Clinical trial NCT06460493
Conditions: COPD
Sponsor: Verona Pharma plc
Start date: 2024-06-11; Completion date: 2024-12-03
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this open-label, single center trial is to assess the effect of twice daily nebulized ensifentrine (3 mg) on COPD symptoms measured by the COPD Assessment Test (CAT™) scores over 12 weeks in subjects with symptomatic, moderate to severe COPD, taking maintenance LAMA/LABA or LAMA/LABA/ICS therapy. Subjects will continue the maintenance treatment during study participation.

Detailed description:

Arms: arm 1: Inhaled ensifentrine twice daily for 12 weeks via standard jet nebulizer in addition to standard dual (LAMA/LABA) or triple (LAMA/LABA/ICS) COPD therapy.
Interventions: intervention 1: Ensifentrine 3 mg twice daily
Intervention descriptions: intervention 1: All subjects will receive ensifentrine.

Protocol documents:
Prot_000.pdf: 
Verona Pharma plc
CONFIDENTIAL
Page 1 of 76
CLINICAL STUDY PROTOCOL
Protocol Title:
A Study Assessing the Effect of Ensifentrine on CAT™
Scores over 12 Weeks in Subjects with Moderate to 
Severe COPD
Protocol Number:
RPL554-CO-303
Version:
4.0
Investigational Product:
Ensifentrine
Short Title:
Ensifentrine CAT Study
Study Phase:
IIIb
Principal Investigator:
 
Sponsor Name:
Verona Pharma plc
Legal Registered Address
3 More London Riverside
London, SE1 2RE
UK
Regulatory Agency 
Identifying Number(s):
US IND Number: 133146
US NDA Number: 217389
Date of Protocol:
19 August 2024


Protocol RPL554-CO-303
Version 4.0; 19 August 2024
Verona Pharma plc
CONFIDENTIAL
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Sponsor Signatory:
Medical Monitor name and contact information can be found in Appendix 2.


Protocol RPL554-CO-303 
 
 
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TABLE OF CONTENTS 
 
CLINICAL STUDY PROTOCOL ............................................................................. 1 
LIST OF IN-TEXT TABLES ..................................................................................... 6 
LIST OF IN-TEXT FIGURES ................................................................................... 6 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ................................... 7 
1.0 
PROTOCOL SUMMARY ............................................................................ 17 
1.1 
Synopsis ..................................................................................................... 17 
1.2 
Schema ...................................................................................................... 21 
1.3 
Schedule of Activities ............................................................................... 22 
2.0 
INTRODUCTION.......................................................................................... 24 
2.1 
Study Rationale ........................................................................................ 24 
2.2 
Background .............................................................................................. 24 
2.2.1 
Chronic Obstructive Pulmonary Disease ........................................... 24 
2.2.2 
COPD Assessment Test™ (CAT™) ................................................. 24 
2.2.3 
Ensifentrine ........................................................................................ 25 
2.3 
Benefit/Risk Assessment .......................................................................... 26 
3.0 
OBJECTIVES AND ENDPOINTS .............................................................. 28 
3.1 
Objectives.................................................................................................. 28 
3.2 
Endpoints .................................................................................................. 28 
4.0 
STUDY DESIGN ............................................................................................ 29 
4.1 
Overall Design .......................................................................................... 29 
4.2 
Justification for Dose ............................................................................... 30 
4.3 
End of Study Definition ........................................................................... 30 
5.0 
STUDY POPULATION ................................................................................ 31 
5.1 
Inclusion Criteria ..................................................................................... 31 
5.2 
Exclusion Criteria .................................................................................... 32 
5.3 
Rescreening ............................................................................................... 33 
5.4 
Screen Failures ......................................................................................... 34 
6.0 
STUDY TREATMENT ................................................................................. 35 
6.1 
Dispensing of Medical Devices ................................................................ 35 
6.2 
Dispensing of Study Medication ............................................................. 35 
6.3 
Administration of Study Medication ...................................................... 35 
6.3.1 
Dosing in the Clinic ........................................................................... 35 
6.3.2 
Dosing at Home ................................................................................. 36 


