to local 
requirements. 
Blinded study medication and/or rescue medication can be collected, and compliance can 
be assessed at the next in-clinic visit. 
8.6.2.2 
Study Supplied Nebulizer Replacement 
If a study supplied nebulizer cannot be distributed at a scheduled clinic visit or if the 
study supplied nebulizer requires replacement before attending a scheduled clinic visit, 
the study supplied nebulizer may either be picked-up by the patient directly outside the 
clinic, sent to the patient’s home via trackable mail/postal service (unless restricted by 
local requirements), or given to the patient at the next scheduled visit. 
8.6.2.3 
Other Contingencies 
x eDiary: In the event of a problem with the eDiary or the paper diary for recording 
of medications and information specific to the PK procedures and sample analysis, 
a replacement eDiary and/or paper diary may either be picked-up by the patient 
directly outside the clinic or sent to the patients home according to local 
requirements. 
x Rescue medication (albuterol/salbutamol): In the event that albuterol/salbutamol is 
in short supply/not available in a given country or region, another medication may 
be substituted following consultation and approval by the Medical Monitor (unless 
restricted by local requirements). 
x COVID-19 Testing for Active Disease: A COVID-19 test may be conducted 
anytime a patient is suspected/exhibiting signs of active disease. If a COVID-19 
test is positive for active disease, see Section 7.1.6 for next steps and Section 8.7.9 
for AE and other reporting. 
x Information relating to disruption of study participation due to COVID-19 will be 
captured in the eCRF (eg, reason for implementation of contingency measures, 
reason for missing data and relationship to COVID-19). 
8.7 
Adverse Events 
The definitions of an AE or SAE can be found in Section 11.7.  
Adverse events will be reported by the patient.  
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 patient to discontinue the study (Section 11.7).  


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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 one exception. Serious Adverse Events assessed as 
related to study participation (eg, 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 Section 11.7. 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 patient 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 AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Section 11.7. 
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 patient 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 
patient at subsequent visits/contacts. All SAEs, will be followed until resolution, 
stabilization, the event is otherwise explained, through the follow-up contact, or the 
patient is lost to follow-up (as defined in Section 7.4). Further information on follow-up 
of AEs and SAEs is given in Section 11.7. 
8.7.4 Regulatory Reporting Requirements for SAEs 
x Prompt notification by the Investigator to the Sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of patients and the 
safety of a blinded study medication under clinical investigation are met.  


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x The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a blinded 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.  
x 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.  
x 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 
x Details of all pregnancies in female patients will be collected after the start of blinded 
study medication and until 30 days after the last dose of blinded study medication.  
x 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 
Section 11.8. 
x Abnormal pregnancy outcomes (eg spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.7.6 Adverse Events of Special Interest 
Adverse events of special interest have not been identified for ensifentrine.  
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 will 
not be collected as an AE unless they meet the definition of an SAE. COPD exacerbations 
should be captured on the COPD exacerbation eCRF (See Section 11.6). 
8.7.8 Medical Device Incidents (Including Malfunctions) 
The PARI LC Sprint nebulizer and PARI Vios PRO Aerosol Delivery System, and PARI 
BOY compressor or equivalent are being provided for use in this study for administration 
of blinded study medication.  
In order to fulfill regulatory reporting obligations worldwide, the Investigator is 
responsible for the detection and documentation of events meeting the definitions of 
incident or malfunction that occur during the study with such devices. 
The definition of a medical device incident, examples of incidents, and instructions for 
documenting and reporting medical device incidents are provided in Section 11.10. 


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Medical Device incidents fulfilling the definition of an AE/SAE will also follow the 
processes outlined in Section 11.7. 
8.7.8.1 
Time Period for Detecting Medical Device Incidents 
x Medical device incidents or malfunctions of the device that result in an incident 
will be detected, documented, and reported during all periods of the study in 
which the medical device is used. 
x If the Investigator learns of any incident at any time after a patient has been 
discharged from the study, and such incident is considered reasonably related to a 
medical device provided for the study, the Investigator will promptly notify the 
Sponsor. 
x The method of documenting Medical Device Incidents is provided in 
Section 11.10. 
8.7.8.2 
Follow-up of Medical Device Incidents 
x All medical device incidents involving an AE will be followed and reported in the 
same manner as other AEs (see Section 11.7). This applies to all patients, 
including those who discontinue blinded study medication. 
x The Investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality of 
the incident. 
x New or updated information will be recorded on the originally completed form 
with all changes signed and dated by the Investigator. 
8.7.8.3 
Prompt Reporting of Medical Device Incidents to Sponsor/Sponsor 
Representative 
x Medical device incidents will be reported to the Sponsor/Sponsor’s designee 
within 24 hours after the Investigator determines that the event meets the protocol 
definition of a medical device incident. 
x The Medical Device Incident Report Form will be sent to the Sponsor/Sponsor’s 
designee by the same method as used for SAE reporting (Section 11.7).  
x Contacts for Medical Device Incident reporting are the same as SAE reporting and 
can be found in Section 11.2 on the Medical Monitor Contact Information Page.  
8.7.8.4 
Regulatory Reporting Requirements for Medical Device Incidents 
x The Investigator will promptly report all incidents occurring with any medical 
device provided for use in the study in order for the Sponsor/Representative to 
fulfill the legal responsibility to notify appropriate regulatory authorities and other 
entities about certain safety information relating to medical devices being used in 
clinical studies. 


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x The Investigator, or responsible person according to local requirements (eg, the 
head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC. 
8.7.9 
COVID-19 Positive for Active Disease 
An AE/SAE of positive COVID-19 active disease should be documented as any AE/SAE 
occurring in this study would be documented per the guidance throughout this section 
(Section 8.7). In addition, local guidelines for reporting COVID-19 to local and/or health 
authorities should be followed. 
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.  
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.  
 


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9.0 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
The aim of this study is to show superiority of ensifentrine over placebo regarding 
selected efficacy measures. The null hypothesis to be tested for each endpoint will be that 
there is no difference between ensifentrine and placebo, against the alternative hypothesis 
that ensifentrine is better than placebo. All tests will be two-sided at a 5% significance 
level. Primary and key secondary endpoints used for claims will be tested in a sequential 
order to preserve the alpha level. Testing will stop once a not significant result is 
achieved. Test order will be FEV1 AUC0-12h at 12 weeks, peak FEV1 at 12 weeks, weekly 
mean E-RS total symptom score at week 24, SGRQ total score at Week 24, morning 
trough FEV1 at Week 12, FEV1 AUC0-4h at 12 weeks and proportion of SGRQ responders 
at 24 weeks. 
9.2 
Sample Size Determination 
Approximately 800 patients will be randomized. The standard deviation for the change in 
FEV1 AUC0-12h is estimated to be 250 mL. With a 2-sided test at a 5% significance level 
and 500 vs. 300 evaluable patients in the two groups, there will be an 90% power to 
detect a true difference of 59 mL between the treatments. If the withdrawal rate at 
24 weeks exceeds 25% overall, additional patients may be randomized to the study to 
compensate for the loss of data. 
9.3 
Populations for Analyses 
mITT population: will include all patients randomized and treated with blinded study 
medication in the study. Patients will be handled as randomized in the mITT analyses. 
PP population: will include all patients in the mITT without any major/important protocol 
deviations considered to have an impact on efficacy assessments. Reasons for exclusion 
will be specified at a Blind Data Review Meeting prior to database lock (DBL) and may 
include violations of inclusion/exclusion criteria, violations of withdrawal criteria, 
incorrect randomization, use of prohibited medication and non-compliance. 
Safety set: will include all patients randomized and treated in the study. Patients will be 
handled by actual treatment in the safety analyses. 
Pharmacokinetic set: will include all patients randomized to ensifentrine, receive at least 
one dose of ensifentrine, and have at least one quantified ensifentrine concentration at a 
scheduled PK time point after the start of dosing without important protocol violations 
and/or events with potential to affect PK concentrations. 
The population PK analysis set will be defined in the modeling analysis plan.  


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9.4 
Statistical Analyses 
9.4.1 Efficacy Analyses 
Efficacy analysis will primarily be performed on the mITT population. The primary 
endpoint and key secondary endpoints will also be evaluated using the PP population as a 
sensitivity analysis. Impact of imputations and various baseline characteristics will also 
be checked.  
The primary endpoint, change from baseline in FEV1 AUC0-12h at Week 12, will be 
compared between treatments using an analysis of covariance (ANCOVA) model 
adjusting for treatment, region, background medication strata, and smoking status as 
factors and baseline FEV1 as covariate. The estimated treatment difference with 95% 
confidence interval and associated (two-sided) p-value will be presented. Missing data 
will be imputed to get as close to the mITT population as possible. Primarily imputation 
will be based on data collected at visits performed after treatment withdrawal or at early 
termination visits even if outside visit window. When no such data is available, 
imputation will primarily be done using multiple imputation based on baseline 
characteristics and secondarily, as a sensitivity analysis, by the average change in the 
opposite treatment group as randomized to as a worst-case scenario. Further details on the 
handling of missing data will be given in the Statistical Analysis Plan. 
Key secondary endpoints, FEV1 AUC0-4h, peak FEV1, morning trough FEV1, SGRQ total 
score and weekly mean E-RS total score, and other continuous secondary or exploratory 
endpoints will be assessed repeatedly during the study and the change from baseline to 
pre-specified time point of evaluation will be compared by similar ANCOVA models 
adjusting for treatment, region, background medication strata and smoking status as 
factors and baseline as covariate. Data collected at visits performed after treatment 
withdrawal or at early termination visits will be used in the analyses. Remaining missing 
data will primarily be imputed using multiple imputation based on baseline characteristics 
and data collected at post-randomization visits. Since assessed repeatedly, in contrast to 
primary endpoint, these data will also be analyzed for sensitivity by mixed model 
repeated measures models with treatment, visit and treatment by visit interaction as 
factors, baseline as covariate, subject as random factor and covariance structure by visit. 
The proportion of responders on the SGRQ, patients with an improvement of at least 4 
units, will be compared between treatment groups using a logistic regression model with 
fixed factors treatment, region, and background medication strata, and smoking status. 
Imputation of missing data will be done similar as for continuous endpoints. A sensitivity 
analysis will be performed in which patients with missing data at the required visit will be 
considered non-responder in the analysis.  
The time to first COPD exacerbation during the 24 or 48 week treatment period, 
depending on stratification, will be visualized using a Kaplan-Meier plot and compared 
between treatment groups using the log-rank test, stratified by region, background 
medication strata, and smoking status. As a secondary evaluation a Cox’s proportional 


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hazards model will be used with the same factors. Patients without exacerbations will be 
censored at last day in the treatment period, including period of recording after possible 
treatment withdrawal. The treatment difference in the Cox model will be expressed as a 
hazard ratio. Assumption of proportional hazards will be checked. The number of COPD 
exacerbations during the 24- or 48-week treatment period will be compared between 
treatments using a negative binomial model adjusting for treatment, region, background 
medication strata and smoking status and further using the log exposure time as an offset. 
The treatment difference from the negative binomial model will be expressed as an 
annualized risk ratio. 
Subgroup analyses will be performed for the primary endpoint and selected secondary 
endpoints by gender, age-class (below or above 65 years), region, background medication 
strata, smoking status, ICS use, known chronic bronchitis, and FEV1 reversibility at 
baseline (12% and  200 mL). 
9.4.2 
Safety Analyses 
Safety analysis will be based on the safety set.  
Adverse events will be analyzed using quantitative and qualitative measures. Treatment-
emergent adverse events will be summarized by treatment group for all AEs, related AEs, 
serious adverse events, deaths, adverse events leading to discontinuation of blinded study 
medication or to withdrawal from study, adverse events of different severity and adverse 
events of different chronicity. Treatment-emergent adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) and summarized by system 
organ class and preferred term for each treatment group. For selected adverse events, time 
to first event will be visualized using Kaplan-Meier plots. 
Laboratory data will be summarized by each visit including change from baseline. The 
number of normal, abnormal not clinically significant and abnormal clinically significant 
values on each parameter will be summarized for change over study using shift tables. All 
data will be listed and values outside reference ranges will be highlighted in the listings. 
Vital signs and continuous parameters from the ECGs will be summarized by each visit 
including change from baseline. Values outside pre-specified ranges (low, high) or 
changes exceeding pre-specified limits will be summarized by visit for each parameter. 
The number of normal, abnormal not clinically significant and abnormal clinically 
significant values on the ECG overall evaluation will be summarized for change over 
study using shift tables. All data will be listed and values outside reference ranges will be 
highlighted in the listings.  
9.4.3 
Other Analyses 
The patient flow including total number of screened patients, number of randomized 
patients, completers, withdrawn patients (including reason for withdrawal) and patients 


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included in each of the analysis sets will be summarized by treatment group and for the 
total. 
The number of patients with major protocol deviations will be summarized by category of 
violation and by treatment group 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 each treatment group and for the total number of randomized patients. Medical history 
will be coded using MedDRA and summarized by system organ class and preferred term 
for each treatment group. Prior medications will denote medications used prior to first 
dose of study drug independent of if stopped at randomization or not. Concomitant 
medications will denote medications started prior to but continuing after randomization or 
medications with a start date at or after the randomization date. Prior and concomitant 
medications will be summarized separately by Anatomical Therapeutic Chemical (ATC) 
levels 2 and 4. 
Compliance to blinded study medication will be computed based on the number of 
ampules/foil pouch count dispensed and returned. Non-compliance will be defined as a 
compliance value less than 70% over the full study period. Secondarily, compliance will 
also be computed based on recording of study drug intake in the diary. 
The impact of COVID-19 on the study participation of all patients will captured on a 
separate eCRF page and include items such as attendance at in-clinic study visits. Details 
of presentation will be outlined in the Statistical Analysis Plan. 
9.4.4 
Missing Data 
All data collected after treatment withdrawal will be used in the analyses. Patients 
withdrawn from study will perform an End-of-Study visit after decision to withdraw the 
patient has been made. Data collected at such visits will be used for analysis even if 
outside the visit window for the endpoint. Remaining missing data will primarily be 
imputed using multiple imputation based on baseline characteristics and data collected at 
post-randomization visits. In addition, a worst-case scenario using the average change in 
the opposite treatment group will be used for imputation as a sensitivity analysis. For the 
responder analysis of SGRQ, patients with no available data for imputation will be 
considered non-responders as a sensitivity analysis. In exacerbation analyses, patients are 
included with data collected up to last day in the treatment period/period of recording 
following treatment withdrawal. 
9.4.5 
Pharmacokinetics 
All reported plasma concentrations will be listed and summarized using appropriate 
descriptive statistics. Graphical presentations of concentration data will be provided, if 
appropriate. 
 


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Ensifentrine concentrations will be used for a population PK analysis of ensifentrine. The 
pharmacokinetics of ensifentrine will be characterized by nonlinear mixed effects 
modeling based on sparse sampling. From the established model, the influence of various 
demographic covariates (eg, body weight, gender, genotype) and other patient-specific 
factors on ensifentrine exposure may be assessed. The data from this study may be 
combined with data collected from other studies for a pooled meta-analysis using 
modeling and simulation to estimate PK parameters as well as exposure – response 
(safety) correlations. The population PK (and population PK-PD, if performed) analyses 
will be performed in accordance with a separate modeling data analysis plan and will be 
reported outside of the clinical study report. 
9.5 
Interim Analyses 
There will be no formal interim analysis in the study. Blinded data will be monitored 
continuously and the assumptions for the variability in data checked as well as the 
withdrawal rate. 
 


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10.0 REFERENCE LIST 
Anthonisen NR, Manifreda J, Warren P, Hershfield ES, Harding GK, Nelson NA. 
Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern 
Med. 1987;106:196-204.  
Celli BR, MacNee W; ATS/ERS Task Force. Standards for the diagnosis and treatment of 
patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 
2004;2:932-946. 
Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. 
Criteria Committee. Nomenclature and criteria for diagnosis of diseases of the heart and 
great vessels. 9th ed. Boston, MA: Lippincott Williams and Wilking; March 1, 1994. 
Evaluating-Respiratory Symptoms User Manual (E-RS; v. 3.0). EXACT@2013, Evidera, 
Inc. All rights reserved. 
Fletcher CM. Standardised questionnaire on respiratory symptoms: a statement prepared 
and approved by the MRC Committee on the Aetiology of Chronic Bronchitis (MRC 
breathlessness score). BMJ. 1960;2:1665. 
Franciosi LG, Diamant Z, Banner KH, et al. Efficacy and safety of RPL554, a dual PDE3 
and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic 
obstructive pulmonary disease: findings from four clinical trials. Lancet Respiratory 
Medicine. 2013;1:714–727. 
The Global Initiative for Chronic Obstructive Lung Disease (GOLD): The global strategy 
for the diagnosis, management and prevention of Chronic Obstructive Pulmonary Disease 
(updated 2020). http://www.goldcopd.org. Accessed November 13, 2019. 
Hankinson JL, Odencrantz JR, Fedan KB. Spirometry reference values from a sample of 
the general U.S. Population. Am J Respir Crit Care. 1999;159:179-187. 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen 
overdose and acute liver failure. Drug Metab Dispos. 2009;37(8):1779-1784. 
Jones PW, Quirk FH, Baveystock CM. The St. George’s Respiratory Questionnaire. Resp 
Med 1991;85(suppl B): 2531. 
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Deny P, Gault E. 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. 
J Clin Microbiol. 2005; 43(5):2363-2369. 
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular 
filtration rate. Ann Intern Med. 2009;150(9):604-612. 


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Mahler DA, Weinberg, DH, Wells CK, Feinstein AR. The measurement of dyspnea: 
Contents, interobserver agreement and physiologic correlates of two new clinical indices. 
Chest. 1984;85:751-758. 
Meguro M, Barley EA, Spencer S et al. Development and validation of an improved 
COPD-Specific Version of the St. George Respiratory Questionnaire. Chest. 
2007;132:456-463. 
Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 
2005;26(2):319-338. 
Singh D, Abbott-Banner K, Bengtsson T, Newman K. The short-term bronchodilator 
effects of the Dual Phosphodiesterase 3 and 4 Inhibitor RPL554 in COPD. Eur Respir J. 
2018; 52: 1801074. 
Singh D, Martinez FJ, Watz H, Bengtsson T, Maurer BT. A Dose-Ranging Study of the 
Inhaled Dual Phosphodiesterase 3 and 4 Inhibitor ensifentrine in COPD. Respir Res. 2020; 
10; 21(1); 47. 
Szende A, Janssen B, Cabases J. Self-Reported Population Health: An International 
perspective based on EQ-5D [Internet]. Dorrecht (NL): Springer; 2014. Available from 
https://www.ncbi.nlm.nih.gov/books/NBK500356/ doi:10.1007/978-94-007-7596-1. 
Verona Pharma plc. Ensifentrine Clinical Investigators Brochure v. 20.0. 3Feb2021. 
Verona Pharma plc. RPL554-009-2015 Clinical Study Report. 10Feb2017. 
Verona Pharma plc. RPL554-CO-202 Clinical Study Report. 25Apr2019. 
Verona Pharma plc. RPL554-CO-203 Clinical Study Report. 29Mar2019. 
Verona Pharma plc. RPL554-CO-205 Clinical Study Report. 04May 2020. 


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11.0 APPENDICES 


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11.1 Appendix 1: Abbreviations 
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
Anti-HBc 
Hepatitis B core antibody 
Anti-HBs 
Hepatitis B surface antibody 
AST
Aspartate aminotransferase
ATC 
Anatomical Therapeutic Chemical Classification System 
ATS 
American Thoracic Society 
AUC 
Area under the curve 
AV
Atrioventricular
BDI 
Baseline dyspnea index 
BID
Twice daily
bmp 
Beats per minute 
CFR 
Code of Federal Regulations 
BMI 
Body mass index 
CI
Confidence interval
COPD 
Chronic obstructive pulmonary disease 
COVID-19 
Coronavirus disease 2019 
CSR 
Clinical Study Report 
CRP
C-reactive protein
CXR
Chest X-ray
CT
Computed tomography
CV 
DBL 
Coefficient of variation
Data Base Lock
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF 
Electronic case report form
e-Diary
Electronic diary
EQ-5D-5L
EuroQol-5-Domain Questionnaire
E-RS
Evaluating Respiratory Symptoms
ERS
European Respiratory Society
ERT
eResearch Technology
FAS
Full Analysis Set
FEV1
Forced expiratory volume in 1 second


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FSH 
Follicle stimulating hormone 
FVC
Forced vital capacity
GCP 
Good Clinical Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HBsAg 
Hepatitis B surface antigen 
HCV
Hepatitis C virus
HIV 
Human immunodeficiency virus 
HRT
Hormonal replacement therapy
HRU
Healthcare resource utilization
IB
Investigator’s brochure
IC
Inspiratory capacity
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICS
Inhaled corticosteroid(s)
IEC
Independent Ethics Committee 
IgM
Immunoglobulin M
IL
Interleukin
INR
International normalized ratio
INN 
International Non-proprietary Name 
IRB
Institutional Review Board
IRT
Interactive Response Technology
IT
Information technology
LABA
Long-acting ȕ2-agonist 
LAHB 
Left anterior hemiblock 
LAMA
Long-acting muscarinic antagonist 
LDPE 
Low density polyethylene 
LPHB 
Left posterior hemiblock 
LOCF 
Last observation carried forward 
LS
Least square
MAD 
Multiple ascending dose(s) 
MCID
Minimum clinically important difference
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT
Modified Intent-to-Treat
mMRC 
Modified Medical Research Council 
MMRM 
Mixed model for repeated measures 
NYH
New York Health


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PDE 
Phosphodiesterase 
PCR 
Polymerase Chain Reaction 
PGAC 
Patient Global Assessment of Change 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol 
PT 
Preferred term 
QoL 
Quality of life 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QTL 
Quality tolerance limit 
RBBB 
Right bundle branch block 
RNA 
Ribonucleic Acid 
SABA 
Short-acting ȕ2 agonists 
SAE 
Serious adverse event 
SAMA 
Short-acting muscarinic antagonists 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOA 
Schedule of Activities 
SOC 
System organ class 
SGRQ 
St George’s Respiratory Questionnaire 
SUSAR 
Suspected unexpected serious adverse reaction 
TDI 
Transition Dyspnea Index 
TEAE 
Treatment-emergent adverse event 
UK 
United Kingdom 
ULN 
Upper limit of normal 
USA 
United States of America 
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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11.2 Appendix 2: Regulatory, Ethical, and Study Oversight 
Consideration 
Regulatory and Ethical Considerations  
x
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.
x
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.
x
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 patients.
x
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.
x
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 (Section 11.12).
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 patients for any potential 
injury or death caused by the study.  
Informed Consent Process 
x
The Investigator or his/her representative will explain the nature of the study to the
patient and/or the patient’s legally authorized representative and answer all questions
regarding the study.
x
Patients must be informed that their participation is voluntary. Patients 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.
x
The medical record must include a statement that written informed consent was
obtained before the patient 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.
x
A copy of the original ICF(s) must be provided to the patient or the patient’s legally
authorized representative.
x
ICF New Information: New information since the time of the original consent can be
presented to patients in format(s) or method(s) including, but not limited to those
listed below unless excluded by local requirements:
-
Revised consent document
-
Addendum to consent


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-
Memo or other communication to patients
-
Orally by phone or in person
Documentation of the method the new information was presented to the patient along 
with the name of the site staff member and date the new information was presented to the 
patient must be documented in the patient’s source document. 
Data Protection 
x
Patients will be assigned a unique identifier by the Sponsor. Any patient records or
datasets that are transferred to the Sponsor will contain the identifier only; patient
names or any information which would make the patient identifiable will not be
transferred.
x
The patient 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 patient.
x
The patient 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.
x
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.
x
The Sponsor/Sponsor’s designee will not provide individual genotype results to
patients, any insurance company, any employer, their family members, general
physician, or any other third party, unless required to do so by law.
x
Extra precautions are taken to preserve confidentiality and prevent genetic data being
linked to the identity of the patient. In exceptional circumstances, however, certain
individuals might see both the genetic data and the personal identifiers of a patient.
For example, in case of a medical emergency, the Sponsor or representative physician
or an Investigator might know a patient’s identity and also have access to his or her
genetic data. Also, regulatory authorities may require access to the relevant files.
Administrative Structure  
The study administrative structure is in Table 11 and the Medical Monitor and the 24-
hour urgent medical contact information is in Table 12. 




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Dissemination of Clinical Study Data  
For studies conducted in the United States, the results of the study are required to be 
reported on clinical trials.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  
x
All patient 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
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 patient by physically or electronically signing the eCRF.
x
The Investigator must maintain accurate documentation (source data) that supports the
information entered in the eCRF.
x
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and
regulatory agency inspections and provide direct access to source data documents.
x
The Sponsor or designee is responsible for the data management of this study
including quality checking of the data.
x
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 patients 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.
x
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.


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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 patients. 
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).  
x
Source documents provide evidence for the existence of the patient and substantiate
the integrity of the data collected. Source documents are filed at the Investigator’s
study center.
x
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.
x
Definition of what constitutes source data can be found in ICH E6(R2) Section 1.51.
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:  
x
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.
x
Inadequate recruitment of patients by the Investigator.
x
Discontinuation of further study medication development.
Publication Policy  
The data generated by this study are confidential information of the Sponsor. 


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11.3 Appendix 3: Clinical Laboratory Tests 
The tests detailed in Table 13 will be performed by the central laboratory. 
x
Fasting is not required prior to laboratory testing.
x
Laboratory tests should be collected prior to dosing with blinded study
medication.


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Table 13: Protocol Required Safety 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 
Bilirubin, direct 
Leukocyte differential count 
Pregnancy test for Women1 
Bilirubin, indirect 
Neutrophils, absolute 
COVID-19 testing2 
Bilirubin, total 
Neutrophils, segs (%) 
Calcium
Neutrophils, bands (%) 
Biomarkers 
Chloride
Basophils (%) 
IL-6
CO2 content/Bicarbonate 
Eosinophils (%) 
IL-8 
Creatinine 
Eosinophils, absolute 
C-Reactive Protein (CRP)
Creatine phosphokinase (CPK), 
total 
Lymphocytes (%) 
Gamma glutamyl transferase 
(GGT) 
Monocytes (%) 
Genotyping 
Glucose
RBC count
CYP2C9
Phosphorus
CYP2D6
Potassium 
Protein, total serum 
Sodium
Urea nitrogen (BUN) 
Uric Acid 
1 Pregnancy test for women of childbearing potential. Serum pregnancy test will be conducted at 
visits where Chemistry and Hematology are performed. Urine pregnancy test will be conducted at 
Visit 1 and visits where no other central laboratory testing is being conducted. 
2COVID-19 test (optional) may be performed locally. 
Abbreviations: CYP=cytochrome P450; CYP2C9=CYP isoenzyme 2C9; CYP2D6=CYP 
isoenzyme 2D6; HBsAg= hepatitis B surface antigen; anti-HBs= hepatitis B surface antibody; 
anti-HBc=total hepatitis B core antibody; IL=interleukin. 
Additional Instructions: 
x
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.
x
If additional tests (Except COVID-19 test) are required to be completed urgently by a
local lab to assess an adverse event or for any other reason, these labs should also be


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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. 
x
COVID-19 test may be performed locally.
x
The laboratory reports must be signed by the investigator who reviewed the report and
filed with the source documents.
x
Clinically significant abnormal laboratory findings are those that are not associated
with the patient’s healthy status and judged by the Investigator to be more severe than
expected.
x
All laboratory tests with values considered clinically significantly abnormal 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 patient
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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11.4 Appendix 4: ECG Exclusion Criteria 
A 12-lead ECG recording at Screening showing any of the following abnormalities: 
x
Sinus tachycardia 110 bpm (Sinus tachycardia 110 bpm should be confirmed by 2
additional readings at least 5 minutes apart.).
x
Sinus bradycardia < 45 bpm (Sinus bradycardia < 45 bpm should be confirmed by 2
additional readings at least 5 minutes apart).
x
Multifocal atrial tachycardia
x
Junctional (heart rate >100 bpm)
x
Supraventricular tachycardia (>100 bpm)
x
Ventricular tachycardia
x
Atrial fibrillation with rapid ventricular response (rate >100 bpm).
x
Atrial flutter
x
Frequent VPCs (>2 on a 10 sec ECG)
x
Ventricular flutter
x
Ventricular fibrillation
x
Torsades de Pointes
x
Wide QRS tachycardia (diagnosis unknown)
x
Electrical alternans
x
Pacemaker or ICD
x
Idioventricular rhythm – heart rate <100 bpm
x
Mobitz type II second degree or third degree atrioventricular (AV) block.
x
AV dissociation
x
Bifascicular Block (RBBB plus LAHB or RBBB plus LPHB)
x
Left bundle branch block
x
Wolff Parkinson White Syndrome
x
Brugada Syndrome pattern
x
QTcF  480 msec when RBBB is present
x
Patients 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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11.5 Appendix 5: ECG Withdrawal Criteria 
All ECGs conducted or overread after a patient has been randomized will be subject to 
ECG Withdrawal Criteria (including the pre-dose ECGs at Visit 1 and subsequent visits). 
A patient 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 patients from study treatment for any other clinically 
significant finding (Section 7.0). Triplicate ECGs (over a brief period of time) should be 
performed on patients 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 patient should also take 
into consideration the patient’s medical history and prior/baseline ECGs. 
x
Sinus tachycardia 120 bpm (Sinus tachycardia 120 bpm should be confirmed by 2
additional readings at least 5 minutes apart.).
x
Sinus bradycardia < 37 bpm (Sinus bradycardia < 37 bpm should be confirmed by 2
additional readings at least 5 minutes apart).
x
Increase in heart rate 40 bpm relative to baseline.
x
Multifocal atrial tachycardia
x
Supraventricular tachycardia (>100 bpm)
x
Atrial fibrillation with rapid ventricular response (rate >120 bpm).
x
Atrial flutter with rapid ventricular response (rate >120 bpm).
x
Ventricular tachycardia (non-sustained, sustained, polymorphic or monomorphic)
x
Ventricular flutter
x
Ventricular fibrillation
x
Torsades de Pointes
x
Evidence of Mobitz type II second degree or third degree atrioventricular (AV) block.
x
AV dissociation
x
2:1 AV block
x
Bifascicular Block (RBBB plus LAHB or RBBB plus LPHB)
x
An increase in QTcF >60 msec from baseline ECG
x
Uncorrected QT >600 msec
x
For patients 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).
x
For patients 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).
x
Myocardial infarction (acute or recent) Note: Evidence of an old resolved Myocardial
infarction is not exclusionary.


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11.6 
Appendix 6: Guidelines for Identifying COPD Exacerbation 
11.6.1 COPD Exacerbation Signs and Symptoms 
The following are signs and symptoms of an exacerbation of COPD (Anthonisen, 1987): 
 
Worsening of two or more of the following major symptoms for at least two consecutive 
days: 
x Dyspnea 
x Sputum volume 
x Sputum purulence (color) 
OR 
Worsening of any one major symptom together with any one of the following minor 
symptoms for at least two consecutive days: 
x Sore throat 
x Colds (nasal discharge and/or nasal congestion) 
x Fever (oral temperature >37.5 °C) without other cause 
x Increased cough 
x Increased wheeze 
Patients experiencing worsening COPD symptoms for greater than 24 hours should: 
x Contact the Investigator/study site immediately if they feel they need medical 
assistance.  
x If the patient is unable to contact the Investigator/ study site, they should contact 
their primary care physician (or other health care practitioner as required) and 
contact the study site as soon as possible. 
x Continue to record their symptoms and rescue albuterol/salbutamol use in their 
eDiary. 
x If the patient seeks emergency/acute care for worsening respiratory symptoms, 
he/she should request the Health Care Provider (HCP) to contact the Investigator as 
soon as possible.  
11.6.2 COPD Symptom Verification 
Each exacerbation event will be verified with symptoms as defined in Section 11.6.1 and 
these symptoms will be documented in the case report form as part of the exacerbation 
assessment. 


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11.6.3 COPD Exacerbation Severity: 
The definition of COPD exacerbation severity is as follows: 
11.6.3.1 Moderate 
A moderate exacerbation is defined as worsening symptoms of COPD requiring a minimum 
of three days of treatment with oral/systemic corticosteroids and/or antibiotics. 
11.6.3.2 Severe 
A severe exacerbation is defined as worsening symptoms of COPD requiring in-patient 
hospitalization. 
11.6.3.3 Guideline for assessing exacerbations that increase in severity 
If an exacerbation begins as moderate but becomes severe, the exacerbation should be 
captured as severe. 
11.6.4 Onset and Resolution of COPD Exacerbations: 
The date of onset is the first day of the worsening of signs and symptoms of COPD 
exacerbation.  
The date of resolution is when the Investigator and/or patient ascertain the signs and 
symptoms have returned to pre-exacerbation levels or to a new baseline.  
The date of onset and the date of resolution will be recorded in the eCRF. 
11.6.5 Treatment of COPD Exacerbations  
11.6.5.1 Guidelines for Treatment with Corticosteroids 
x
The duration of treatment with oral/systemic corticosteroids should be less than or
equal to 14 days (dose and type according to local practice).
x
The duration of treatment with oral/systemic corticosteroids greater than 14 days
should be discussed with the Medical Monitor and Sponsor to determine if the patient
should remain in the study.
x
Any course of oral/systemic corticosteroids started within 7 days of finishing a
previous course will be considered as treatment for a single exacerbation.
11.6.5.2 Guidelines for Treatment with Antibiotics 
If there is evidence of respiratory infection that warrants treatment with antibiotics in the 
opinion of the Investigator or treating physician, the following guidelines should be used: 


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x
The duration of treatment with antibiotics should be 7 to 14 days (dose and type
according to local practice). If first antibiotic treatment fails and additional antibiotics
are warranted, the total duration of antibiotic treatment should not exceed 30 days. If
the duration of treatment with antibiotics needs to be greater than 30 days, the
Investigator or treating physician should discuss the patient with the Medical Monitor
and Sponsor to determine if the patient should remain in the study.
x
Any course of antibiotics started within 7 days of finishing a previous course will be
considered as treatment for a single exacerbation.
Use of antibiotics for the treatment of upper or lower respiratory tract infections is not 
considered a COPD exacerbation unless the patient experiences worsening of signs and 
symptoms associated with exacerbations as given above. 
11.6.6 Recording COPD Exacerbations 
Exacerbation details will be recorded in the exacerbation form of the eCRF. COPD 
exacerbations will not be recorded as adverse events (AE), unless they meet the definition 
of a serious adverse event (SAE). Pneumonia details will be recorded in the Pneumonia 
form of the eCRF and will also be recorded as an AE or SAE. Pneumonia should be 
confirmed by chest-x-ray. Every effort should be made to obtain a chest x-ray within 48 
hours suspected pneumonia. 
11.6.7 
Study Continuation or Withdrawal Due to COPD Exacerbation 
x
Patients who experience a single COPD exacerbation during the treatment period
may remain in the study and should continue to take their blinded study medication
if possible and record their symptoms and rescue albuterol/salbutamol usage in their
eDiary.
x
Patients who experience a second COPD exacerbation and/or a severe COPD
exacerbation that requires in-patient hospitalization will be discontinued from study
treatment (Section 7.0).


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11.7 Appendix 7: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
Definition of AE 
x An AE is any untoward medical occurrence in a patient or subject, temporally 
associated with the use of blinded study medication, whether or not considered related 
to the blinded study medication. 
x 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. 
Events Meeting the AE Definition 
x Any abnormal laboratory test results (eg, hematology, clinical chemistry) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), including 
those that worsen from baseline, considered clinically significant in the medical and 
scientific judgment of the Investigator (ie, not related to progression of underlying 
disease).  
x Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
x New conditions detected or diagnosed after blinded study medication administration 
even though it may have been present before the start of the study.  
x Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.  
x 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. 
x “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 
x
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 patient’s condition.
x
The disease/disorder being studied or expected progression, signs, or symptoms of
the disease/disorder being studied, unless more severe than expected for the
patient’s condition.
x
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that
leads to the procedure is the AE.
x
Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).
x
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 (eg, 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 patient 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 patient 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  
x The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  
x This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, 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 patient 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 
x When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.  
x The Investigator will then record all relevant AE/SAE information in the eCRF. 
Each event must be recorded separately. 
x It is not acceptable for the Investigator to send photocopies of the patient’s 
medical records to Sponsor/Sponsor’s designee in lieu of completion of the 
Verona Pharma /AE/SAE eCRF page.  
x 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 patient 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.  
x 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. 


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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: 
x Mild: An event that is easily tolerated by the patient, causing minimal discomfort and 
not interfering with everyday activities.  
x Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.  
x 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 
x Single occasion: Single event with limited duration. 
x Intermittent: Several episodes of an event, each of limited duration 
x Persistent: Event which remained indefinitely. 
Assessment of Causality 
x 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 
unrelated, unlikely to be related, possibly related, probably related, or unknown 
(unable to judge).  
- “Probably related” conveys that there are facts, evidence, and/or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out.  
- “Possibly related” suggests that the association of the AE with the blinded study 
medication is unknown; however, the AE is not reasonably supported by other 
conditions.  
- “Unlikely to be related” suggests that only a remote connection exists between the 
blinded study medication and the AE. Other conditions, including chronic illness, 
progression or expression of the disease state or reaction to concomitant therapy, 
appear to explain the reported AE.  
- “Unrelated” is used if there is not a reasonable possibility that the blinded study 
medication caused the AE.  
- All efforts should be made to classify the AE according to the above categories. 
The category “unknown” (unable to judge) may be used only if the causality is not 
assessable (eg, because of insufficient evidence, conflicting evidence, conflicting 
data, or poor documentation). 
x The Investigator will use clinical judgment to determine the relationship.  