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CONFIDENTIAL 
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6.4 
Investigational Product/ Study Medication ........................................... 36 
6.4.1 
Study Medication Formulation Information ...................................... 37 
6.5 
Preparation/Handling/Storage/Accountability ..................................... 37 
6.6 
Study Medication Compliance ................................................................ 38 
6.7 
Concomitant Therapy .............................................................................. 38 
6.7.1 
Permitted Medications/Therapy ........................................................ 39 
6.7.2 
Prohibited Medications/Therapy ....................................................... 39 
6.7.3 
Recording Use of Concomitant Medications .................................... 40 
6.8 
End of Study Procedures ......................................................................... 41 
6.9 
Treatment After the End of Study ......................................................... 41 
7.0 
DISCONTINUATION OF STUDY MEDICATION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL .................................................... 42 
7.1 
Discontinuation of Study Medication ..................................................... 42 
7.1.1 
Does Not Meet Criteria ..................................................................... 42 
7.1.2 
Positive Pregnancy Test in Females .................................................. 42 
7.1.3 
COPD Exacerbation Withdrawal Criteria ......................................... 42 
7.1.4 
Liver Chemistry Stopping Criteria .................................................... 42 
7.1.5 
Other Criteria ..................................................................................... 43 
7.1.6 
Discontinuation of the Study ............................................................. 43 
7.2 
Subject Discontinuation/Withdrawal from the Study .......................... 44 
7.3 
Lost to Follow-up ..................................................................................... 44 
8.0 
STUDY ASSESSMENTS AND PROCEDURES ........................................ 45 
8.1 
Visits .......................................................................................................... 45 
8.1.1 
Visit 1 ................................................................................................ 45 
8.1.2 
Visit 2 ................................................................................................ 46 
8.1.3 
Visit 3 ................................................................................................ 48 
8.1.4 
Visit 4 ................................................................................................ 48 
8.1.5 
Telephone Follow-up ......................................................................... 49 
8.2 
Efficacy Assessment ................................................................................. 49 
8.3 
Safety Assessments ................................................................................... 49 
8.3.1 
Vital Signs ......................................................................................... 49 
8.3.2 
Adverse Event Assessment ................................................................ 50 
8.4 
Adverse Events ......................................................................................... 50 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information
 ........................................................................................................... 50 
8.4.2 
Method of Detecting AEs and SAEs ................................................. 50 
8.4.3 
Regulatory Reporting Requirements for SAEs ................................. 51 
8.4.4 
Follow-up of AEs and SAEs ............................................................. 51 
8.4.5 
Pregnancy .......................................................................................... 51 
8.4.6 
Adverse Events of Special Interest .................................................... 51 
8.4.7 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs ............................................................... 51 
8.4.8 
Device Incidents ................................................................................ 52 
8.5 
Treatment of Overdose ............................................................................ 52 
8.6 
Data Monitoring Committee ................................................................... 52 


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9.0 
STATISTICAL CONSIDERATIONS ......................................................... 53 
9.1 
Statistical Hypotheses .............................................................................. 53 
9.2 
Sample Size Determination ..................................................................... 53 
9.3 
Statistical Methods ................................................................................... 53 
9.3.1 
Populations for Analyses ................................................................... 53 
9.3.2 
Statistical Analyses ............................................................................ 54 
9.3.3 
Efficacy Analyses .............................................................................. 54 
9.3.4 
Safety Analyses ................................................................................. 55 
9.3.5 
Other Analyses .................................................................................. 55 
9.3.6 
Missing Data ...................................................................................... 56 
9.4 
Interim Analyses ...................................................................................... 56 
10.0 
REFERENCE LIST ....................................................................................... 57 
APPENDIX 1 
ABBREVIATIONS ................................................................ 59 
APPENDIX 2 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATION ....................................................................................... 60 
APPENDIX 3 
ADVERSE EVENTS: DEFINITIONS AND 
PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP 
AND REPORTING ........................................................................................ 65 
APPENDIX 4 
CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION ................................................................. 71 
APPENDIX 5 
QUESTIONNAIRES ............................................................. 74 
SIGNATURE OF INVESTIGATOR ....................................................................... 76 
 
 
 


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LIST OF IN-TEXT TABLES 
Table 1: Schedule of Assessments and Procedures ..................................................... 22 
Table 2: Investigational Product/Study Medication Details ........................................ 37 
Table 3: Study Medication Formulation Constituents and Concentrations ................. 37 
Table 4: Permitted Rescue and Background Medications ........................................... 39 
Table 5: Prohibited Medications/Therapy ................................................................... 40 
Table 6: Study Administrative Structure ..................................................................... 62 
Table 7: Medical Monitor ............................................................................................ 63 
Table 8: Highly Effective Contraceptive Methods ...................................................... 72 
 
LIST OF IN-TEXT FIGURES 
Figure 1: Study Schematic ........................................................................................... 21 
 
 
 


Protocol RPL554-CO-303 
 
 
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CONFIDENTIAL 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document History 
Protocol Version 
Amendment # 
Version Date 
Substantial - timing 
Version 1.0 
Original protocol 
11 April 2024 
Original protocol 
Version 2.0 
Amendment 1.0 
03 June 2024 
Yes – prior to 
enrollment 
Version 3.0 
Amendment 2.0 
27 June 2024 
No – during enrollment 
Version 4.0 
Amendment 3.0 
19 August 2024 
No – during enrollment 
 
Protocol Version 2.0, Amendment 1.0: 03 June 2024 
Overall Rationale for the Amendment: 
The protocol is amended to revise study objective and endpoint order, in addition to 
updating Table 5. Prohibited Medications/Therapy; Table 5. Permitted Medications; 
Table 6. Study Administrative Structure; Safety information; and Appendix 3 and 
Appendix 4. Minor administrative items were also addressed (e.g., spelling, punctuation, 
spaces, linked sections, and tables as well as Table and Section numbering, as 
appropriate). 
Description of Changes in Protocol Version 2.0, Amendment 1.0: 03 June 2024 
Section # and Name 
Description of Change 
Brief Rationale
1.1. Synopsis 
3.1. Objectives 
 
The primary and secondary objectives were re-ordered as follows 
(bold=added text, strikethrough=deleted text): 
 
 
Primary: To assess the proportion of responders to treatment 
with ensifentrine based on the improvement in individual CAT 
scores when added to standard of care in symptomatic subjects 
with moderate to severe COPD in routine clinical practice. To 
investigate the effects of ensifentrine on COPD symptoms, as 
measured by the CAT in symptomatic subjects with moderate to 
severe COPD when added to standard of care in routine clinical 
practice. 
 
Secondary: To investigate the effects of ensifentrine on COPD 
symptoms, as measured by the CAT in symptomatic subjects 
with moderate to severe COPD when added to standard of care 
in routine clinical practice. Assess the proportion of responders to 
treatment with ensifentrine based on the improvement in individual 
CAT when added to standard of care in routine clinical practice. 
Objectives and 
endpoints were 
re-ordered. 
1.1. Synopsis 
3.2. Endpoints 
The primary and secondary endpoints were re-ordered as follows 
(bold=added text, strikethrough=deleted text): 
 
 
Primary: The proportion of CAT score responders, defined as 
 
 
Secondary:  
• 
The proportion of CAT score responders, defined as an 
 
• 
CAT score at Week 6 and Week 12 (change from 
baseline).  
• 
CAT score at Week 6 and Week 12 (item-level change 
from baseline). 
 