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x
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.
x
The Investigator will also consult the Investigator’s Brochure (IB) in his/her
assessment.
x
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.
x
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.
x
The Investigator may change his/her opinion of causality in light of follow-up
information and send a SAE follow-up report with the updated causality assessment.
x
The causality assessment is one of the criteria used when determining regulatory
reporting requirements.
Action and Outcome 
x
Action taken with blinded study medication (none, blinded study medication
stopped, blinded study medication temporarily interrupted)
x
Other actions (none, concomitant medication, study discontinuation,
hospitalization, other)
x
The outcome and date of outcome according to the following definitions:
-
Recovered or resolved (adverse event disappeared)
-
Recovered or resolving (patient 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 patient has been lost to follow-up)
x
Seriousness (yes or no)
Follow-up of AEs and SAEs 
x
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.
x
If a patient 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.
x
New or updated information will be recorded in the originally completed eCRF.


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x The Investigator will submit any updated SAE data to the Sponsor/Sponsor’s 
Designee within 24 hours of receipt of the information. 
Reporting of SAEs 
SAE Reporting to the Sponsor/Sponsor’s designee via an Electronic Data Collection 
Tool 
x The primary mechanism for reporting an SAE to the Sponsor/Sponsor’s designee 
will be the electronic data collection tool.  
x If the electronic system is unavailable, then the study center will use the paper 
SAE data collection tool (see next section).  
x The study center will enter the SAE data into the electronic system as soon as it 
becomes available.  
x 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. 
x If a study center receives a report of a new SAE from a patient 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/SAE coordinator by 
telephone.  
x Contacts for SAE reporting can be found in Section 11.2 on the Medical Monitor 
Contact Information page. 
SAE Reporting to Sponsor/ Sponsor’s Designee via Paper CRF if eCRF is not 
available 
x If the eCRF is not available, facsimile transmission of the SAE paper CRF may be 
used to transmit this information to the Medical Monitor or the SAE coordinator.  
x In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.  
x 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.  
x Contacts for SAE reporting can be found in Section 11.2 on the Medical Monitor 
Contact Information page. 
 


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11.8 Appendix 8: 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. Premenarchal: Note premenarchal females ARE NOT ELIGIBLE TO PARTICIPATE
in this study.
2. 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 patient’s medical records, medical examination, or
medical history interview.
3. Postmenopausal female:
a) Postmenopausal females are defined as amenorrhoeic for greater than 1 year with an
appropriate clinical profile, eg, age appropriate, > 45 years, in the absence of hormone
replacement therapy.
Contraception Guidance  
Male Patients 
x
Male patients 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 Table 14 when having
penile-vaginal intercourse with a woman of childbearing potential who is
not currently pregnant.
x
In addition, male patients must refrain from donating sperm for the duration of the
study and for 30 days after the last dose of study medication.
x
Male patients 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.


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Female patients 
Female patients 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 14: 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 
x Oral 
x Intravaginal 
x Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
x Oral 
x Injectable 
Highly Effective Contraceptive Methods That Are User Independent a 
Implantable progestogen only hormonal contraception associated with inhibition of 
ovulationb  
x Intrauterine device (IUD) 
x 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 patient. 
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 patients participating in clinical studies. 


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Table 14: Highly Effective Contraceptive Methods 
bHormonal 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: 
x WOCBP should only be included after a negative highly sensitive pregnancy test. 
x 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  
Male patients with partners who become pregnant 
The Investigator will attempt to collect pregnancy information on any male patient’s 
female partner who becomes pregnant while the male patient is in the study. This applies 
only to male patients who receive ensifentrine. 
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. 
Female Patients who become pregnant 
x The Investigator will collect pregnancy information on any female patient who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the Sponsor within 24 hours of learning of a 
patient’s pregnancy. 
x The patient will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the patient and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for 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.  
x 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.  


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x
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 patients, he or she may learn of an SAE through spontaneous reporting.
x
Any female patient who becomes pregnant while participating in the study will
discontinue blinded study medication and be withdrawn from the study.


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11.9 Appendix 9: Liver Safety 
Phase III-IV liver chemistry stopping and follow-up criteria have been designed to assure 
patient safety and evaluate liver event etiology (in alignment with the FDA premarketing 
clinical liver safety guidance). Phase III-IV liver chemistry stopping criteria 1-5 are 
defined below. Investigators may at their discretion refer patients 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  3xULN and bilirubin  2xULN (35% direct bilirubin) (or ALT  3xULN 
and INR > 1.5, if INR measured. 
Note: if serum bilirubin fractionation is not immediately available, withdraw study 
drug for that patient if ALT  3xULN and bilirubin  2xULN. 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  8xULN. 
3. ALT  5xULN but < < 8 xULN persists for  2 weeks. 
4. ALT  3xULN 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  5xULN but < 8 xULN and cannot be monitored weekly for  2 weeks. 
When any of the liver stopping criteria 1-5 is met do the following: 
x Immediately discontinue blinded study medication/investigational product for 
that patient. 
x Report the event to IQVIA within 24 hours of learning its occurrence. 
x Complete the liver event CRF and SAE data collection tool if the event also meets 
the criteria for an SAE. All events of ALT  3xULN and bilirubin  2xULN (35% 
direct bilirubin) (or ALT  3xULN and INR > 1.5, if INR measured); INR 
measurement is not required and the threshold value stated will not apply to 
patients 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 patient if ALT  3xULN and bilirubin  
2xULN. 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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x
Complete the liver imaging and/or liver biopsy CRFs if these tests are performed.
x
Perform liver event follow-up assessments and monitor the patient until liver
chemistries resolve, stabilize, or return to baseline values as described below.
x
Discontinue blinded study medication/investigational product after completion of
the liver chemistry monitoring as described below.
x
Do not restart investigational product.
In addition, for criterion 1: 
x
Make every reasonable attempt to have patients return to clinic within 24 hours
for repeat liver chemistries, liver event follow-up assessments (see below), and
close monitoring.
x
A specialist or hepatology consultation is recommended.
x
Monitor patients 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:  
x
Make every reasonable attempt to have patients return to clinic within 24-72 hours
for repeat liver chemistries and liver event follow-up assessments (see below).
x
Monitor patients weekly until liver chemistries (ALT, AST, alkaline phosphatase,
bilirubin) resolve, stabilize, or return to within baseline values; criterion 5 patients
should be monitored as frequently as possible.
Patients with ALT  5xULN and < 8xULN which exhibit a decrease to ALT 3xULN, 
but <5xULN and bilirubin <2xULN without hepatitis symptoms or rash, and who can be 
monitored for 4 weeks: 
x
Notify the IQVIA Medical Monitor within 24 hours or learning of the abnormality
to discuss patient safety.
x
Can continue investigational product
x
Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase,
bilirubin) until they resolve, stabilize or return to within baseline.
x
If at any time these patients meet the liver chemistry stopping criteria, proceed as
described above.
x
If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor
patients twice monthly until live chemistries normalize or return to within baseline
values.


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For criteria 1-5, make every attempt to carry out the liver event follow up assessments 
described below: 
x
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
x
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 patient’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.
x
Serum creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH)
x
Fractionate bilirubin, if total bilirubin  2xULN
x
Obtain complete blood count with differential to assess eosinophilia.
x
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.
x
Record use of concomitant medications, acetaminophen, herbal remedies, or over
the counter medications, or putative hepatotoxins, on the concomitant medications
report form.
x
Record alcohol use on the liver event alcohol intake case report form.
The following are required for patients with ALT  3xULN and bilirubin  2xULN (35% 
direct) but are optional for the other abnormal liver chemistries: 
x
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney
microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma
globulins).


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x Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in patients with definite or likely acetaminophen use in 
the preceding week [James, 2009]. NOTE: not required in China. 
x 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  
(Le Gal, 2005). 
 


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11.10 Appendix 10: Medical Device Information 
Definitions of a Medical Device Incident 
The detection and documentation procedures described in this protocol apply to all 
Sponsor medical devices provided for use in the study (see Section 6.2.2) for the list of 
Sponsor medical devices). 
Medical Device Incident Definition 
x
A medical device incident is any malfunction or deterioration in the characteristics
and/or performance of a device as well as any inadequacy in the labeling or the
instructions for use which, directly or indirectly, might lead to or might have led
to the death of a patient/user/other person or to a serious deterioration in his/her
state of health.
x
Not all incidents lead to death or serious deterioration in health. The
nonoccurrence of such a result might have been due to other fortunate
circumstances or to the intervention of health care personnel.
It is sufficient that: 
x
An incident associated with a device happened.
AND
x
The incident was such that, if it occurred again, might lead to death or a serious
deterioration in health.
A serious deterioration in state of health can include any of the following: 
x
Life-threatening illness.
x
Permanent impairment of body function or permanent damage to body structure.
x
Condition necessitating medical or surgical intervention to prevent 1 of the above.
x
Fetal distress, fetal death, or any congenital abnormality or birth defects.
Examples of Incidents 
x
A patient, user, caregiver, or healthcare professional is injured as a result of a
medical device failure or its misuse.
x
A patient’s blinded study medication is interrupted or compromised by a medical
device failure.
x
A misdiagnosis due to medical device failure leads to inappropriate treatment.
x
A patient’s health deteriorates due to medical device failure.


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Documenting Medical Device Incidents 
Medical Device Incident Documenting 
x
Any medical device incident occurring during the study will be documented in the
patient’s medical records, in accordance with the Investigator’s normal clinical
practice, and on the appropriate form of the CRF.
x
For incidents fulfilling the definition of an AE or an SAE, the appropriate
AE/SAE CRF page will be completed as described in Section 11.7.
x
The CRF will be completed as thoroughly as possible and signed by the
Investigator before transmittal to the Sponsor or designee.
x
It is very important that the Investigator provides his/her assessment of causality
(relationship to the medical device provided by the Sponsor) at the time of the
initial AE or SAE report and describes any corrective or remedial actions taken to
prevent recurrence of the incident.
x
A remedial action is any action other than routine maintenance or servicing of a
medical device where such action is necessary to prevent recurrence of an
incident. This includes any amendment to the device design to prevent recurrence.


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11.11 Appendix 11: Country Specific Requirements 
Germany: a CXR or CT scan must be available in the 12 months prior to Screening for 
eligibility.


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11.12 Appendix 12: Signature of Investigator 
PROTOCOL TITLE:  A Phase III Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of Ensifentrine over 24 Weeks in Patients with 
Moderate to Severe Chronic Obstructive Pulmonary Disease.  
PROTOCOL NO: RPL554-CO-302  
VERSION: 5.0  
Version Date: 30 April 2021  
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 in which 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: 
 
 
 
 
 

SAP_001.pdf: 






Verona Pharma
PROTOCOL No. RPL554-CO-302
Statistical Analysis Plan
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly proh bited.
MODIFICATION HISTORY
Unique 
Identifier 
for this 
Version 
Date of the 
Document 
Version 
Author 
Significant Changes from 
Previous Authorized Version 
1.0
25JUL2022
Marco Sequi
Not Applicable – First Version


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Statistical Analysis Plan
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ABBREVIATIONS
AE
Adverse Event
ACS
Abnormal, Clinically Significant
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance 
ANCS
Abnormal, Not Clinically Significant
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Clinical Classification System
AUC0-t
Area Under the Curve over t hours
BDI
Baseline Dyspnea Index 
BDR
Blinded Data Review
BLQ
Below the Lower Limit of Quantitation
BMI
Body Mass Index
BPM
Beats Per Minute
COPD
Chronic Obstructive Pulmonary Disease 
CRF
Case Report Form 
CV
Coefficient of Variation
DBL
Database Lock
DBP
Diastolic Blood Pressure
DMC
Data Monitoring Committee
ECG
Echocardiogram
ENR
All Patients Enrolled
EOS
End of Study
EQ-5D-5L
EuroQol-5-Domain Questionnaire
E-RSTM: COPD
Evaluating Respiratory Symptoms for COPD 
ERT
eResearch Technology
FEV1
Forced Expiratory Volume in 1 second 
FVC
Forced Vital Capacity
GGT
Gamma Glutamyltransferase
HRU
Healthcare Resource Utilization
IL
Interleukin
IV
Intravenous
LABA
Long-acting Beta 2 Agonist
LAMA
Long-acting Muscarinic Antagonist
LOCF
Last Observation Carried Forward
LOQ
Limit of Quantitation
MAR
Missing at Random
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple Imputation


Verona Pharma
PROTOCOL No. RPL554-CO-302
Statistical Analysis Plan
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FINAL v1.0
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly proh bited.
mITT
Modified Intent-to-Treat
mMRC
Modified Medical Research Council
MMRM
Mixed Model for Repeated Measures
PD
Protocol Deviation
PK
Pharmacokinetics
POPPK
Population Pharmacokinetics
PP
Per-Protocol
PT
Preferred Term
Qol
Quality of Life
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RND
All Patients Randomized
SAP
Statistical Analysis Plan
SABA
Short-acting Beta 2 Agonist
SAE
Serious Adverse Event
SAF
Safety Analysis
SAS
Statistical Analysis Software
SBP
Systolic Blood Pressure
SD
Standard Deviation
SGRQ
St. George’s Respiratory Questionnaire 
SI
Standard International
SOC
System Organ Class
TDI
Transition Dyspnea Index 
TEAE
Treatment-Emergent Adverse Event
WHO
World Health Organization


Verona Pharma
PROTOCOL No. RPL554-CO-302
Statistical Analysis Plan
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TABLE OF CONTENTS
1.
INTRODUCTION............................................................................................................. 13
2.
STUDY OBJECTIVES AND ESTIMANDS .................................................................. 14 
2.1. 
Primary Objective .........................................................................................................................................14 
2.2. 
Secondary Objectives ....................................................................................................................................14 
2.3. 
Other Objectives............................................................................................................................................14 
2.4. 
Safety Objectives............................................................................................................................................14 
2.5. 
Estimands .......................................................................................................................................................14 
3.
STUDY DESIGN............................................................................................................... 18 
3.1. 
General Description.......................................................................................................................................18 
3.2. 
Schedule of Events.........................................................................................................................................19 
3.3. 
Changes to Analysis from Protocol ..............................................................................................................19 
4.
PLANNED ANALYSES................................................................................................... 19 
4.1. 
Data Monitoring Committee (DMC)............................................................................................................19 
4.2. 
Interim Analysis.............................................................................................................................................20 
4.3. 
Final Analysis.................................................................................................................................................20 
5.
ANALYSIS SETS.............................................................................................................. 20 
5.1. 
Process for Analysis Set Assignment............................................................................................................21 
5.2. 
All Patients Enrolled Set ...............................................................................................................................21 
5.3. 
All Patients Randomized Set.........................................................................................................................22 
5.4. 
Extended Randomized Set ............................................................................................................................22 


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Statistical Analysis Plan
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5.5. 
modified Intent-to-Treat Population............................................................................................................22 
5.6. 
Extended modified Intent-to-Treat Population...........................................................................................22 
5.7. 
Per-Protocol Population................................................................................................................................23 
5.8. 
Safety Analysis Set.........................................................................................................................................23 
5.9. 
Extended Safety Analysis Set........................................................................................................................23 
5.10. 
Pharmacokinetic Set..................................................................................................................................23 
6.
GENERAL CONSIDERATIONS ................................................................................... 24 
6.1. 
Reference Dates and Study Day ...................................................................................................................24 
6.2. 
Baseline...........................................................................................................................................................24 
6.3. 
Retests, Unscheduled Visits and Early Termination Data .........................................................................25 
6.4. 
Windowing Conventions ...............................................................................................................................25 
6.5. 
Statistical Tests ..............................................................................................................................................28 
6.6. 
Common Calculations ...................................................................................................................................28 
6.7. 
Actual Treatment...........................................................................................................................................28 
6.8. 
Software Version............................................................................................................................................29 
6.9. 
Strata calculations .........................................................................................................................................29 
7.
STATISTICAL CONSIDERATIONS ............................................................................ 29 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses .......................................................29 
7.2. 
Multicenter Studies........................................................................................................................................30 
7.3. 
Missing data ...................................................................................................................................................31 
7.4. 
Multiple Comparisons/ Multiplicity.............................................................................................................31 
7.5. 
Examination of Subgroups............................................................................................................................31 




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Questionnaires .................................................................................................................................47 
Rescue Medications .........................................................................................................................49 
16.2.2. 
Missing Data Methods for Secondary Efficacy Variables.......................................................................49 
MI method – continuous data ..........................................................................................................49 
MI method – binary data..................................................................................................................51 
MI method – range data...................................................................................................................52 
Other methods..................................................................................................................................52 
16.2.3. 
Analysis of Secondary Efficacy Variables...............................................................................................52 
Change from baseline variables, incl. TDI ......................................................................................52 
Proportion of SGRQ total responders ..............................................................................................53 
16.2.4. 
Sensitivity Analysis of Secondary Efficacy Variables.............................................................................53 
16.3. 
Other Efficacy............................................................................................................................................54 
16.3.1. 
Other Efficacy Variables & Derivations..................................................................................................54 
COPD exacerbation .........................................................................................................................54 
EQ-5D-5L........................................................................................................................................54 
HRU.................................................................................................................................................55 
Genotype/phenotype ........................................................................................................................55 
Patient Perception Survey................................................................................................................55 
FEV1 AUC6-12h.................................................................................................................................55 
E-RS total score responder...............................................................................................................55 
Morning trough FEV1 responder......................................................................................................55 
16.3.2. 
Missing Data Methods for Other Efficacy Variables...............................................................................56 
16.3.3. 
Analysis of Other Efficacy Variables ......................................................................................................56 
16.3.4. 
Sensitivity Analysis of Other Efficacy Variables ....................................................................................57 
16.4. 
Evaluation including excluded sites .........................................................................................................58 
17.
SAFETY OUTCOMES .................................................................................................... 58 
17.1. 
Adverse Events...........................................................................................................................................58 
17.1.1. 
All TEAEs ...............................................................................................................................................59 
Severity............................................................................................................................................59 
Relationship to Study Medication....................................................................................................59 
17.1.2. 
TEAEs Leading to Discontinuation of Study Medication .......................................................................59 
17.1.3. 
Serious Adverse Events ...........................................................................................................................60 
17.1.4. 
Adverse Events Leading to Death............................................................................................................60 
17.2. 
Laboratory Evaluations ............................................................................................................................60 
17.2.1. 
Laboratory Reference Ranges and Clinically Significant Abnormal Criteria..........................................61 
17.3. 
ECG Evaluations .......................................................................................................................................61 
17.3.1. 
ECG Markedly Abnormal Criteria...........................................................................................................63 
17.4. 
Vital Signs...................................................................................................................................................63 
17.4.1. 
Vital Signs Markedly Abnormal Criteria.................................................................................................64 


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17.5. 
COVID-19...................................................................................................................................................64 
17.6. 
Pneumonia..................................................................................................................................................64 
17.7. 
Evaluation including excluded sites .........................................................................................................65 
18.
GENETIC ANALYSIS..................................................................................................... 65 
19.
BIOMARKER ANALYSIS.............................................................................................. 65 
20.
PHARMACOKINETIC ANALYSIS.............................................................................. 65 
20.1. 
Deviations Related to PK ..........................................................................................................................65 
20.2. 
Pharmacokinetics Drug Concentrations in Plasma ................................................................................66 
20.3. 
Population PK Analysis.............................................................................................................................67 
21.
DATA NOT SUMMARIZED OR PRESENTED .......................................................... 67 
22.
REFERENCES.................................................................................................................. 68
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS.............................. 69 
Dates & Times............................................................................................................................................................69 
Spelling Format..........................................................................................................................................................69 
Presentation of Treatment Groups ..........................................................................................................................69 
Decimal Places ...........................................................................................................................................................69 
Presentation of Visits.................................................................................................................................................70 
Listings .......................................................................................................................................................................70 
Tables..........................................................................................................................................................................71 
APPENDIX 2. PARTIAL DATE CONVENTIONS ............................................................. 72 
Algorithm for Treatment Emergence of Adverse Events: .....................................................................................72 
Algorithm for Prior/ Prior Concomitant / Concomitant Medications:.................................................................73 
Algorithm for Concomitant Illnesses:......................................................................................................................76 
APPENDIX 3. ANNOTATED EXACT FOR RAW SCORE ASSIGNMENT................... 78 


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APPENDIX 4. RAW SUMMED SCORE TO SCALE CONVERSION TABLE FOR 
EXACT TOTAL SCORE........................................................................................................... 81 
APPENDIX 5. SGRQ ITEM WEIGHTS............................................................................... 82 
APPENDIX 6. EQ-5D-5L WEIGHTS.................................................................................... 87 
Poland.........................................................................................................................................................................87 
England.......................................................................................................................................................................89 
US................................................................................................................................................................................90 


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1. INTRODUCTION
This document describes the rules and conventions to be used in the presentation and analysis of 
efficacy and safety data, including genotyping data for Protocol RPL554-CO-302. It describes 
the data to be summarized and analyzed, including specifics of the statistical analyses to be 
performed. 
This statistical analysis plan (SAP) is based on protocol version 5.0, dated 30th April 2021.
A separate analysis plan will be created which will include the details of the population PK 
(POPPK) analysis, as well as the design and modelling of the PK collection data. Only
summarization of PK concentrations will be described in this SAP.
A separate pooled SAP will be created which will include the details of pooled analysis between 
RPL554-CO-301 and RPL554-CO-302.
There will also be a separate blinded data review (BDR) plan that will outline the process for 
identification and decision making on patient’s exclusion from analysis sets and on major 
protocol deviations specified in the BDR plan. These will then be summarized in BDR report 
created for the data review outputs. This document will summarize each analysis set and reasons 
for the exclusion. In the BDR report protocol deviations (PDs) will also be outlined, specifying 
which patients were identified with each PD and whether these led to exclusion from the PP 
population. All analysis sets will be defined, and all possible PDs will be identified prior to 
unblinding. If there are any PDs which can only be identified post-unblinding (e.g. in PK or 
Biomarker data), an unblinded data review report will be created to detail these after database 
lock (DBL).


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2. STUDY OBJECTIVES AND ESTIMANDS
2.1.PRIMARY OBJECTIVE
The primary objective of this study is to evaluate the efficacy of ensifentrine on lung function 
compared to placebo over a 12-hour dosing interval in patients with moderate to severe chronic 
obstructive pulmonary disease (COPD).
2.2.SECONDARY OBJECTIVES
x
To evaluate the effect of ensifentrine on other lung function parameters.
x
To evaluate the effect of ensifentrine on COPD symptoms.
x
To evaluate the effect of ensifentrine on health-related quality of life.
2.3.OTHER OBJECTIVES
x
To evaluate the effect of ensifentrine on moderate/severe COPD exacerbations.
x
To evaluate the effect of ensifentrine on health utility and healthcare resource utilization
(HRU).
x
To characterize the pharmacokinetics of ensifentrine in patients with COPD.
x
To evaluate the effect of ensifentrine on inflammatory biomarkers.
2.4.SAFETY OBJECTIVES
To evaluate the safety and tolerability of ensifentrine over 24 Weeks.
2.5.ESTIMANDS
The primary and secondary estimands to support regulatory decisions are described in Table 1.


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List of Estimands
Estimand
Definition
Attributes
Population
Variable/ Endpoint
Intercurrent event 
handling strategy
Population-level summary 
measure
Primary 
The efficacy of 
ensifentrine on
lung function 
compared to 
placebo over a 
12-hour dosing
interval in
patients with
moderate to
severe COPD.
Patients with moderate 
to severe COPD aged 
40-80 years (inclusive)
that are in the modified
intent-to-treat (mITT)
population. See full list
of inclusion and
exclusion criteria in
sections 5.1, 5.2 and 5.3
of study protocol.
Change from baseline forced 
expiratory volume in 1 second 
(FEV1) to average FEV1 area 
under the curve over 12 hours 
(AUC0-12h) at Week 12.
Regardless of
whether the patient
discontinues 
treatment 
prematurely and 
regardless of major 
protocol deviation, 
as per the 
Treatment Policy 
strategy.
Estimated treatment 
difference at Week 12 of the
double-blind period (and 
corresponding 95% 
confidence interval [CI])
from analysis of covariance 
(ANCOVA) analysis.
Secondary
To evaluate the 
effect of 
ensifentrine on 
other lung 
function 
parameters.
Patients with moderate 
to severe COPD aged 
40-80 years (inclusive)
that are in the mITT
population. See full list
of inclusion and
exclusion criteria in
sections 5.1, 5.2 and 5.3
of study protocol.
1. Change from baseline
FEV1 to average FEV1
AUC0-4h at Week 12
2. Change from baseline
FEV1 to peak FEV1 at
Week 12
3. Change from baseline
FEV1 to morning
trough FEV1 at Week
12
Regardless of
whether the patient
discontinues 
treatment 
prematurely and 
regardless of major 
protocol deviation, 
as per the 
Treatment Policy 
strategy.
Estimated treatment 
difference at Week 12 of the 
double-blind period (and
corresponding 95% CI) from 
ANCOVA analysis.


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Secondary
To evaluate the 
effect of 
ensifentrine on 
COPD 
symptoms.
Patients with moderate 
to severe COPD aged 
40-80 years (inclusive)
that are in the mITT
population. See full list
of inclusion and
exclusion criteria in
sections 5.1, 5.2 and 5.3
of study protocol.
Change from baseline (i.e. 
mean over the last 7 days of 
run-in) to the mean weekly 
value at Week 24 in COPD 
symptoms, as measured by 
daily diary (Evaluating 
Respiratory Symptoms for 
COPD [E-RSTM:COPD])
Regardless of
whether the patient
discontinues 
treatment 
prematurely and 
regardless of major 
protocol deviation, 
as per the 
Treatment Policy 
strategy.
Estimated treatment 
difference at the end of the 
double-blind period (and 
corresponding 95% CI) from 
ANCOVA analysis.
Secondary
To evaluate the 
effect of 
ensifentrine on 
health-related 
quality of life.
Patients with moderate 
to severe COPD aged 
40-80 years (inclusive)
that are in the mITT
population. See full list
of inclusion and
exclusion criteria in
sections 5.1, 5.2 and 5.3
of study protocol.
1. Change from baseline in
the St. George’s
Respiratory
Questionnaire (SGRQ)
total score at Week 24
2. Proportion of SGRQ
responders at Week 24
Regardless of
whether the patient
discontinues 
treatment 
prematurely and 
regardless of major 
protocol deviation, 
as per the 
Treatment Policy 
strategy.
1. Estimated treatment
difference at the end
of the double-blind
period (and
corresponding 95%
CI) from ANCOVA
analysis.
2. Odds ratio for
proportion of
responders with an
improvement of at
least 4 units at the end
of the double-blind
period (and
corresponding 95%
CI) from logistic


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regression analysis.


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3. STUDY DESIGN
3.1.GENERAL DESCRIPTION
This is a Phase III, multicenter, randomized, double-blind, parallel group, placebo-controlled 
study. A flow chart illustrating the key components of the study is provided in Figure 1:
Figure 1:
Study Flow Chart
Approximately 800 patients with moderate to severe COPD aged 40 to 80 years (inclusive) will 
be stratified by two different factors: stable background maintenance long-acting muscarinic 
antagonist (LAMA) or long-acting beta-2 agonist (LABA) therapy use (yes or no) and cigarette 
smoking (current or former), then randomized 5:3 to receive ensifentrine (3 mg): placebo for 
24 weeks. The background therapy strata will be capped at 50%. Up to 20% of patients are 
allowed to take inhaled corticosteroids during the study under certain provisions, as detailed in
the sections 6.7.2 and 6.7.3 of the study protocol. Patients in the background maintenance 
LAMA or LABA therapy strata must withhold twice-daily maintenance LAMA or LABA (or 
LAMA/ICS or LABA/ICS) for 24 hours and once-daily maintenance LAMA or LABA (or
LAMA/ICS or LABA/ICS) for 48 hours prior to initiation of any spirometry. All patients must 
withhold short-acting beta-2 agonist (SABA) rescue medication for at least 4 hours prior to 
initiation of any spirometry.
Patients are expected to take the study medication twice daily, administered via a standard jet 
nebulizer, during the study period. Schedule of in-clinic dosing can be found in section 1.4 of 
the study protocol.


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3.2.SCHEDULE OF EVENTS
Schedule of activities can be found in section 1.3 of the study protocol.
3.3.CHANGES TO ANALYSIS FROM PROTOCOL
Changes to analysis from protocol include:
x
“COPD severity” added as a subgroup analysis.
x
Per-protocol population definition updated to exclude patients that discontinued study
medication before study day 74.
x
Sections 9.4.1 and 9.4.4 in the protocol states, “A sensitivity analysis [on the proportion of
responders on the SGRQ] will be performed in which patients with missing data at the
required visit will be considered non-responder in the analysis”, and “For the responder
analysis of SGRQ, patients with no available data for imputation will be considered non-
responders as a sensitivity analysis”, respectively. However, a non-responder analysis may
create an unintentional bias in favour of the treatment arm. I.e. if placebo patients
discontinue, this technique may inadvertently set more values in the placebo arm to “non-
responder”. Therefore, this technique for missing data analysis will not be implemented.
x
Analysis of E-RS total score responder, defined as a decrease from baseline in the week
mean total of E-RS score of greater than or equal to 2, added in the Section 16.3.1.7.
x
Analysis of Morning trough FEV1 responder, defined as an improvement from baseline of
100 mL or more, added in the Section 16.3.1.8.
x
Chronicity section removed from Adverse Events section.
x
A sensitivity analysis will be performed for weekly mean E-RS total score, using
ANCOVA approach, as described in section 16.2.4 of the SAP, in which all patients with
baseline mean = 0 will be excluded.
x
Due to the unreliability of the data, site 
will be removed from efficacy and safety
analyses in any section.
x
Extended randomized, extended mITT and extended Safety populations set will be included
as new populations to manage this site to be removed. Added in the Section 5.
4. PLANNED ANALYSES
A final analysis after DBL is planned for this study.
4.1.DATA MONITORING COMMITTEE (DMC)
There will be no DMC for this study.




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Protocol 
deviations
X
Demograph
ic and other 
baseline 
characteristi
cs
X
X
X
Surgical 
and medical 
history
X
Prior and 
concomitant 
medication
X
Compliance
X
Efficacy: 
Primary 
endpoint
X
X
X
Efficacy: 
Secondary 
endpoints
X
X
X
Efficacy: 
Other 
endpoints
X
X
Sensitivity 
Analyses
X
X
X
Safety
X
X
Pharmacoki
netics
X
5.1.PROCESS FOR ANALYSIS SET ASSIGNMENT
Analysis set assignments and any associated reasons for analyses set exclusion will be
described in the BDR plan and finalized within the BDR report prior to unblinding.
5.2.ALL PATIENTS ENROLLED SET
The all patients enrolled (ENR) set will contain all patients who provide informed consent for 


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this study. Patients will be classified according to randomized treatment with patients not 
randomized presented in a separate category, see APPENDIX 1.
5.3.ALL PATIENTS RANDOMIZED SET
The all patients randomized (RND) set will contain all patients in the ENR set who were 
randomized to study medication. For analyses and displays based on RND, patients will be 
classified according to randomized treatment. Site number 
 will be excluded from this 
population.
5.4.EXTENDED RANDOMIZED SET
The Extended randomized (RND) set will contain all patients in the ENR set who were 
randomized to study medication. For analyses and displays based on RND, patients will be 
classified according to randomized treatment. Site number 
will be included in this 
population.
5.5.MODIFIED INTENT-TO-TREAT POPULATION
The mITT population will contain all patients in the RND set who received at least one dose
(or partial dose) of study medication and patients will be classified according to randomized 
treatment. The intent-to-treat principle is preserved, despite the exclusion of patients
randomized who did not take the study medication, because the decision of whether or not to 
begin the treatment could not be influenced by knowledge of the assigned treatment, i.e. the 
study medication is blinded. Site number 
will be excluded from this population.
5.6.EXTENDED MODIFIED INTENT-TO-TREAT POPULATION
The Extended mITT population will contain all patients in the RND set who received at least 
one dose (or partial dose) of study medication and patients will be classified according to 
randomized treatment. The intent-to-treat principle is preserved, despite the exclusion of 
patients randomized who did not take the study medication, because the decision of whether or 
not to begin the treatment could not be influenced by knowledge of the assigned treatment, i.e. 
the study medication is blinded. Site number 
will be included in this population.


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5.7.PER-PROTOCOL POPULATION
The per-protocol (PP) population will contain all patients in the mITT who did not discontinue 
the study medication before study day 74, and did not experience any major/important PDs
considered to have an impact on efficacy assessments involving lung function at week 12.
Reasons for exclusion will be specified at a BDR meeting prior to DBL and may include 
violations of inclusion/exclusion criteria, violations of withdrawal criteria, incorrect 
randomization, use of prohibited medication, did not follow blinding procedures and non-
compliance. Patients will be classified according to randomized treatment.
If protocol deviations in terms of dosing errors are detected post unblinding, these will lead to 
exclusion only if patient has received and used the opposite study drug compared to what was 
specified in the randomization and that this use occurred prior to week 12.
5.8.SAFETY ANALYSIS SET
The safety analysis (SAF) set will contain all patients in the RND set who receive at least one 
dose (or partial dose) of study medication and patients will be classified according to treatment 
received. 
If there is any doubt whether a patient was treated or not, they will be assumed treated for the 
purposes of analysis. Site number 
will be excluded from this population.
5.9.EXTENDED SAFETY ANALYSIS SET
The Extended safety analysis (SAF) set will contain all patients in the RND set who receive at 
least one dose (or partial dose) of study medication and patients will be classified according to 
treatment received. 
If there is any doubt whether a patient was treated or not, they will be assumed treated for the 
purposes of analysis. Site number 
will be included in this population.
5.10.
PHARMACOKINETIC SET
The PK analysis set (PKAS) will include all patients randomized to ensifentrine, who receive at 
least one dose of ensifentrine, and have at least one quantified ensifentrine concentration at a
scheduled PK time point after the start of dosing without important protocol violations and/or 
events with potential to affect PK concentrations.
The population PK analysis set will be defined separately in the modeling data analysis plan 
prepared by Verona Pharma/Designee.


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6. GENERAL CONSIDERATIONS
6.1.REFERENCE DATES AND STUDY DAY
Study Day will be calculated from the reference start date and will be used to show start/stop
day of assessments and events.
Reference start date is defined as the day of the first dose of study medication (Day 1 is the day 
of the first dose of study medication) and will appear in every listing where an assessment date 
or event date appears. 
x
If the date of the event is on or after the reference start date, then:
Study Day = (date of event – reference start date) + 1.
x
If the date of the event is prior to the reference start date, then:
Study Day = (date of event – reference start date).
In the situation where the event date is partial or missing, the date will appear partial or missing 
in the listings, and Study Day, and any corresponding durations will be presented based on the 
imputations specified in Appendix 2 of the SAP.
Reference end date is defined as the date of the last dose of study medication.
6.2.BASELINE
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior 
to reference start date (including unscheduled assessments). In the case where the last non-
missing measurement and the reference start date coincide, that measurement will be 
considered baseline, unless time is present. If time of the assessment is on or after the study 
treatment start date, then the assessment is not considered baseline except in the following 
case: for main and responder SGRQ analysis, if the assessment on the day of randomization is
done after dosing but prior to leaving the clinic after the 4 hour spirometry, the assessment is 
considered baseline. Adverse Events (AEs) and medications commencing on the reference start 
date will be considered post-baseline, ECG abnormalities from pre-dose assessments and 
laboratory abnormalities from pre-dose draws that are analyzed externally post-dose are still 
considered baseline.


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Baseline for the spirometry endpoints is defined as the mean of the 2 measurements taken pre-
dose on Day 1 prior to reference start date and time, unless only 1 measurement is taken pre-
dose on Day 1 prior to reference start date and time.
If the baseline visit is split across in 2 days with dosing on Day 1, then measurement from day 
– 1 will constitute baseline for spirometry endpoints.
6.3.RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA
In general, for by-visit summaries, data recorded at the nominal visit will be presented.
Patients who were a screen failure and received approval from the Medical Monitor for 
rescreening will go through all of the original screening assessments. Data from the latest 
rescreened visit will be used in the summaries, however all screening information will be 
listed. Rescreened patients will keep the same patient number, as for the initial screening.
Unscheduled measurements will not be included in by-visit summaries but will contribute to 
the EOS value, or best/ worst case value where required (e.g. shift table).
Early termination data will be mapped to the next available visit number for by-visit 
summaries, as described in section 6.4 of the SAP.
Post-randomization if ECG result is Abnormal, Clinically Significant, then triplicate ECGs 
should be provided.
Listings will include scheduled, unscheduled, retest and early discontinuation data.
6.4.WINDOWING CONVENTIONS
Each visit (except for Day 1 visit) will have a±10 days window. No visit windowing will be 
applied during the analysis to the data that is only collected at scheduled site visits for patients 
that have completed the study, and therefore the data will be presented as per the visit reported 
in the database.
For the patients that discontinued from the study, the End of Study (EOS) visit will be 
windowed to the corresponding visit, based on the study day, for questionnaire, spirometry and 
rescue medication data. The EOS visit can only be windowed to a visit that is missing or has a 
missing result. The rules for the windowing are described below.
x
For spirometry raw data and derived data that happens at every visit, windowing will be
done as per the corresponding visits.