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CONFIDENTIAL 
Page 8 of 76 
Description of Changes in Protocol Version 2.0, Amendment 1.0: 03 June 2024 
Section # and Name 
Description of Change 
Brief Rationale
 
1.1. Synopsis 
4.1. Overall Design 
Sentence was revised as follows (bold=added text, strikethrough=deleted 
text): 
At Visit 2, subject eligibility will be confirmed (screening tests will be 
verified, and it will be assured that the subject meets all inclusion 
criteria are met, and no exclusion criteria are met). 
Clarifies Visit 
2. 
1.3. Schedule of 
Activities 
The column heading for ‘End of Study’ was revised as follows (bold=added 
text, strikethrough=deleted text): 
 
Week 13 7 ± 3 days after Visit 4 
 
Eligibility and history revised to review, update for Visit 2. 
Review, Confirm Update 
 
Nebulizer equipment dispensing/collection was marked with ‘X” at Visit 3 
and Visit 4 to Section 6.1 and Section 6.6. 
 
Concomitant medication review was marked with ‘X’ at Follow-up visit (At 
Visit 4 and EW/T Visit) because it is listed in the protocol in Sections 6.8 
and 8.1.5. 
 
Footnote F modified for clarity. 
F. Collect study supplied compressor if allowed per local site practices, 
otherwise study supplied compressors will note be returned and collected. 
Clarifies to 
match the 
schema. 
2.3. Benefit/Risk 
Assessment 
This section was revised as follows (bold=added text): 
Non-clinical and clinical data to date do not indicate any areas of 
medical safety concern considered related to ensifentrine treatment. 
Hypertension may be a potential risk due to incidence of 
 in 
both RPL554-CO-301 and RPL554-CO-
increase in psychiatric adverse reactions were reported with use of 
ensifentrine. The most commonly reported psychiatric adverse 
reactions in the pooled 24-week safety population from the Phase III 
-related reactions were 
epression 
receiving placebo. One patient who received ensifentrine in the 
pooled 24-week safety population experienced a suicide-related 
adverse reaction (suicide attempt), and in Phase IIb study RPL554-
CO-203, one patient who received ensifentrine 1.5 mg experienced a 
suicide-related adverse reaction (suicide). A causal relationship 
between ensifentrine and increased rates of psychiatric events could 
not be established. 
In a reproductive performance study, male rats had decreased 
sperm counts in the testis were observed at all doses. The clinical 
relevance of this observation is undetermined.  
Ensifentrine has demonstrated statistically and clinically significant 
bronchodilator as well as anti-inflammatory effects in non-clinical 
models and clinical studies with the potential to treat obstructive 
and inflammatory diseases of the respiratory tract, such as COPD, 
non-CF bronchiectasis, CF, and asthma. Ensifentrine has been 
assessed in clinical studies to date in COPD, CF, hospitalized 
COVID-19, and asthmatic patients. Considering the consistent 
improvements in lung function in subjects with COPD, asthma and 
Change reflects 
updated 
language to 
Investigator 
Brochure. 


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CONFIDENTIAL 
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Description of Changes in Protocol Version 2.0, Amendment 1.0: 03 June 2024 
Section # and Name 
Description of Change 
Brief Rationale
CF, and improvements in symptoms, and health-related quality of 
life across multiple studies in subjects with COPD, and substantial 
reduction in the rate and risk of moderate/severe COPD 
exacerbations along with the overall favorable safety profile in 
studies to date, the benefit- risk profile of ensifentrine is considered 
positive.  
As always, Investigators should remain alert to the possibility of AEs 
manifesting in their patients and should handle these in accordance 
with protocol requirements. 
No significant medical risks to subjects 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 subjects 
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. 
Rare cases of suicidal ideation and behavior, including one completed 
suicide, were also observed; however, a causal relationship with 
ensifentrine could not be established. Otherwise, the 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 antiinflammatory effects. As such, the clinical development of 
ensifentrine is focused on the treatment of obstructive and inflammatory 
lung diseases, including COPD. Considering the consistent 
improvements in lung function, symptoms, and health-related quality of 
life across multiple studies in subjects with COPD and the overall 
favorable safety profile in studies to date, the benefit/risk profile of 
ensifentrine is considered positive.  
 
 
4.2. Justification for 
Dose 
The 1st and 2nd paragraphs of this section were revised to read as follows 
(bold=added text, strikethrough=deleted text): 
A 3 mg twice daily dose was selected as the Phase III 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 subjects patients with or without additional 
bronchodilator background therapy. Two phase III studies, RPL554-
CO-301 and RPL554-CO-302 confirmed the efficacy and safety of 3 
mg ensifentrine BID in subjects with COPD. 
 