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 Day 1 = Day 1
 Week 6 = after Day 1 and up to and including Day 53
 Week 12 = after Day 53 and up to and including Day 95
 Week 24= after Day 95 and up to and including Day 179
x
For spirometry derived data that only happen at certain visits, windowing will be done for
the corresponding visits.
o For morning trough:
 Week 6 = after Day 1 and up to and including Day 53
 Week 12 = after Day 53 and up to and including Day 95
 Week 24= after Day 95 and up to and including Day 179
o For evening trough and AUC0-12h:
 Week 12 = after Day 1 and up to and including Day 95
x
For rescue medication data, E-RS/EXACT-PRO, e-diary data and COPD exacerbation,
windowing will be done as per the corresponding visits.
o
For patients who completed the study or who discontinue study medication but
continue in the study:
 Week 1 = Actual study Day of Week 24 visit minus 168 days (inclusive) up
to and including actual study day of week 24 visit minus 161 days
 Week 2 = Actual study Day of Week 24 visit minus 161 days up to and
including actual study day of week 24 visit minus 154 days
 Week 3 = Actual study Day of Week 24 visit minus 154 days up to and
including actual study day of week 24 visit minus 147 days
 Week 4 = Actual study Day of Week 24 visit minus 147 days up to and
including actual study day of week 24 visit minus 140 days
 Week 5 = Actual study Day of Week 24 visit minus 140 days up to and
including actual study day of week 24 visit minus 133 days
 Week 6 = Actual study Day of Week 24 visit minus 133 days up to and
including actual study day of week 24 visit minus 126 days
 Week 7 = Actual study Day of Week 24 visit minus 126 days up to and
including actual study day of week 24 visit minus 119 days
 Week 8 = Actual study Day of Week 24 visit minus 119 days up to and
including actual study day of week 24 visit minus 112 days
 Week 9 = Actual study Day of Week 24 visit minus 112 days up to and
including actual study day of week 24 visit minus 105 days
 Week 10 = Actual study Day of Week 24 visit minus 105 days up to and
including actual study day of week 24 visit minus 98 days
 Week 11 = Actual study Day of Week 24 visit minus 98 days up to and


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including actual study day of week 24 visit minus 91 days
 Week 12 = Actual study Day of Week 24 visit minus 91 days up to and
including actual study day of week 24 visit minus 84 days
 Week 13 = Actual study Day of Week 24 visit minus 84 days up to and
including actual study day of week 24 visit minus 77 days
 Week 14 = Actual study Day of Week 24 visit minus 77 days up to and
including actual study day of week 24 visit minus 70 days
 Week 15 = Actual study Day of Week 24 visit minus 70 days up to and
including actual study day of week 24 visit minus 63 days
 Week 16 = Actual study Day of Week 24 visit minus 63 days up to and
including actual study day of week 24 visit minus 56 days
 Week 17 = Actual study Day of Week 24 visit minus 56 days up to and
including actual study day of week 24 visit minus 49 days
 Week 18 = Actual study Day of Week 24 visit minus 49 days up to and
including actual study day of week 24 visit minus 42 days
 Week 19 = Actual study Day of Week 24 visit minus 42 days up to and
including actual study day of week 24 visit minus 35 days
 Week 20 = Actual study Day of Week 24 visit minus 35 days up to and
including actual study day of week 24 visit minus 28 days
 Week 21 = Actual study Day of Week 24 visit minus 28 days up to and
including actual study day of week 24 visit minus 21 days
 Week 22 = Actual study Day of Week 24 visit minus 21 days up to and
including actual study day of week 24 visit minus 14 days
 Week 23 = Actual study Day of Week 24 visit minus 14 days up to and
including actual study day of week 24 visit minus 7 days
 Week 24 = Actual study Day of Week 24 visit minus 7 days up to and
including actual study day of week 24 visit
o
For patients who discontinue the study before Week 24:
 Week 1 = on or after Day 1 and up to and including Day 8
 Week 2 = after Day 8 and up to and including Day 15
 Week 3 = after Day 15 and up to and including Day 22
 Week 4 = after Day 22 and up to and including Day 29
 Week 5 = after Day 29 and up to and including Day 36
 Week 6 = after Day 36 and up to and including Day 43
 Week 7 = after Day 43 and up to and including Day 50
 Week 8 = after Day 50 and up to and including Day 57
 Week 9 = after Day 57 and up to and including Day 64
 Week 10 = after Day 64 and up to and including Day 71


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 Week 11 = after Day 71 and up to and including Day 78
 Week 12 = after Day 78 and up to and including Day 85
 Week 13 = after Day 85 and up to and including Day 92
 Week 14 = after Day 92 and up to and including Day 99
 Week 15 = after Day 99 and up to and including Day 106
 Week 16 = after Day 106 and up to and including Day 113
 Week 17 = after Day 113 and up to and including Day 120
 Week 18 = after Day 120 and up to and including Day 127
 Week 19 = after Day 127 and up to and including Day 134
 Week 20 = after Day 134 and up to and including Day 141
 Week 21 = after Day 141 and up to and including Day 148
 Week 22 = after Day 148 and up to and including Day 155
 Week 23 = after Day 155 and up to and including Day 162
 Week 24 = after Day 162 and up to and including Day 169
6.5.STATISTICAL TESTS
In general, unless stated otherwise, continuous variables will be summarized using descriptive 
statistics (number of patients, mean, standard deviation [SD], median, minimum and maximum 
values) and for categorical (nominal) variables, the number and percentage of patients will be 
used.
The default significant level will be 5%; CIs will be 95% and all tests will be two-sided, unless 
otherwise specified in the description of the analyses.
6.6.COMMON CALCULATIONS
x
Change from baseline: Test Value at Visit X – Baseline Value
x
Percentage change from baseline:
     Ȃ  
 
כ ͳͲͲΨ
6.7.ACTUAL TREATMENT
Once the study unblinds, the patient’s actual treatment will be assigned based on the most 
frequent medication they have received throughout the study. Patients are only expected to 
receive either 3 mg of ensifentrine, or placebo. The external vendor, Cenduit, will provide the 
Material List document after confirmation of a DBL. This document will contain the kit 


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numbers, which will be merged with the site data to obtain the treatment that was dispensed at 
each visit.
If a patient takes more than one medication and the ratio of actual treatments taking the placebo 
and ensifentrine is the same, then the patient will be assigned ensifentrine.
6.8.SOFTWARE VERSION
All analyses will be conducted using SAS version 9.4 or higher.
6.9.STRATA CALCULATIONS
There are two separate stratification factors used: background maintenance therapy strata and 
smoking strata. For both factors planned and actual will be created.
For background maintenance therapy strata:
x
Planned – As recorded in the Cenduit report.
x
Actual - As recorded in the “Concomitant medications” eCRF page: Patients that take
LAMA or LABA (or LAMA/ICS or LABA/ICS) medication with start date being before or
on randomization date and end date is either ongoing/post-randomization are classified as
being on background maintenance therapy strata. Patients that do not meet this criteria will
be classified as “No”.
For smoking strata:
x
Planned – As recorded in the Cenduit report.
x
Actual – As recorded in the “COPD and Smoking History” eCRF page.
7. STATISTICAL CONSIDERATIONS
7.1.ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN
ANALYSES
The following covariates and factors are used in the analyses. For details of their inclusion in 
the models, see the specific analysis section.
x
Fixed effects: treatment (ensifentrine, placebo), region (Europe, North America), visit (Day
1, Week 6, Week 12, Week 18, Week 24), visit*treatment, stable background maintenance
of LABA or LAMA (or LAMA/ICS or LABA/ICS) therapy use (yes, no), cigarette
smoking (current, former)


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x
Random effect: patient
x
Covariate: baseline
7.2.MULTICENTER STUDIES
This study will be conducted by multiple investigators at multiple centers internationally.
Randomization to treatment arms is not stratified by country/ center.
When specified, statistical analysis will be adjusted for geographic region. Geographic region 
will be categorized as shown in Table 3:.




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by subgroup the results will be summarized as follows:
x
Complete data with added fixed effect to the model: subgroup*treatment.
x
Data split by subgroup using the main model.
The following subgroups will be assessed and described within the analysis sections 16.1.4 and 
16.2.4 of the SAP.
x
Gender at birth:
o Female
o Male
x
Age-class (years):
o <65
o 65
x
Region
o Europe
o North America
x
Actual Background medication strata
o Yes
o No
x
Actual Smoking strata
o Current
o Former
x
Actual ICS use
o Yes
o No
x
Known chronic bronchitis
o Yes
o No
x
FEV1 reversibility at screening (12% and 200mL increase in FEV1)
o Yes
o No
x
COPD severity
o Moderate (50%  post-bronchodilator FEV1 at screening < 80% predicted)
o Severe (30%  post-bronchodilator FEV1 at screening <50% predicted)
o Very severe (post-bronchodilator FEV1 at screening <30% predicted)


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8. OUTPUT PRESENTATIONS
Appendix 1 shows conventions for presentation of data in outputs. 
The shells document provided with this SAP describe the presentations for this study and 
therefore the format and content of the summary tables, figures, and listings to be provided by 
IQVIA Biostatistics.
9. DISPOSITION AND WITHDRAWALS
All patients who provide informed consent will be accounted for in this study. 
Cenduit will be the primary source for the randomization information.
9.1.DISPOSITION
Patient disposition and withdrawals will be presented for the RND set. Study medication and 
study withdrawals of patients will be presented by the date of the “End of 
Treatment/Disposition” page of the eCRF  date of study withdrawal will be last available date 
within eCRF, the date of study medication withdrawal will be identified from End of Treatment 
page of the eCRF.
The number of study withdrawals and study medication withdrawals over the study will be 
summarized by treatment group and analyzed and presented through Kaplan-Meier plot using 
log-rank test, as described in section 16.3.3 of the SAP.
Time to study medication discontinuation by subgroups of actual background medication strata 
and actual smoking strata will be presented through Kaplan-Meier plot.
Reasons for exclusion from each analysis set, as well as patients not meeting eligibility and 
randomization criteria will be presented for the ENR set with patients classified according to 
the randomized treatment. Patients not randomized will be presented in a separate category.
9.1.1. DERIVATIONS
Study day of early study medication discontinuation = Last day of study medication intake -
First day of study medication intake + 1.
Study day of early study discontinuation = Last day in the study - First day of study medication 
intake + 1.
Visit for discontinuation will be presented using four subgroups (Not treated,  day 1 and 


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Document:
…\Verona_Pharma\RPL554\GZA93254\Biostatistics\Documentation\SAP\Verona CO-302 SAP FINAL 
v1.0_20220725
Author:
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Effective Date: 02Dec2019
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly proh bited.
week 6, > week 6 and  week 12 and > week 12 and  week 24), using the corresponding visit 
day windowing: 
x
week 6 = study day 53
x
week 12 = study day 95
x
week 24 = study day 179
9.2.PROTOCOL DEVIATIONS
PDs will be defined in the BDR report and the list will be finalized before the DBL.
9.3. EVALUATION INCLUDING EXCLUDED SITES
Site 
was removed from the Randomized set. As a check of this exclusion, the patient 
disposition will be performed in the Extended Randomized set.
10.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Demographic data and other baseline characteristics will be presented for the RND. If there is a 
difference in patients between RND and mITT population, then demographic data and other 
baseline characteristics will also be presented for mITT.
Demographic data and other baseline characteristics will also be presented by subgroups of 
actual background medication strata and actual smoking strata for mITT.
No statistical testing is planned be carried out for demographic or other baseline characteristics.
The following demographic and other baseline characteristics will be reported for this study:
x
Age (years)
x
Age-class (years) (<65, 65)
x
Gender at birth
x
Ethnicity (Hispanic or Latino, Not Hispanic or Latino (subgroup for rest of categories), Not
Reported)
x
Race
x
Country
x
Weight (kg)
x
Height (cm)
x
BMI (kg/m2)
x
FEV1 reversibility at screening (yes, no)
x
Modified Medical Research Council (mMRC) questionnaire score


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x
Pre- and post-bronchodilator FEV1 (both in liters and in percentage of predicted normal)
x
Post-bronchodilator FEV1/forced vital capacity (FVC)
x
Time since initial diagnosis of COPD (years)
x
Background medication strata [yes (subgroup for yes: LAMA, LAMA/ICS, LABA,
LABA/ICS), no] –actual
x
Known to have Chronic Bronchitis (yes, no)
x
Known to have Emphysema (yes, no)
x
Smoking strata (current (also includes stopped less than 6 months), former – stopped
greater than 6 months ago) –actual recorded in the eCRF
x
Number of cigarettes per day, Number of years smoking, Number of Pack Years
x
COPD severity based on post-bronchodilator FEV1 (Moderate, Severe, Very severe)
10.1.
DERIVATIONS
x
BMI (kg/ m2) = weight (kg)/ height (m)2
x
Time since initial diagnosis of COPD = (date of consent – date first diagnosed)/365.25
x
Pack Years = Number of packs per day x number of years smoking
Reversibility status is calculated based on pre-bronchodilator and post-bronchodilator FEV1
values taken at Screening. If patient has increase of 12% and 200mL then patient is 
reversible, else patient is non-reversible.
Age (years) collected in the eCRF will be used for the analysis.
Pack Years is automatically calculated in the eCRF and this value will be used in the 
summaries.
COPD severity will be derived as follows based on post-bronchodilator screening spirometry:
x
Mild: post-bronchodilator FEV1  80% predicted
x
Moderate: 50%  post-bronchodilator FEV1 < 80% predicted
x
Severe: 30%  post-bronchodilator FEV1 <50% predicted
x
Very severe: post-bronchodilator FEV1 <30% predicted
10.2.
EVALUATION INCLUDING EXCLUDED SITES
As a check of the exclusion of site 
from mITT, the demography and baseline disease 
characteristics will be performed in the mITT Extended.
x


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11.
SURGICAL AND MEDICAL HISTORY
Surgical and Medical History information will be presented for the SAF set.
x
Surgical History will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) central coding dictionary. The version of MedDRA to be used will be specified
prior to database lock. Data captured on the “Surgical Procedure History” page of the eCRF
will be presented by System Organ Class (SOC) and Preferred Term (PT) for each
treatment group.
x
Medical History will be coded using MedDRA central coding dictionary. The version of
MedDRA to be used will be specified prior to database lock.
o Medical History conditions, captured on the “Medical History” page of the eCRF,
are defined as those conditions which stop prior to or at Screening visit and will be
presented by SOC and PT for each treatment group.
12.
CONCOMITANT ILLNESSES
Concomitant illnesses will be presented for the SAF set.
x
Concomitant Illnesses will be coded using MedDRA central coding dictionary. The version
of MedDRA to be used will be specified prior to database lock.
o Concomitant Illnesses, captured on the “Medical History” page of the eCRF, are
conditions which started prior to the first treatment dose and are ongoing at the date
of first treatment dose, and will be presented by SOC and PT for each treatment
group.
o
13.
MEDICATIONS
Prior, prior concomitant and concomitant medications will be presented separately for the SAF 
set and coded using the World Health Organization (WHO) drug code and summarized by 
Anatomical Therapeutic Clinical Classification System (ATC) levels 1, levels 2 and 4.
Possible therapeutic subgroups include ICS, LABA, LAMA, corticosteroids, short-acting B2 
agonist, short-acting anti-muscarinic and combinations specified below, which are defined in a 
separate spreadsheet provided by the medical data reviewer. Combinations to be analyzed:
1. Oral or intravenous (IV) Corticosteroids
2. Oral or IV Corticosteroid & Other combinations
3. LAMA
4. LAMA/LABA


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5. LAMA & OTHER COMBINATIONS
6. LABA
7. LABA & Other combinations
8. ICS/LAMA/LABA or ICS/LABA/LAMA
9. ICS/LAMA
10. ICS/LABA
11. ICS & Other Combinations
12. SABA/Short-Acting Anti-Muscarinic
13. SABA
14. SABA & other combinations
15. SABA/ICS
16. SABA/ Corticosteroid
17. Short-Acting Anti-Muscarinic
See APPENDIX 2 for handling of partial dates for medications, in the case where it is not 
possible to define a medication as prior, concomitant, or post treatment, the medication will be 
classified by the worst case; i.e. concomitant. 
x
‘Prior’ medications are medications which started prior to the first dose of study medication
and stopped prior to the first dose of study medication.
x
‘Prior Concomitant’ medications are medications which started prior to the first dose of
study medication and ended on or after the date of first dose of study medication or were
ongoing at the end of the study.
x
‘Concomitant’ medications are medications which:
o started on or after the first dose of study medication and started no later than last
day of study medication intake,
o AND ended on or after the date of first dose of study medication or were ongoing
at the end of the study.
x
‘Post’ medications are medications which started from the day after the last dose of study
medication.
Prior, prior concomitant and concomitant COPD medications will be presented separately for 
the SAF set. COPD medications are those provided by medical review and will be presented as 
preferred term and ATC levels 1, levels 2 and 4.
Data captured on the “Concomitant Medications” page of the eCRF will be presented for each 
treatment group. Patients with multiple medications within an ATC/ therapeutic subgroup will 
only be counted once for that level.


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Oxygen therapy and CPAP will be listed separately to other medications. Oxygen therapy is 
defined by ATC code: “V03AN” and route is not Oral; CPAP is defined by ATC code: 
“R07AX” and route is not Oral.
14.
STUDY MEDICATION EXPOSURE
Exposure to study medication in days will be presented for the SAF set.
The dates of first dose of study medication administration will be taken from the “Drug 
Exposure” page of the eCRF (Day 1). The date of last dose of study medication administration 
will be taken as the latest date among all from the “Drug Exposure” and “Drug Exposure –
Evening Blinded Study Medication Clinic Dosing” pages of the eCRF.
If no drug exposure were made at last visit and the dispensed drug supply was insufficient to 
cover use up to last visit, the last exposure day will be set to the day the drug supply should 
have been empty if patient had been compliant to twice daily regimen.
Interruptions and compliance are not taken into account for duration of exposure. 
Study medication exposure will be presented using summary statistics by total number of days, 
and using frequency counts by subgroups: 1-42 days, 43-84 days, 85-126 days, 127-168 days 
and >168 days.
14.1.
DERIVATIONS
Duration of exposure (days) = date of last study medication administration – date of first study 
medication administration + 1.
15.
COMPLIANCE
Compliance to study medication based on dispensed and returned unused ampules and 
secondarily based on e-Diary entries will be presented for the SAF set.
Compliance will be presented using summary statistics by time intervals (Day 1 to Week12,
Weeks 12-24 and full study length), as well as using frequency counts by subgroups: <50%, 
50-70%, 70-80%, 80-90%, 90-100% and >100%.


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15.1.
STUDY MEDICATION COMPLIANCE
Study medication compliance will be summarized by treatment group in 2 ways:
x
The number of ampules dispensed and unused returned will be taken from “Drug
Accountability” page of the eCRF.
x
Drug intake as recorded in the e-diary.
Patient is non-compliant, for study medication intake collected through the number of ampules 
dispensed/returned, if identified as taking less than or equal to 70% of blinded study 
medication during the period Day 1 to Week 12, or less than or equal to 50% over the study 
(Day 1 to Week 24). Calculations will not include time after treatment withdrawal.
15.1.1. DERIVATIONS
Compliance with study medication will be calculated on the number of ampules count (total 
dispensed – total returned) divided by the prescribed number of ampules expressed as a 
percentage, see calculations below. 
Patient should take the study medication twice daily and record it in their e-Diary apart from 
Week 24 visit when patient’s last dose will be in the morning.
Patients are dispensed ampules at Visit X and return at Visit X+1, however in the eCRF 
returned ampules will be recorded under Visit X. 
x
For time interval compliance to study medication will be calculated as follows:
ሺሾ      ሿെሾ      ሿሻ
ͳ
כ ͳͲͲ 
Where Denominator1 is calculated with the following rules:
o N1 = Number of ampules expected calculated based on total N of Ampules
dispensed, taking into account 2 ampules per day, apart from last dose date for
completed patients where we would only consider 1 ampule per day.
o For non-Week 24 return ampules visit: N2 = Number of ampules between
dispensing and returning visit calculated: {[Date of Visit Y] - [Date of Dispensing
at Visit X]+1}* 2.
o For Week 24 return ampules visit: N2 = Number of ampules between dispensing
and returning visit calculated: {{[Date of Visit Y] - [Date of Dispensing at Visit
X]+1}* 2}-1.


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o If N1  N2 then Denominator1 = N2.
o If N1<N2 then Denominator1 = N1.
x
Overall Compliance to study medication will be calculated as follows:
ሺ     െ     ሻ
ʹ
כ ͳͲͲ 
Where Denominator2 is calculated with the following rules:
o N1 = Number of days calculated based on total N of Ampules dispensed, taking
into account 2 ampules per day, apart from last dose date for completed patients
where we would only consider 1 ampule per day.
o N2 = Number of days between dispensing and returning visit calculated: {{[Date of
Visit X(n)] - [Date of Dispensing at Visit 1]+1}* 2}-1.
o If N1  N2 then Denominator2 = N2.
o If N1<N2 then Denominator2 = N1.
For patients who permanently discontinue the study medication, the “Date of Visit X(n)”/
“Date of Visit Y” will be replaced by the last dose date of study medication, as specified in 
section 14 of the SAP. Whereas for patients who completed study, the “Date of Visit X(n)”/
“Date of Visit Y” will be replaced by date of last dose.
Drug intake as recorded in the e-diary: percent of ‘yes’ responses. The denominator is the 
number of records for which the patient provided an answer (Yes or No) to drug intake 
questions (morning and evening) in the e-diary.
For time interval study medication e-diary compliance, use week’s windowing conventions 
described in section 6.4 of the SAP. Use study day assigned to determine the date for weeks
required or the time intervals, Week 12 and Week 24. The compliance will be calculated as 
follows:
ሺ כ ൏  Ԣǯ      ൑ ሻ
ሺ כ ൏   െ      െ ൑ ሻכ ͳͲͲ 
*If Week X = Day 1, update “<” to be “”. If Week Y is Week 24 and patient has completed
treatment then the last entry we expect in the morning. Patient should not log any entries from
and including evening of Week 24.


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15.2.
E-DIARY COMPLIANCE
The flow of the eDiary entries patient has to follow is:
1.
E-RS
2.
Study medication compliance
3.
Background medication compliance (if applicable)
4.
Rescue medication use
Based on this, we can assess if patient has been compliant with their E-RS questions, based on 
their study medication compliance and therefore no further E-RS compliance needs to be 
assessed.
15.2.1. DERIVATIONS
E-diary compliance will be calculated as per the following. Use study day assigned to
determine the date for each week, as pe the windowing conventions described in section 6.4 of
the SAP:
ሺ כ ൏           െ ൑ ሻ
ሾ    ሿȂ ሾ    ሽ൅ͳ
כ ͳͲͲ 
*If Week X = Day 1, update “<” to be “”.
16.
EFFICACY OUTCOMES
16.1.
PRIMARY EFFICACY
The primary efficacy analysis will be performed for the mITT population.
16.1.1. PRIMARY EFFICACY VARIABLE & DERIVATION
The primary efficacy variable is change from baseline in FEV1 AUC0-12h at Week 12.
FEV1 data captured in the eResearch Technology (ERT) database will be used for the model in 
determining baseline value and for AUC calculation.
AUC0-T
Spirometry (FEV1) will be performed at Screening and the following time points during, each
treatment:


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x
Day 1: 40 minutes pre-dose (2 measurements); 30 minutes, 1, 2 and 4 hours post-dose.
x
Week 6 and Week 24: 40 minutes pre-dose; 30 minutes, 1, 2 and 4 hours post-dose.
x
Week 12 and Early Termination: 40 minutes pre-dose; 30 minutes, 1, 2, 4, 6, 8 and 12
hours post-dose.
Baseline FEV1 is the mean of the two measurements taken before study medication on the day 
of first dosing, i.e. 40 minutes pre-dose on Day 1.
The average effect will be calculated as the AUC divided by the length of the time interval of 
interest (for example, 12 hours for AUC0-12h or 4 hours for AUC0-4h). AUC will be calculated 
using the trapezoidal method, as follows:
 ൌͳ
ʹ ෍ሺ୧ାଵെ୧ሻሺ୧ାଵ൅୧ሻ
୬ିଵ
୧ୀଵ
Where Ti is the ith time value, Ci is the ith effect value, n is the number of time values. The 
change from the baseline FEV1 to average FEV1 (AUC) will be summarized and analyzed.
If two last data points are missing the AUC is set to missing, that is for AUC0-12h we require at 
least up to 8 hours of assessments and for AUC0-4h we require at least up to 2 hours of 
assessments. This would mean if we only have 8 hours of assessments, then we would calculate 
AUC0-8h, however it would still be labelled as AUC0-12h. If there is no pre-dose measurement
available for the calculation of the AUC, then the AUC will not be calculated. The pre-dose
measurement used in the calculation of AUC is the latest value measured 40 minutes pre-
dose. The pre-dose value will be used as time 0 when computing AUC0-T.
For AUC6-12h we require at least the 6-hour and 12-hour timepoint for analysis.
16.1.2. MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE
The main analysis for the primary endpoint will include estimates from missing data 
imputation described below. This is done to investigate the influence of missing data due to 
drop-outs. Only patients with non-missing baseline will be included in the analysis.
The primary analysis will be analyzed using MI based on the missing data assumption Missing 
at Random (MAR). This process will follow four steps:
1. Partially impute the data for a monotone missing pattern with 100 as a number of
imputations and “20905” as seed number. Employ the Markov Chain Monte Carlo
(MCMC) method with treatment, region, background medication strata, smoking strata,
baseline FEV1 and average FEV1 AUC0-12h at Week 12.
The following SAS codes will be used:
proc mi data=<data1> out=<data2> nimpute=100 seed=20905; 


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var <treatment>  <region>  <BackgroundMedStrata>  <SmokingStrata>  
<baseline>  <visits>; 
 mcmc impute=monotone chain=multiple; 
run; 
2. Impute the monotone data using a regression imputation model. Apply by imputation
using seed number “20905” with treatment, region, background medication strata,
smoking strata, baseline FEV1 and average FEV1 AUC0-12h at Week 12.
The following SAS codes will be used:
proc mi data=<data2> out=<dataout> nimpute=1 seed=20905;
by _imputation_; 
class <treatment>  <region>  <BackgroundMedStrata>  
<SmokingStrata>; 
var <treatment>  <region>  <BackgroundMedStrata>  
<SmokingStrata> <baseline>  <visits>; 
monotone regression; 
run;
3. Each multiple imputed dataset in Step 2 will be analyzed separately, as described in
section 16.1.3 of the SAP.
4. The estimates (LS means, SE, CI, and p-value) from the model analysis in Step 3 will
be combined using Rubin’s combination rules for statistical inference.
Sensitivity analysis will be done using:
x
Average imputation will be based on data collected on treatment at required visit, or at
early termination visit. This will be done on patient level. If there is no such data available,
impute with average change from baseline for the particular visit in the opposite
randomized treatment group.
x
Tipping point approach will repeat the ANCOVA analysis, under Missing not at Random
(MNAR) assumption, to assess the robustness of p-value significance. In case the original
analysis will produce a p-value<0.05, then the imputed values will be adjusted by a value k
(positive) added or subtracted (depending on what worsens the endpoint) to the endpoint of
the patients in Ensifentrine group (worsening results) and added or subtracted (depending
on what improves the endpoint) from the endpoint of the patients in placebo group
(improving results). The value for k is determined by adjusting the bias starting with a
value of 0.01 and increasing it with increments of 0.01 until p-value obtained from MI
method is no longer statistically significant (p-value>0.05). Seed number used will be the
same as for MI analysis, “20905”. If the primary analysis is not significant (p-value>0.05),
then the tipping point is reversed by determining value for k by adjusting the bias until p-
value0.05. If the p-value<0.05 with more improvement in the placebo group comparably


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to Ensifentrine group, then the tipping point is reversed by adjusting until there will be no 
more treatment difference between groups.
16.1.3. PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE
The primary objective of this study is to test the hypothesis that there is a difference between 
ensifentrine in comparison with placebo.
The change from baseline FEV1 to average FEV1 AUC0-12h will be compared between 
ensifentrine and placebo using ANCOVA with fixed effects for treatment, region, background 
medication strata and smoking strata and baseline FEV1 as covariate. Missing data will be 
imputed using imputation described in section 16.1.2 of the SAP. The estimated treatment 
difference will be presented with 95% CI and associated p-value. Furthermore, SD will be 
presented for the treatment difference to check the sample size with 90% power.
Summary statistics will be performed on the imputed values.
Model assumptions will be tested as per the following rules on the blinded data, before the 
DBL.
1. Residual vs Predicted plots will be created to check residuals are uncorrelated and
normally distributed.
2. Normality of the data will be checked using Kolmogorov-Smirnov normality test.
If any of the checks specified above fail the test, then alternative approaches will be discussed,
including different ways of transposing data. The SAP will be updated to reflect any changes 
prior to DBL.
Only spirometry measurements with best test review (BTR) grades “Acceptable” and 
“Borderline Acceptable” are used in the analysis and baseline calculations.
16.1.4. SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE
The primary endpoint will be presented for the following:
x
Subgroup analysis will be performed by subgroups, including data imputation described in
sections 7.5 and 16.1.2 of the SAP, respectively.
x
Observed data analysis will be performed by the following subgroups:
o
Analysis with no data imputation, including all patients with data collected, on
treatment or not, and at required timepoint or at EOS visit (excluding patients with
missing data).
o
Analysis with no data imputation, including only patients with data collected at the


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required visit while still on randomized treatment at scheduled visit, or at end of study
visit within the visit window.
x
Average imputation, as described in section 16.1.2 of the SAP.
x
Analysis with tipping point approach, as described in section 16.1.2 of the SAP.
x
Analysis with multiple imputation, as described in sections 16.1.2 and 16.1.3 of the SAP,
based on PP population.


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16.2.
SECONDARY EFFICACY
The secondary efficacy analyses will be performed for the mITT population.
These include:
x
Change from baseline FEV1 to peak FEV1 on Day 1 and at Weeks 6, 12 and 24
x
Change from baseline (i.e. mean over the last 7 days of run-in) to the mean weekly value at
Weeks 6, 12 and 24 in COPD symptoms, as measured by daily diary (E-RSTM:COPD)
x
Change from baseline in the SGRQ total score at Weeks 6, 12 and 24
x
Change from baseline FEV1 to morning trough FEV1 at Weeks 6, 12 and 24
x
Change from baseline FEV1 to average FEV1 AUC0-4h on Day 1 and at Weeks 6, 12 and 24
x
Proportion of SGRQ responders at Weeks 6, 12 and 24
x
Change from baseline (i.e. mean over the last 7 days of run-in) to the mean weekly value in
the number of puffs of rescue medication at Weeks 6, 12 and 24
x
TDI questionnaire at Weeks 6, 12 and 24
x
Change from baseline FEV1 to evening trough FEV1 at Week 12
16.2.1. SECONDARY EFFICACY VARIABLES & DERIVATIONS
Spirometry
Spirometry measurement’s best test time which is used in the analysis is measured in ERT and 
first time for spirometry measurements is measured in the eCRF and will be listed alongside 
the ERT best time.
Peak FEV1 will be computed as the maximum value in the 4 hours after dosing (4 timepoints 
after dosing: 30 minutes, 1 hour, 2 hours and 4 hours). Baseline FEV1 is the average of the two 
measurements taken before study medication on the day of first dosing, i.e. 40 minutes pre-
dose on Day 1.
Average FEV1 AUC0-4h is calculated as described in section 16.1.1.1 of the SAP.
Morning trough FEV1 is the last value collected prior to the morning dose.
Evening trough FEV1 is the value collected at the 12 hours post-morning dose timepoint and 
prior to the evening dose.
All measurements, including unscheduled measurements, within specified time period will be 
used for deriving parameters; for scheduled 12 hours post-morning dose measurement use 
regardless of being within specified time period.


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Questionnaires
E-RSTM:COPD
EXACT-Respiratory Symptoms for COPD (E-RSTM: COPD) data will be collected within 
EXACT-PRO questionnaire (consisting of 14 questions), as shown in Appendix 3. Please note 
that items 3, 8, 9, 10, 11 and 14 have separate scoring instructions, namely with the same raw 
score being assigned to several answer options. E-RSTM: COPD consists of 11 questions, with 
subdomains of: Breathlessness, Cough and Sputum, and Chest Symptoms. This data will be 
collected everyday throughout the duration of the study.
Calculating the score
E-RS subdomains:
x
Breathlessness – items 7, 8, 9, 10 and 11 (score range: 0-17)
x
Cough and Sputum – items 2, 3 and 4 (score range: 0-11)
x
Chest Symptoms – items 1, 5 and 6 (score range: 0-12)
The E-RS Total score is derived as the sum of the raw scores of the 11 items (score range: 0-
40). Total and subdomain scores are derived weekly as the mean over the days within each
window, as specified in the section 6.4 of the SAP, using only days where data was recorded.
Baseline is the mean over the 7 days prior to the first intake of study treatment, using only days
where data was recorded. If less than 4 days of data are available for the week, the weekly
mean is set to missing. Furthermore, all questions need to be answered to be evaluable for that
day.
If a patient discontinued then use treatment study end date, as the date of their last expected
visit.
The EXACT-PRO total score will be calculated by first summing the raw scores of all 14 items 
(score range: 0-51) and then looking up the corresponding EXACT-PRO total score in the table 
described in the APPENDIX 4 (converted score range: 0-100).
E-RS subdomain score is calculated as the sum from the relevant questions.
SGRQ
St. George’s Respiratory Questionnaire (SGRQ) is a questionnaire consisting of 17 questions, 
split into two parts. Part 1 consists of the first 8 questions and is related to the Symptoms 
subdomain. The remaining 9 questions are in Part 2, which are related to the Activity and 
Impacts subdomains. Each possible answer to each question has a weight assigned described in 
the APPENDIX 5.


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Note that question 6 (How long did the worst respiratory attack last?) has an additional 
instruction, “Go to Question 7 if you did not have a severe attack”. If question 6 has not been 
answered, it will be assigned a weight of zero.
Calculating the score
Subdomains:
x
Symptoms – items 1 to 8
x
Activity – items 11 and 15
x
Impacts – items 9, 10, 12, 13, 14, 16 and 17
The score for each component is calculated separately by dividing the summed weights by the 
maximum possible weight for that component and expressing the result as a percentage. It is 
not possible to have missing items in the questionnaire, as the data are collected in an 
electronic tablet which doesn’t allow patients to skip between items.
ܥ݋݉݌݋݊݁݊ݐݏܿ݋ݎ݁ൌͳͲͲ כ ܵݑ݉݋݂ݓ݄݁݅݃ݐݏ݂ݎ݋݈݈݉ܽ݌݋ݏ݅ݐ݅ݒ݁݅ݐ݁݉ݏ݅݊ݐ݄ܽݐܿ݋݉݌݋݊݁݊ݐ
ܵݑ݉݋݂݉ܽݔ݅݉ݑ݉ݓ݄݁݅݃ݐݏ݂݋ݎ݈݈ܽ݅ݐ݁݉ݏ݅݊ݐ݄ܽݐܿ݋݉݌݋݊݁݊ݐ
The total score is calculated similarly
ܶ݋ݐ݈ܽݏܿ݋ݎ݁ൌͳͲͲ כ ܵݑ݉݋݂ݓ݄݁݅݃ݐݏ݂ݎ݋݈݈݉ܽ݌݋ݏ݅ݐ݅ݒ݁݅ݐ݁݉ݏ݅݊ݐ݄ܽݐݍݑ݁ݏݐ݅݋݊݊ܽ݅ݎ݁
ܵݑ݉݋݂݉ܽݔ݅݉ݑ݉ݓ݄݁݅݃ݐݏ݂݋ݎ݈݈ܽ݅ݐ݁݉ݏ݅݊ݐ݄ܽݐݍݑ݁ݏݐ݅݋݊݊ܽ݅ݎ݁
The higher the score the more severe impact of COPD on patient’s life.
Sum of maximum possible weights for each component and Total:
Symptoms = 662.5
Activity = 1209.1
Impacts = 2117.8
Total = 3989.4
BDI/ TDI
Baseline Dyspnea Index (BDI) and Translational Dyspnea (TDI) are questionnaires that focus 
on three subdomains: Functional impairment, Magnitude of task and Magnitude of effort. BDI 
is collected at baseline (Day 1) and TDI is collected post-baseline (Weeks 6, 12 and 24).
Subdomain score is calculated as the sum from the related questions.
Total score is calculated as the sum of the subdomain scores.


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If at least one of the scores is missing, then total score is set to missing.
Rescue Medications
Baseline use of rescue medication is the mean over the last 7 days of run-in phase, using only 
days where data was recorded:
ܵݑ݉݋݂݊ݑܾ݉݁ݎ݋݂݌ݑ݂݂ݏݐܽ݇݁݊
݀ܽݕݏݎ݁ܿ݋ݎ݀݁݀
Use of medication per week is calculated as the mean use daily over 7 days, as described in the 
windowing conventions section of the SAP, calculated only based on the days data was 
recorded/verified. 
If less than 4 days of data are available for the week, the weekly mean is set to missing.
If a patient discontinued then use study discontinuation end date, as the date of their last 
expected data input.
This will be documented as Albuterol/Salbutamol in the “Rescue Medication” page of the 
eCRF, as well as in the “Rescue Medication Use” diary entry.
The rescue medication use will be confirmed in the diary using the following rules:
1. If patient has put in rescue medication use then analyze as expected
2. If patient has not put in rescue medication use, then to confirm that there was no diary
compliance issue, or IT issue, question “No Rescue Medication Confirmation” will be
checked to make sure it is filled in correctly.
3. If patient has not put in rescue medication use and question “No Rescue Medication
Confirmation” was not filled in correctly then this will be treated as diary compliance
or IT issue and therefore this day will not be used as the day recorded for the weekly
means calculation.
16.2.2. MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLES
MI method – continuous data
The analysis for key secondary endpoints (FEV1 AUC0-4h, peak FEV1, morning trough FEV1,
SGRQ total score and weekly mean E-RS total score) and for evening trough FEV1 and weekly 
rescue medication will be performed using MI based on the missing data assumption MAR. 
This process will follow four steps (below the example uses baseline FEV1, but it is repeated 
also for baseline of other key secondary endpoints mentioned above, excluding the ones 
evaluated weekly):
1. Partially impute the data for a monotone missing pattern with 100 as a number of


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imputations and “20905” as seed number. Employ the Markov Chain Monte Carlo 
(MCMC) method with treatment, region, background medication strata, smoking strata,
baseline FEV1 and <Visit data>. <Visit data> corresponds to all scheduled visits
available for the parameter analyzed. Each visit will correspond to a covariate within
the model.
The following SAS codes will be used:
proc mi data=<data1> out=<data2> nimpute=100 seed=20905; 
var <treatment>  <region>  <BackgroundMedStrata>  <SmokingStrata>  
<baseline>  <visits>; 
 mcmc impute=monotone chain=multiple; 
run;
2. Impute the monotone data using a regression imputation model. Apply by imputation
using seed number “20905” with treatment, region, background medication strata,
smoking strata, baseline FEV1 and <Visit data>.
The following SAS codes will be used:
proc mi data=<data2> out=<dataout> nimpute=1 seed=20905;
by _imputation_; 
class <treatment>  <region>  <BackgroundMedStrata>  
<SmokingStrata>; 
var <treatment>  <region>  <BackgroundMedStrata>  
<SmokingStrata> <baseline>  <visits>; 
monotone regression; 
run;
3. Each multiple imputed dataset in Step 2 will be analyzed separately, as described in
section 16.2.3 of the SAP.
4. The estimates (LS means, SE, CI and p-value) from the model analysis in Step 3 will be
combined using Rubin’s combination rules for statistical inference.
Note: For secondary endpoints that are evaluated weekly, the following updates will be 
implemented for the first 2 steps:
1. MI model will contain weekly means at all weeks available to impute the data to create
a monotone missingness pattern, so will be imputed missing values at any week (i.e
Week 1, Week 2, etc.).
2. After this, the fully imputed dataset will include weekly means at weeks corresponding
to scheduled visits in the MI model, and also only impute missing values at weeks
corresponding to scheduled visits.