A review of safety and tolerability across all COPD studies including 
over 24 and 48 weeks has shown a safety profile similar to placebo, even 
when added on top of other bronchodilator therapies, including LAMA 
and LABA therapies with or without ICS. 
Updated for 
justification. 


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CONFIDENTIAL 
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Description of Changes in Protocol Version 2.0, Amendment 1.0: 03 June 2024 
Section # and Name 
Description of Change 
Brief Rationale
6.7.1. Permitted 
Medications 
Table 4. Permitted medications was revised to read as follows (bold=added 
text): 
 
Medication: LAMA+LABA ± ICS 
Condition: Subjects will be required to remain on their maintenance 
COPD treatment inhaler(s) at a stable dose for the duration of the study.  
Must withhold prior to Visit 2 spirometry: 48 (once-daily) or 24 (twice-
daily) hours. 
Only approved COPD doses of ICS are permitted for enrollment 
and during study participation (e.g., Trelegy containing 100 mcg 
FF). 
Maintenance therapy should resume once Visit 2 has been completed. 
Changes to 
clarify COPD 
dose of inhaled 
corticosteroid. 
6.7.2. Prohibited 
Medications/Therapy 
Table 5. Prohibited Medications/Therapy was revised as follows 
(bold=added text, strikethrough=deleted text): 
 
Medication 
Time interval withheld prior to screening Visit 2 
Inhaled 
Corticosteroids 
(e.g., ICS 
monotherapy, 
high dose 
inhaled 
corticosteroids) 
IF taking LAMA+LABA, the use of ICS is 
prohibited at least 8 weeks prior and prohibited 
during the study.  
IF taking LAMA+LABA+ICS, the use of ICS 
must be at a stable dose for at least 8 weeks 
prior and continue for the duration of the 
study.  
IF taking LAMA+LABA+ICS, ICS doses not 
approved for COPD are prohibited for 8 
week prior and during study participation 
(e.g., > 100 mcg/day). 
ICS monotherapy is not permitted. ICS should 
not be initiated, dose changed, or discontinued 
during the study except for safety reasons 
High dose 
inhaled 
corticosteroids 
(e.g., >1000 mcg 
of fluticasone 
propionate or 
equivalent) 
4 weeks prior and prohibited during the study. 
Theophylline 
and PDE4 
inhibitors (e.g., 
roflumilast, 
apremilast, 
crisaborole) 
8 weeks 48 hours prior and prohibited during the 
study. 
 
Changes reflect 
when 
medications 
should not be 
used in relation 
to Visit 2 as 
well as 
clarification for 
steroid use 
(oral, systemic, 
or inhaled).  
8.1.2.3 
End of this section was revised to read as follows (bold=added text): 
Investigators should pay special attention to clinical signs to ensure subjects 
have had no previous serious physical or mental illness(es). Refer to Note at 
the end of Section 8.1.1.5. 
Clarification for 
Physical Exam 
8.1.4. Visit 4 
The following bullet was added to match with Table 1 (bold=added text): 
Study equipment (Section 6.1) will be collected. 
To match Table 
1. 


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Description of Changes in Protocol Version 2.0, Amendment 1.0: 03 June 2024 
Section # and Name 
Description of Change 
Brief Rationale
8.4.7. Disease-related 
Events and/or 
Disease-related 
Outcomes Not 
Qualifying as AEs or 
SAEs 
 
The 2nd paragraph of this section was revised to read as follows (bold=added 
text): 
COPD exacerbations are an expected disease-related outcome, unless 
the exacerbations manifest in an unusual or uncharacteristic 
manner. COPD exacerbations including daily expected COPD 
symptoms (e.g., dyspnea, chest tightness, wheezing, cough, sputum, that 
are not associated with the dosing event) will not be collected as an AE 
unless they meet the definition of an SAE. 
Clarification 
necessary for 
COPD 
exacerbation 
events. 
8.4.8. Device 
Incidents 
 
The 1st paragraph of this section was revised to read as follows (bold=added 
text): 
The Investigator, or responsible person according to local requirements 
(e.g., the head of the medical institution), will comply with the 
applicable local regulatory requirements relating to the reporting of 
device incidents to the IRB/IEC, device manufacturer, or regulatory 
authorities, as required. 
 