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MI method – binary data
For the analyses of proportion of SGRQ, weekly mean total E-RS and Morning trough FEV1
responders, an analysis will be performed using MI based on the missing data assumption 
MAR. This process will impute the continuous underlying data, as per 16.2.2.1 (morning 
trough FEV1, SGRQ total score and weekly mean total E-RS), and then recalculate the binary 
outcome of responder or non-responder. The analysis will follow the steps below (Ratitch and 
O’Kelly, 2014, pp.124 - 127) (below the example uses morning trough FEV1, but it is repeated 
also for other endpoints mentioned above):
1) Follow steps 1 and 2 from 16.2.2.1 for the continuous morning trough FEV1 results.
2) For the imputed results re-calculate response, where a response is an improvement from
baseline in morning trough FEV1 of 100 mL.
3) Analyse each multiply imputed dataset separately, as described in section 16.2.3 of the
SAP, producing LS Means, odd ratios and corresponding 95% confidence interval and p-
value.
4) For the odds ratios:
a) Before applying Rubin’s rule, apply a normalising transformation to the odds ratios as
well as their standard errors. The distribution of the log of odds ratios approximates to a
normal distribution. Therefore, calculate the transformed values, where OR is odds
ratio, Lower/Upper CL are the confidence interval estimates of the ORs:
ܱܴ௡௢௥௠ൌሺܱܴሻ
ܵܧ௡௢௥௠ൌሺሺܷ݌݌݁ݎܥܮሻെሺܮ݋ݓ݁ݎܥܮሻሻ
ሺʹ ൈͳǤͻ͸ሻ
b) Appy Rubin’s rule with PROC MIANALYZE to the transformed odds ratios with
corresponding transformed standard errors.
c) Back-transform the combined results as follows:
ܱܴ௕௧ൌ݁ݔ݌ைோ೙೚ೝ೘
ܮ݋ݓ݁ݎܥܮ௕௧ൌܱܴ௕௧ൈ݁ሺିଵǤଽ଺ൈௌா೙೚ೝ೘ሻ
ܷ݌݌݁ݎܥܮ௕௧ൌܱܴ௕௧ൈ݁ሺଵǤଽ଺ൈௌா೙೚ೝ೘ሻ
5) For the odds of response per treatment arm
a) Take the LS means to be estimates of the log-odds of response per treatment arm and
assume that they asymptotically tend to a normal distributions.


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b) Appy Rubin’s rule with PROC MIANALYZE to the LS means.
c) Transform the combined results by exponentiating to get the odds of response per
treatment arm.
MI method – range data
The sensitivity analysis for key secondary endpoints (SGRQ total score and weekly mean E-RS 
total score), the main analysis of TDI and EQ-5D-5L will be performed using MI based on the 
missing data assumption MAR as described in the section 16.2.2.1 of the SAP. Additionally, in
the first 2 steps the MIN= and MAX= options will be used to restrict the possible values that 
can be drawn referred to each endpoint (Laura Rodwell, 2014).
Other methods
As a sensitivity analysis, other missing data method for key secondary endpoints will follow 
the average imputation and tipping point approach taken for primary endpoint outlined in 
section 16.1.2 of the SAP.
16.2.3. ANALYSIS OF SECONDARY EFFICACY VARIABLES
Change from baseline variables, incl. TDI
All variables used in change from baseline analysis (incl. average FEV1 AUC0-4h, peak FEV1,
morning trough FEV1, evening trough FEV1, mean weekly E-RSTM: COPD, SGRQ, mean 
weekly rescue medication and TDI) will be analyzed using ANCOVA approach, as described 
in section 16.1.3 of the SAP. BDI will be used as a baseline for TDI. Missing data will be 
imputed using imputation described in section 16.2.2.3 of the SAP.
Model assumptions will be tested and solved, if failed, as per section 16.1.3 of the SAP.
A plot of the mean change from baseline FEV1 to each post-dose FEV1 result over time will be 
created by subgroups of actual background medication strata and actual smoking strata, visit 
and treatment group. 
A plot of the least squares means change from baseline to event over time will be presented 
(based on the ANCOVA analysis). Events will include weekly mean total E-RS score, SGRQ 
and weekly mean rescue medication use.


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Only FEV1 measurements with BTR grades “Acceptable” and “Borderline Acceptable” are 
used in the analysis.
Proportion of SGRQ total responders 
Proportion of responders, with an improvement from baseline in SGRQ total score of 4 or more 
will be analyzed using a logistic regression model with fixed effects for treatment, region, 
actual background medication strata and actual smoking strata at baseline and baseline SGRQ 
total score as covariate. Missing data will be imputed as described in section 16.2.2.3.
16.2.4. SENSITIVITY ANALYSIS OF SECONDARY EFFICACY VARIABLES
For the key secondary endpoints, the following sensitivity analysis will be performed at Week 
12.
Subgroup analysis as specified in section 7.5 of the SAP.
x
ANCOVA analysis with average imputation, as described in section 16.2.2 of the SAP.
x
ANCOVA analysis with MI, only considering baseline and Week 12 (for lung function
parameters) in the imputation model, as described in section 16.1.2 and 16.1.3 of the SAP.
x
ANCOVA analysis with MI using the range data method as described in section 16.2.2.3
for SGRQ total score and weekly mean total E-RS.
x
Tipping point approach, as described in section 16.1.2 of the SAP.
x
Analysis with MI method, as described in sections 16.2.2 and 16.2.3 of the SAP, based on
PP population.
For FEV1 key secondary endpoints (FEV1 AUC0-4h, peak FEV1, morning trough FEV1)
additional sensitivity analysis will be performed:
x
MMRM model with treatment, visit and treatment by visit as fixed effect; baseline as
covariate; patient as random factor; unstructured covariance by visit. If the model does not
converge a compound symmetry covariance structure will be used. Kenward-Roger method
will be used to estimate the model degrees of freedom.weeks.
For weekly mean E-RS total score and SGRQ total score, additional analysis will be 
performed:
x
For weekly mean E-RS total score at 6, 12 and 24 weeks, using ANCOVA approach, as
described in section 16.2.3 of the SAP, all patients with baseline weekly mean = 0 will be
excluded.
x
For SQRG total score at 6, 12 and 24 weeks, using ANCOVA approach, as described in
section 16.2.3.1 of the SAP, all patients with baseline assessment done after dosing time
and date will be excluded.


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16.3.
OTHER EFFICACY
The other efficacy analyses will be performed for the mITT population.
x
Moderate/severe COPD exacerbation frequency over 24 weeks.
x
Time to first moderate/severe COPD exacerbation over 24 weeks.
x
Study withdrawal before scheduled visit at 24 weeks.
x
Change from baseline to post-baseline EQ-5D-5L at Week 12
x
HRU over 24 weeks
x
Change from baseline FEV1 to average FEV1 AUC6-12h at Week 12
x
Ensifentrine concentrations following sparse PK sample collection at Weeks 6, 12 and 24
x
Patient genotype/phenotype including but not limited to cytochrome P-450 (CYP)2C9 and
CYP2D6 metabolic activity
x
Interleukin (IL)-6, IL-8 and C-reactive protein at Weeks 12 and 24
x
E-RS responder analysis
x
Morning trough FEV1 responder analysis
16.3.1. OTHER EFFICACY VARIABLES & DERIVATIONS
COPD exacerbation 
COPD exacerbations are collected on the “COPD Exacerbation” page of the eCRF and severity 
will be derived separately using data collected in the eCRF and as per the criteria specified in 
section 11.6.1. of the study protocol.
Site must enter at least 2 major symptoms, or one major symptom and one minor symptom 
AND meet the severity criteria below, considered as a moderate or severe exacerbation of 
COPD.
The severity of the COPD exacerbation will be calculated as per the following:
Moderate: Worsening symptoms of COPD requiring a minimum of three days of treatment 
with oral/systemic corticosteroids and/ or antibiotics.
Severe: Worsening symptoms of COPD requiring in-patient hospitalization.
EQ-5D-5L
Quality of Life (QoL) was assessed using the EQ-5D-5L questionnaire. This questionnaire 


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consits of 5 domains: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression with 5 possible responses from 1 (no problem) to 5 (unable). The sixth item,
referred to as a visual analogue scale (VAS) score, is an index score to self-rate health from 0 
(worst) to 100 (best). Each of the 5 domains will be summed through weighing system into a 
health index. The health index and VAS score will be analysed and listed and 5 domains will 
be only listed. It is not possible to have missing items in the questionnaire, as the data are 
collected in an electronic tablet which doesn’t allow patients to skip between items. The 
weighting system is described in APPENDIX 6 of the SAP.
HRU
HRU is measured by the following events: unscheduled visits to a physician office, visits to 
urgent care, visits to emergency department and hospitalizations for any cause and/or related to 
COPD and visits/contact due to COPD exacerbation. These will be recoded on the Log Form 
and “COPD Exacerbation” pages of the eCRF, respectively .
Genotype/phenotype
Genetics analysis is described in section 18 of the SAP.
Patient Perception Survey
At the follow-up contact each patient will fill in a survey on their perception of what drug they 
were on. Data recorded on “Patient Perception Survey” page of the eCRF will be listed and 
summarized by treatment group for the following categories:
x
Patients who correctly guessed their drug
x
Patients who incorrectly guessed their drug
x
Patients who were unsure of their drug
FEV1 AUC6-12h
Average FEV1 AUC6-12h is calculated as described in section 16.1.1.1 of the SAP.
E-RS total score responder
E-RS total score responder is defined as a decrease from baseline in the week mean total of E-
RS score greater than or equal to 2.
Morning trough FEV1 responder 
Morning trough FEV1 responder is defined as an increase from baseline in the Morning trough 
FEV1 greater than or equal to 100 mL.


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16.3.2. MISSING DATA METHODS FOR OTHER EFFICACY VARIABLES
For EQ-5D-5L missing data will be imputed using imputation described in section 16.2.2.3 of
the SAP and FEV1 AUC6-12h missing data will be imputed using imputation described in 
section 16.2.2.1 of the SAP. Morning trough FEV1 responder missing data will be handled as 
described in sections 16.2.2.2 of the SAP. E-RS total score responder missing data will be 
imputed similar to the SGRQ total score responder analysis as described in sections 16.2.2.3 of
the SAP.
16.3.3. ANALYSIS OF OTHER EFFICACY VARIABLES
Change from baseline to average FEV1 AUC6-12h will be analyzed using ANCOVA approach 
and missing data will be imputed using imputation, as described in sections 16.1.3 and 16.2.2.1
of the SAP, respectively. 
Model assumptions will be tested and solved, if failed, as per section 16.1.3 of the SAP.
The number of moderate or severe COPD exacerbations will be analyzed using a negative 
binomial model adjusting for treatment, region, actual background medication strata and actual 
smoking strata, as well as using log study time (years) as an offset. For study time, Visit 5 will 
be taken into account for completer patients, and End of Study visit or last contact date for 
withdrawal patients. The treatment difference from the negative binomial model will be 
expressed as an annualized risk ratio. The data will also be summarized by treatment group
over duration of the study period. 
Time to first moderate or severe COPD exacerbation during the study period will be presented 
as per following:
x
Primary approach: Analyzed using the log-rank test, stratified by region, actual
background medication strata and actual smoking strata. Summary of number of
patients with events and number of patients censored will be summarized. Outcome
visualized using a Kaplan-Meier plot.
x
Sensitivity analysis: Analyzed using Cox proportional hazards Regression model
stratified by region, background medication strata and smoking strata. Patients without
exacerbations will be censored at last day in the treatment period, including period of
recording after possible treatment withdrawal. The treatment difference in the Cox
model will be expressed as a hazard ratio.
Testing proportional hazard assumptions:


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1. Check that the covariates are independent of each other through proc phreg in SAS
software.
2. Check that the hazard (hazard ratio) is independent of time through log(-log(survival))
vs log(time) plot and an interaction test for treatment times log(time).
The health index and VAS score for EQ-5D-5L questionnaire will be analyzed using 
ANCOVA approach, as described in section 16.1.3 of the SAP, with data imputation described 
in section 16.2.2.3 of the SAP.
HRU over 24 weeks will be summarized for each event and for overall count.
Analysis for the genetics data is described in section 18 of the SAP.
Sensitivity analysis of subgroup analysis may be considered following results of the patient 
perception survey. The survey will be summarized to investigate if there are any signs of
breeching of the blind related to the appearance of study medication.
Proportion of E-RS total score responders will be analyzed by means of a logistic regression 
model with fixed effects for treatment, region, actual background medication strata and actual 
smoking strata at baseline and baseline E-RS total score as covariate. Missing data will be 
imputed as described in sections 16.2.2.2 and 16.2.2.3.
Proportion of responders, with an improvement from baseline in Morning trough FEV1 of 100
mL or more will be analyzed using a logistic regression model with fixed effects for treatment, 
region, actual background medication strata and actual smoking strata at baseline and baseline 
Morning trough FEV1 as covariate. Missing data will be imputed as described in sections
16.2.2.2 and 16.2.2.3.
16.3.4. SENSITIVITY ANALYSIS OF OTHER EFFICACY VARIABLES
Sensitivity analysis with no data imputation, including only patients with data collected at the 
required visit while still on randomized treatment at scheduled visit, or at end of study visit 
within the visit window will be performed on the health index and VAS score for EQ-5D-5L 
questionnaire and analyzed using ANCOVA approach, as described in section 16.1.3 of the 
SAP.
Time to first moderate or severe COPD exacerbation will be analyzed using Cox proportional 
hazards Regression model as described in section 16.3.3.


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16.4.
EVALUATION INCLUDING EXCLUDED SITES
Site 
 was removed from the mITT. As a check of the impact of this exclusion, the
following analyses will be performed in the mITT Extended dataset.
x
Analysis of FEV1 AUC0-12
x
Analysis of peak FEV1
x
Analysis of E-RS total score
x
Analysis of SGRQ total score
x
Analysis of morning trough FEV1
x
Responder analysis of SGRQ total score
17.
SAFETY OUTCOMES
All outputs for safety outcomes will be based on the SAF set.
There will be no statistical comparisons between the treatment groups for safety data, unless 
otherwise specified with the relevant section. 
17.1.
ADVERSE EVENTS
Adverse Events (AEs) will be coded using MedDRA central coding dictionary. The version of 
MedDRA to be used will be specified prior to database lock.
Treatment-emergent adverse events (TEAEs) are defined as AEs that started or worsened in 
severity on or after the first dose of study medication. Laboratory or ECG findings from 
procedures or samples drawn prior to the first does of study medication that are 
assessed/overread after randomization will be considered pre-treatment.
In the case where it is not possible to define an AE as treatment-emergent or not, the AE will 
be classified by the worst case; i.e. treatment-emergent. 
See Appendix 2 for handling of partial dates for AEs.
An overall summary of number of patients within each of the categories described in the sub-
section below, will be provided as specified in the shells. In addition, the number of patients 
with each of the following AE events will be presented by SOC and PT and summarized by 
treatment group and different period (i.e. Treatment period, Follow-up and Overall):
x
TEAE
x
TEAEs causally related to study medication


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x
Serious TEAEs
x
TEAEs with an outcome of death
x
TEAEs leading to discontinuation of blinded study medication
x
TEAEs leading to withdrawal from study (TEAEs with a diagnosis of COVID-19, TEAEs
with no diagnosis of COVID-19)
x
TEAEs by maximum severity
AEs will be identified by using the “Adverse Events” page of the eCRF. Listings will include 
TEAEs and Non-TEAEs.
Treatment period is defined as the period from the date and time of first dose up to the date and 
time of last dose.
Follow-up is defined as the period from after the date and time of last dose up to the last date 
recorded on the study.
17.1.1. ALL TEAES
Incidence of TEAEs will be presented by SOC and PT and broken down further by maximum 
severity and relationship to study medication.
Severity
Severity is classed as mild/ moderate/ severe (increasing severity). TEAEs starting after the 
first dose of study medication with a missing severity will be classified as severe. If patient
reports a TEAE more than once within that SOC/ PT, the AE with the worst-case severity will 
be used in the corresponding severity summaries.
Relationship to Study Medication
Relationship, as indicated by the Investigator, is classed as “unknown”, “unrelated”, “unlikely 
to be related”, “possibly related” and “probably related” (increasing probability of
relationship). A ”related” TEAE is defined as a TEAE with a relationship to study medication 
as ”possibly related” or ”probably related” to study medication. TEAEs with a missing 
relationship to study medication will be regarded as ”probably related” to study medication. If 
a patient reports the same AE more than once within that SOC/ PT, the AE with the worst case 
relationship to study medication will be used in the corresponding relationship summaries. 
17.1.2. TEAES LEADING TO DISCONTINUATION OF STUDY MEDICATION
TEAEs leading to discontinuation of study medication are AEs recorded as “Study Treatment 
Permanently Discontinued” on the “Adverse Events” page of the eCRF.


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For TEAEs leading to discontinuation of study medication, summaries of incidence rates 
(frequencies and percentages) by SOC and PT will be prepared.
17.1.3. SERIOUS ADVERSE EVENTS
Serious adverse events (SAEs) are those events recorded as ”Serious” on the “Adverse Events”
page of the eCRF. A summary of serious TEAEs by SOC and PT and by treatment group and 
different period (i.e. Treatment period, Follow-up and Overall) will be prepared.
17.1.4. ADVERSE EVENTS LEADING TO DEATH
TEAEs leading to Death are those events which are recorded as ”Fatal” on the “Adverse 
Events” page of the eCRF. A summary of TEAEs leading to death by SOC and PT will be 
prepared.
17.2.
LABORATORY EVALUATIONS
Results from the central laboratory (or local laboratory where this is required) will be included 
in the reporting of this study for chemistry, hematology and viral serology. A list of laboratory 
assessments to be included in the outputs is included in the Appendix 3 of the study protocol.
Presentations of all laboratory tests will use standard international (SI) units. However, certain 
laboratory tests will also be presenting using US units, including liver tests.
The handling of re-test and unscheduled measurements is detailed in section 6.4 of the SAP.
The following summaries will be provided for chemistry and hematology data:
x
Actual and change from baseline by visit (for quantitative measurements)
x
Incidence of abnormal values according to normal range criteria
x
Shift from baseline according to normal range criteria (for quantitative measurements and
categorical measurements)
x
Shift from baseline according to markedly abnormal criteria (for quantitative measurements
and categorical measurements)
x
Listing of patients meeting markedly abnormal criteria
Viral serology, COVID-19 sample, chemistry and hematology will be listed. 