A device incident is defined as an incident related to the failure of a 
medical device, deterioration in its effectiveness, or inadequacy in its 
labeling or directions that led to the death or serious deterioration in 
health of a patient subject, user, or other person, or could do so were it 
to recur. 
Clarification 
necessary for 
device events. 
9.3.4 Safety Analyses 
This section was revised to read as follows (bold=added text): 
TEAEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) and summarized by system organ class (SOC) and 
preferred term (PT) for each treatment. Adverse events will be included 
in subject patient listings. Seriousness, relatedness, and outcome will be 
identified in subject patient listings.  
 
Vital signs will be summarized as change from baseline values for each 
parameter. Vital signs will be included in subject patient listings. 
Abnormal values and marked abnormalities will be identified in subject 
listings.  
Administrative 
change 
Appendix 2. 
Regulatory, Ethical, 
and Study Oversight 
Consideration 
Table 6. Study Administrative Structure was revised for pharmacovigilance 
as follows (bold=added text, strikethrough=deleted text): 
United BioSource, LLC (UBC) 
920 Harvest Drive, Blue Bell, PA 19422 
1000 Continental Drive, Suite 600 
King of Prussia, PA 19406 
All SAE paper reporting CRFs should be sent to UBC (Appendix 3). 
Changes reflect 
new address for 
UBC . 
Appendix 3. Adverse 
Events: Definitions 
and Procedures for 
Recording, 
Evaluating, Follow-
up and Reporting 
The section entitled “Events not Meeting the AE Definition” is revised as 
follows (bold=added text): Medical or surgical procedure (e.g., endoscopy, 
appendectomy): the condition that leads to the procedure should be assessed 
using the AE/SAE definitions. 
 
 
The section entitled “Assessment of Causality” was revised as follows 
(bold=added text, strikethrough=deleted text): The Investigator may change 
his/her opinion of causality in light of considering follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
 
The section entitled “Follow-up of AEs and SAEs” was revised to add 
(bold=added text) as applicable local regulatory requirements will allow. 
 
SAEs will be 
reported on a 
paper form. 
Changes reflect 
how SAEs are 
reported and the 
SAE email 
address. 


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Description of Changes in Protocol Version 2.0, Amendment 1.0: 03 June 2024 
Section # and Name 
Description of Change 
Brief Rationale
The section entitled “SAE Reporting to the Sponsor/Sponsor’s designee via 
an Electronic Data Collection Tool” was removed entirely because there is 
no electronic data collection tool for SAEs for this study. 
 
The section entitled “SAE Reporting to Sponsor/ Sponsor’s Designee via 
Paper CRF if eCRF is not Available” is revised as follows (bold=added text, 
strikethrough=deleted text): 
 
SAE Reporting to Sponsor/ Sponsor’s Designee via Paper Form CRF if 
eCRF is not Available 
 
The Medical Monitor contact information can be found in 
Appendix 2 (Table 7). 
 
The primary mechanism for reporting an SAE to the 
Sponsor/Sponsor’s designee will be the paper SAE reporting form. 
electronic data collection tool. 
 
The SAE reporting form should be sent by fax to the fax 
number which appears on the form.  As an alternative, the 
completed SAE reporting form can be scanned and sent as an 
attachment via email to: VeronaSafety@ubc.com. 
 
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. 
 
In rare circumstances and in the absence of facsimile or scanning 
equipment, notification by telephone is acceptable with a copy of 
the SAE data collection forms sent by overnight mail or courier 
service to the medical monitor or the SAE coordinator UBC. The 
address is listed in Appendix 2 (Table 6). 
 
Initial notification via telephone does not replace the need for the 
Investigator to complete and sign the SAE CRF pages within the 
designated reporting time frames. 
 