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x
QRS Interval (msec)
x
QT Interval (msec)
x
QTcF Interval (msec)
x
QTcB Interval (msec)
x
Heart Rate (beats per minute [bpm])
x
Overall assessment of ECG (Investigator’s judgment):
o Normal
o Abnormal, Not Clinically Significant (ANCS)
o Abnormal, Clinically Significant (ACS)
On Day 1, prior to dosing, triplicate ECGs must be performed. Triplicate results will be used in 
the summaries by taking an average of the 3 results. The average of the 3 results will be the 
baseline. Baseline for the investigator’s judgement will be the mode judgment of the 3 results. 
In the case of multiple modes, the mode with the worst-case judgment (Normal<ANCS<ACS) 
will be used as baseline.
If only 2 ECG measurements instead of triplicate on Day 1 pre-dose, take average of the two; if 
only 1 measurement then this will be the baseline.
The handling of re-test and unscheduled measurements is detailed in section 6.3of the SAP.
If there were more measurements on a scheduled visit, choose measurement as follows:
1. Choose first triplicate, if more than one done.
2. If done on Day 1, ensure you choose measurement that it is prior to dosing.
3. If there are more than 1 ECG measurements, choose the scheduled one where
interpretation of the measurement from the vendor data is not ”UNABLE TO
EVALUATE” .
a.
If pre-dose/post-dose and interpretation of the measurement from the vendor
data is ”UNABLE TO EVALUATE” and no further pre-dose/post-dose
unscheduled visits on the same day, respectively – set to missing
b. If pre-dose/post-dose and interpretation of the measurement from the vendor
data is ”UNABLE TO EVALUATE” and there is another unscheduled pre-
dose/post-dose – choose next unscheduled visit on the same day
The following summaries will be provided for ECG data:
x
Actual and change from baseline by visit (for quantitative measurements)
x
Shift table representing changes from Normal, ANCS and ACS, using Investigator’s
judgement
x
Incidence of markedly abnormal criteria


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x
Listing of patients meeting markedly abnormal criteria
17.3.1. ECG MARKEDLY ABNORMAL CRITERIA
Markedly abnormal quantitative ECG measurements will be identified in accordance with the 
following predefined markedly abnormal criteria:
x
Absolute values for QT interval, QTcB interval and QTcF interval will be classified as:
o > 450 msec
o > 480 msec
o > 500 msec
x
Change from Baseline for QT interval, QTcB interval and QTcF will be classified as:
o >30 msec increase from baseline
o >60 msec increase from baseline
17.4.
VITAL SIGNS
The following Vital Signs measurements will be reported for this study:
x
Supine Systolic Blood Pressure (mmHg)
x
Supine Diastolic Blood Pressure (mmHg)
x
Supine Pulse Rate (bpm)
x
Respiratory Rate (breaths/min)
x
Temperature (ၨC)
x
Body weight (kg)
x
Height (cm)
x
BMI (kg/m2)
The following summaries will be provided for vital signs data (excluding respiratory rate, 
temperature, body weight, height and BMI):
x
Actual and change from baseline by visit
x
Incidence of markedly abnormal values
x
Shift from baseline according to markedly abnormal criteria
x
Listing of patients meeting markedly abnormal criteria
Respiratory rate, temperature, body weight, height and BMI will be listed.




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17.7.
EVALUATION INCLUDING EXCLUDED SITES
The following analyses will be performed on the Extended Safety Set:
x
Summary of TEAEs
x
TEAEs by SOC and PT
x
Related TEAEs by SOC and PT
x
Serious TEAEs by SOC and PT
x
Markedly abnormal values for selected chemistry parameters
x
Markedly abnormal values for vital signs
x
Markedly abnormal values for ECG parameters
18.
GENETIC ANALYSIS
Genotyping analyses (CYP2C9 and CYP2D6 phenotypes) will be completed as exploratory 
analysis by the sponsor and are not covered in this SAP.
19.
BIOMARKER ANALYSIS
Assessment of Biomarkers (IL-6, IL-8 and C-Reactive Protein [CRP]) will be analyzed for the 
mITT using ANCOVA approach, as described in section 16.1.3 of the SAP at Weeks 12 and 
24. Log transformation will be done on the data for the ANCOVA analysis. Values that are
below limit of quantitation (LOQ) will be treated as LOQ/2 for analyses and summaries.
Missing data will not be imputed. Biomarker data are blinded until after DBL.
20.
PHARMACOKINETIC ANALYSIS
20.1.
DEVIATIONS RELATED TO PK
Changes to the procedures or events, which may impact the quality of the pharmacokinetic 
(PK) data, will be considered important PDs for the purpose of inclusion of the affected results 
in the concentration summary. These changes or events will include any circumstances that 
will alter the evaluation of the PK. Examples include, but may not be limited to, an 
incomplete/inaccurate dose of ensifentrine inhaled and/or a prolonged interruption of 
nebulization (example due to prolonged coughing, etc.), sample handling/shipment/processing 
errors that lead to inaccurate bioanalytical results, and/or noncompliance in ensifentrine 
administration (inaccurate and/or incomplete dose administration). Interruption of nebulization 




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summaries. There will be no imputation of missing data.
A listing of PK blood sample collection times, derived sampling time deviations, and actual 
sample time will be also provided. Blood samples are to be collected as per schedule of Table 9 
in Protocol. All PK concentrations will be listed with the same precision as the source data 
provided by the bioanalytical laboratory regardless of how many significant figures or decimal 
places the data carry. 
For the reporting of descriptive statistics of PK concentrations, the mean and SD will be 
presented to 1 digit more precision than the source data. The minimum, median, and maximum 
will be presented to the same precision as the source data. CV% will always be reported to 1 
decimal place. A minimum of n=3 is required for all descriptive statistics to be generated. If n
is less than 3, only N, n, minimum, and maximum will be reported. 
The concentration listing and summary will be described as appropriate in the clinical study 
report.
20.3.
POPULATION PK ANALYSIS
The strategy for the population PK analysis and any related exposure-response modeling 
utilizing the ensifentrine concentration and response data from this study will be outlined 
separately in the modeling data analysis plan prepared by Verona Pharma/Designee.
21.
DATA NOT SUMMARIZED OR PRESENTED
The other variables and/or domains not summarized or presented are:
x
Comments
x
Physical Examinations, as it is not collected within eCRF
These domains and/or variables will not be summarized or presented, but if collected will be 
available in the clinical study database, SDTM and/or ADaM datasets.


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22.
REFERENCES
Devlin N, S. K. (2017, June). Valuing health-related quality of life: An EQ-5D-5L value set. 
EMA. 
(2014, 
October). 
EXACT-PRO 
Initiative. 
Retrieved 
from 
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/04/WC500185444.pdf 
EQ-5D. (2019, September). EQ-5D-5L User Guide v3.0. Retrieved from EQ-5D. 
Golicki D, J. M. (2019, June). Valuation of EQ-5D-5L Health States in Poland: the First EQ-VT-Based. 
ICH. (2019). ADDENDUM ON ESTIMANDS AND SENSITIVITY ANALYSIS IN CLINICAL TRIALS.  
Jones, P. P. (2009, June). ST GEORGE’S RESPIRATORY QUESTIONNAIRE MANUAL.  
Laura Rodwell, K. J. (2014). Comparison of methods for imputing limited-range variables: a simulation study. BMC 
Medical Research Methodology. 
Merinopoulou E, R.-C. M. (2016). COPD exacerbations by disease severity in England. Int J Chron Obstruct Pulmon 
Dis. 
Pickard S, L. E. (2019, August). United States Valuation of EQ-5D-5L Health States Using an International. 
Ratitch B., O. M. (2014). Clinical Trials with Missing Data: A Guide for Practitioners. John Wiley & Sons, Ltd. 
SAS Institute, Inc. (1999). SAS Procedures Guide, version 8. Cary, NC: SAS Institute. 


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APPENDIX 1.
PROGRAMMING CONVENTIONS FOR OUTPUTS
DATES & TIMES
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss.
SPELLING FORMAT
English US.
PRESENTATION OF TREATMENT GROUPS
For outputs, treatment groups will be represented as follows and in the given order:
Treatment Group
For Tables, Listings and Graphs
Ensifentrine
Ensifentrine
Placebo
Placebo
Not Randomized
Not Randomized
DECIMAL PLACES
The decimal places for this study will use the following rules, unless otherwise stated.
Value = x dp
Mean = x+1 dp
Standard Deviation = x+2 dp
Median = x+1 dp
Q1/Q3 = x+1 dp
Minimum/Maximum = x dp
CI = x+1 dp
In case a variable has values with infinite decimal places, the following rules will be used:
Value = 1 dp
Mean = 2 dp
Standard Deviation = 3 dp
Median = 2 dp
Q1/Q3 = 2 dp
Minimum/Maximum = 1 dp


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CI = 2 dp
For spirometry data we will present outputs with decimal places for value as follows:
x
Values in liters = 3 dp, i.e. mean/median/Q1/Q3/CI in liters = 4 dp, standard deviation =
5 dp and minimum/maximum = 3 dp.
x
Values in milliliters = 0 dp, i.e. mean/median/Q1/Q3/CI in liters = 1 dp, standard
deviation = 2 dp and minimum/maximum = 0 dp.
x
Percentage values = 1 dp, i.e. mean/median/Q1/Q3/CI in liters = 2 dp, standard
deviation = 3 dp and minimum/maximum = 1 dp.
P-values will be presented to 4dp.
PRESENTATION OF VISITS
For outputs, visits will be represented as follows and in that order:
Long Name (default)
Short Name 
Screening
Screening
day 1
day 1
week 6
week 6
week 12
week 12
week 18
week 18
week 24
week 24
Follow-up
Follow-up
LISTINGS
All listings will be ordered by the following (unless otherwise indicated in the template):
x
Randomized treatment group (or treatment received if it’s a safety output), first by active
dose and then placebo,
x
Center-patient ID,
x
Date and time (where applicable),
x
For listings where non-randomized patients are included, these will appear in a category


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after the randomized treatment groups labeled ‘Not Randomized’.
TABLES
All tables presenting multiple events that map to a SOC and PT will be counted only once, per 
unique patient, for incidence counts. Events will be presented in descending frequency of SOC 
and PT (unless otherwise indicated in the shells). 








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START 
DATE
STOP 
DATE
ACTION
Missing
Known
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘prior concomitant’ and ‘post treatment’
Partial
Impute stop date as latest possible date (i.e. last day of month if 
day unknown or 31st December if day and month are 
unknown), then:
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘prior concomitant’ and ‘post treatment’
Missing
Assign as concomitant




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Statistical Analysis Plan
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START 
DATE
STOP 
DATE
ACTION
Partial
Impute stop date as latest possible date (i.e. last day of month if 
day unknown or 31st December if day and month are 
unknown), then:
If stop date > date of first treatment dose, assign as concomitant 
illness
Missing
If stop date is missing then assume concomitant illness


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APPENDIX 3.
ANNOTATED EXACT FOR RAW SCORE ASSIGNMENT
1. Did your chest feel congested today?
0.Not at all
1.Slightly
2.Moderately
3.Severely
4.Extremely
2. How often did you cough today?
0.Not at all
1.Rarely
2.Occasionally
3.Frequently
4.Almost constantly
3. How much mucus (phlegm) did you bring up when
coughing today?
0.None at all
1.A little
1.Some
2.A great deal
3.A very great deal
4. How difficult was it to bring up mucus (phlegm)
today?
0.Not at all
1.Slightly
2.Moderately
3.Quite a bit
4.Extremely
5. Did you have chest discomfort today?
0.Not at all
1.Slight
2.Moderate
3.Severe
4.Extreme
6. Did your chest feel tight today?
0.Not at all
1.Slightly
2.Moderately
3.Severely
4.Extremely
7. Were you breathless today?
0.Not at all
1.Slightly
2.Moderately
3.Severely
4.Extremely


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8.Describe how breathless you were today
0.Unaware of breathlessness
1.Breathless during strenuous activity
2.Breathless during light activity
3.Breathless when washing or dressing
3.Present when resting
9. Were you short of breath today when performing
your usual personal care activities like washing or
dressing?
0.Not at all
1.Slightly
2.Moderately
3.Severely
3.Extremely
4.Too breathless to do these
10. Were you short of breath today when performing
your usual indoor activities like cleaning or household
work?
0.Not at all
1.Slightly
2.Moderately
3.Severely
3.Extremely
3.Too breathless to do these
11. Were you short of breath today when performing
your usual activities outside the home such as yard
work or errands?
0.Not at all
1.Slightly
2.Moderately
3.Severely
3.Extremely
3.Too breathless to do these
12. Were you tired or weak today?
0.Not at all
1.Slightly
2.Moderately
3.Severely
4.Extremely
13. Last night, was your sleep disturbed?
0.Not at all
1.Slightly
2.Moderately
3.Severely
4.Extremely
14. How scared or worried were you about your lung
problems today?
0.Not at all
1.Slightly
2.Moderately
3.Severely


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3.Extremely


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APPENDIX 4.
RAW SUMMED SCORE TO SCALE CONVERSION 
TABLE FOR EXACT TOTAL SCORE
Raw Summed 
Score
EXACT Total 
Score
Raw Summed 
Score
EXACT Total 
Score
0
0
26
50
1
8
27
51
2
13
28
52
3
17
29
53
4
20
30
54
5
23
31
55
6
25
32
57
7
27
33
58
8
28
34
59
9
30
35
60
10
31
36
61
11
33
37
63
12
34
38
64
13
36
39
65
14
37
40
67
15
38
41
68
16
39
42
70
17
40
43
72
18
41
44
73
19
42
45
75
20
43
46
77
21
44
47
80
22
46
48
83
23
47
49
87
24
48
50
92
25
49
51
100


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APPENDIX 5.
SGRQ ITEM WEIGHTS
Question
Answers
Weight
Part 1
Question 1: Over the past 4 weeks, I have 
coughed
Almost every day
80.6
Several days a week
63.2
A few days a month
29.3
Only with respiratory infections
28.1
Not at all
0.0
Question 2: Over the past 4 weeks, I have 
brought up phlegm (sputum)
Almost every day
76.8
Several days a week
60.0
A few days a month
34.0
Only with respiratory infections
30.2
Not at all
0.0
Question 3: Over the past 4 weeks, I have 
shortness of breath
Almost every day
87.2
Several days a week
71.4
A few days a month
43.7
Only with respiratory infections
35.7
Not at all
0.0
Question 4: Over the past 4 weeks, I have 
wheezing attacks
Almost every day
86.2
Several days a week
71.0
A few days a month
45.6
Only with respiratory infections
36.4
Not at all
0.0
Question 5: How many times during the 
past 4 weeks have you suffered from 
severe or very unpleasant respiratory 
attacks?
More than 3 times
86.7
3 times
73.5
2 times
60.3
1 time
44.2
None of the time
0.0
Question 6: How long did the worst 
respiratory attack last?
A week or more
89.7
3 or more days
73.5


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(Go to Question 7 if you did not have a 
severe attack)
1 or 2 days
58.8
Less than a day
41.9
Question 7: Over the past 4 weeks, in a 
typical week, how many good days (with 
few respiratory problems) have you had?
No good days
93.3
1 or 2 good days
76.6
3 or 4 good days
61.5
Nearly every day was good
15.4
Every day was good
0.0
Question 8: If youwheeze, is it worse 
when you get up in the morning?
No
0.0
Yes
62.0
Part 2
Question 9: How would you describe 
your respiratory condition?
The most important problem I have
83.2
Causes me quite a lot of problems
82.5
Causes me a few problems
34.6
Causes no problem
0.0
Question 10: If you ever held a job
My respiratory problems made me 
stop working altogether
88.9
My respiratory problems interfere 
with my job or made me change my 
job
77.6
My respiratory problems do not affect 
my job
0.0
Question 11: Questions about what 
activities usually make you short of 
breath these days
Sitting or lying still
90.6
Washing or dressing yourself
82.8
Walking around the house
80.2
Walking outside on level ground
81.4
Walking up a flight of stairs
76.1
Walking up hills
75.1
Playing sports or other physical 
activities
72.1
Question 12: More questions about your 
cough and shortness of breath these days
Coughing hurts
81.1
Coughing makes me tired
79.1


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I am short of breath when I talk
84.5
I am short of breath when I bend over
76.8
My coughing or breathing disturbs 
my sleep
87.9
I get exhausted easily
84.0
Question 13: Questions about other 
effects your respiratory problems may
have on you these days
My cough or breathing is 
embarrassing in public 
74.1
My respiratory problems are a
nuisance to my family, friends or 
neighbors 
79.1
I get afraid or panic when I cannot 
catch my breath 
87.7
I feel that I am not in control of my 
respiratory problems
90.1
I do not expect my respiratory 
problems to get any better
82.3
I have become frail or an invalid 
because of my respiratory problems
89.9
Exercise is not safe for me 
75.7
Everything seems too much of an 
effort
84.5
Question 14: Questions about your 
respiratory treatment
My treatment does not help me very 
much
88.2
I get embarrassed using my 
medication in public
53.9
I have unpleasant side effects from 
my medication
81.1
My treatment interferes with my life a 
lot
70.3
Question 15: Questions about how 
activities may be affected by your 
respiratory problems
I take a long time to get washed or 
dressed
74.2
I cannot take a bath or shower, or I 
take a long time
81.0


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I walk more slowly than other people, 
or I stop to rest
71.7
Jobs such as housework take a long 
time, or I have to stop to rest
70.6
If I walk up one flight of stairs, I have 
to go slowly or stop
71.6
If I hurry or walk fast, I have to stop 
or slow down
72.3
My breathing makes it difficult to do 
things such as walk up hills, carry 
things up
stairs, light gardening such as 
weeding, dance, play bowls or play 
golf
74.5
My breathing makes it difficult to do 
things such as carry heavy loads, dig
in the garden or shovel snow, jog or 
walk briskly (5 miles per hour), play
tennis or swim
71.4
My breathing makes it difficult to do 
things such as very heavy manual 
work, ride a bike, run, swim fast, or
play competitive sports
63.5
Question 16: We would like to know how 
your respiratory problems usually affect 
your daily life
I cannot play sports or other physical 
activities
64.8
I cannot go out for entertainment or 
recreation
79.8
I cannot go out of the house to do the 
shopping
81.0
I cannot do household chores
79.1
I cannot move far from my bed or 
chair
94.0
Question 17: Tick the statement which 
you think best describes how your 
respiratory problems affect you
It does not stop me from doing
anything I would like to do
0.0


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It stops me from doing one or two 
things I would like to do
42.0
It stops me from doing most of the 
things I would like to do
84.2
It stops me from doing everything I 
would like to do
96.7










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5
0.322
Self-care
1
0
2
0.089
3
0.107
4
0.220
5
0.261
Usual Activities
1
0
2
0.068
3
0.101
4
0.255
5
0.255
Pain/discomfort
1
0
2
0.060
3
0.098
4
0.318
5
0.414
Anxiety/ depression
1
0
2
0.057
3
0.123
4
0.299
5
0.321