Contacts for SAE reporting can be found in Appendix 2 on the 
Medical Monitor Contact Information page. 
Appendix 4. 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information 
Minor administrative change was made to section entitled “Pregnancy 
Testing” (bold=added text):  
WOCBP should only be included after a negative pregnancy test at during 
screening is conducted prior to study medication dispensing. 
 
The section entitled “Male subjects with partners who become pregnant” is 
revised as follows (strikethrough=deleted text): 
1st paragraph: The Investigator will attempt to collect pregnancy 
information on any male subject’s female partner who becomes pregnant 
while the male subject is in the study. This applies only to male subjects 
who receive glycopyrrolate. 
 
The section entitled “Female subjects who become pregnant” is revised as 
follows (bold=added text, strikethrough=deleted text): 
1st Bullet -  
 
The Investigator will collect pregnancy information on any female 
subject who becomes pregnant while participating in this study. 
Information will be recorded on the appropriate form and submitted 
to the Sponsor/Sponsor Designee within 24 hours of learning of a 
subject’s pregnancy. 
o 
The Medical Monitor contact information can be found 
in Appendix 2 (Table 7). 
o 
The primary mechanism for reporting Pregnancy to 
the Sponsor/Sponsor’s designee will be the paper 
Pregnancy reporting form. 
Changes reflect 
those made in 
Appendix 3. 


Protocol RPL554-CO-303 
 
 
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Description of Changes in Protocol Version 2.0, Amendment 1.0: 03 June 2024 
Section # and Name 
Description of Change 
Brief Rationale
o 
The Pregnancy reporting form should be sent by fax to 
the fax number which appears on the form.  As an 
alternative, the completed form can be scanned and 
sent as an attachment via email to: 
VeronaSafety@ubc.com.   
2nd Bullet –  
 
Any female subject who becomes pregnant while participating 
in the study will discontinue study medication. The subject will 
be approached and asked to consent to being followed to 
determine the outcome of the pregnancy. The Investigator will 
collect follow-up information on the subject and the neonate, and 
the information will be forwarded to the Sponsor. Generally, 
follow-up will be no longer than 6 to 8 weeks beyond the estimated 
delivery date. Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
3rd Bullet -  
 
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.  For SAE 
reporting, refer to Appendix 3. 
Last Bullet- 
 
Any female subject who becomes pregnant while participating in 
the study will discontinue study medication and be withdrawn from 
the study. 
 
 
Protocol Version 3.0, Amendment 2.0: 27 June 2024 
Overall Rationale for the Amendment: 
The protocol is amended to reflect the FDA approval of ensifentrine (OHTUVAYRE™) 
for the maintenance treatment COPD in adult patients and the updated Clinical 
Investigator Brochure (v25). Minor administrative items were also addressed. 
Description of Changes in Protocol Version 3.0, Amendment 2.0: 27 June 2024 
Section # and Name 
Description of Change 
Brief Rationale
Section 1.1. Synopsis 
Ensifentrine is a selective dual inhibitor of PDE3 and PDE4 which has 
demonstrated pronounced bronchodilation in subjects with chronic 
obstructive pulmonary disease (COPD) as well as anti-inflammatory 
effects in healthy subjects in clinical studies. Ensifentrine inhalation 
suspension 3 mg twice daily was recently approved in the United States 
(US) for the maintenance treatment of COPD in adult patients and is 
marketed under the tradename OHTUVAYRE™ (NDA 217389) . 
Verona Pharma plc. (Verona) is developing inhaled nebulized ensifentrine 
for the maintenance treatment of chronic obstructive pulmonary disease 
(COPD). A New Drug Application for ensifentrine (3 mg) inhalation 
suspension for the maintenance treatment of COPD was submitted to the US 
Food and Drug Administration (FDA) on 26 June 2023 and is currently 
under review by the FDA with a Prescription Drug User Fee Act target 
action date of 26 June 2024. 
Ensifentrine 
was approved in 
the US by the 
FDA and is 
marketed as 
Ohtuvayre™ . 


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Description of Changes in Protocol Version 3.0, Amendment 2.0: 27 June 2024 
Section # and Name 
Description of Change 
Brief Rationale
Section 2.1. Study 
Rationale 
Verona Pharma plc. (Verona) is developing inhaled nebulized ensifentrine 
for the maintenance treatment of chronic obstructive pulmonary disease 
(COPD). A New Drug Application for ensifentrine (3 mg) inhalation 
suspension for the maintenance treatment of COPD was submitted to the US 
Food and Drug Administration (FDA) on 26 June 2023 and is currently 
under review by the FDA with a Prescription Drug User Fee Act target 
action date of 26 June 2024. 
Ensifentrine inhalation suspension 3 mg twice daily was recently 
approved in the United States (US for the maintenance treatment of 
COPD in adult patients and is marketed under the tradename 
OHTUVAYRE™ (NDA 217389, “OHTUVAYRE”). 
Ensifentrine 
was approved 
and is marketed 
as Ohtuvayre™ 
by the FDA. 
Section 2.2.3. 
Ensifentrine 
Ensifentrine is a novel, small molecule, and is a potent, selective dual 
inhibitor of Phosphodiesterase 3 (PDE3) and PDE4. This novel mechanism 
of action leads to downstream bronchodilatory and anti-inflammatory 
effects and represents an important potential additional treatment 
option for patients with moderate to severe COPD, and other 
respiratory indications such as non-cystic fibrosis bronchiectasis 
(NCFBE), asthma and cystic fibrosis whose disease is manifest by 
airways obstruction and/or inflammation. Ensifentrine inhalation 
suspension 3 mg twice daily was recently approved in the United States 
(US) for the maintenance treatment of COPD in adult patients and is 
marketed under the tradename OHTUVAYRE for use with a standard 
jet nebulizer. As a new treatment for COPD, this new mechanism of 
action allows ensifentrine to 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. The dual mechanism of action of 
ensifentrine has both bronchodilatory and anti-inflammatory effects and has 
the potential to offer an important maintenance treatment option for the 
treatment of obstructive and inflammatory diseases of the respiratory tract, 
such as COPD, cystic fibrosis, and asthma.8 
Ensifentrine 
was approved 
and is marketed 
as Ohtuvayre™ 
by the FDA. 
Section 2.3. 
Benefit/Risk 
Assessment 
Non-clinical and clinical data to date do not indicate any areas of medical 
safety concern considered related to ensifentrine treatment. Hypertension 
may be a potential risk due to incidence of hypertension adverse events 
 in both phase III studies, RPL554-
CO-301 and RPL554-CO-
ensifentrine and placebo groups, respectively). An increase in psychiatric 
adverse reactions were reported with use of ensifentrine. The most 
commonly reported psychiatric adverse reactions in the pooled 24-week 
safety population from the phase III3 studies were insomnia (6 subjects 
-
related reactions 
receiving placebo. One subject who received ensifentrine in the pooled 24-
week safety population experienced a suicide-related adverse reaction 
(suicide attempt), and in Phase IIb study RPL554-CO-203, one subject who 
received ensifentrine 1.5 mg experienced a suicide-related adverse reaction 
(suicide). A causal relationship between ensifentrine and increased rates of 
psychiatric events could not be established. 
In a reproductive performance toxicity study, male rats had decreased sperm 
counts in the testis were observed male rats at all doses. The clinical 
relevance of this observation is undetermined.  
Administrative 
change. 
Section 4.2. 
Justification for Dose 
A 3 mg twice daily dose was selected as the Pphase III 3 dose for the 
COPD clinical trials based on data from two 4-week Phase IIb studies 
Ensifentrine 
was approved 


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Description of Changes in Protocol Version 3.0, Amendment 2.0: 27 June 2024 
Section # and Name 
Description of Change 
Brief Rationale
RPL554-CO-203 and RPL554-CO-205 which showed clinically meaningful 
and statistically significant improvements in pulmonary function with the 3 
mg dose over the 12-hour dosing interval, in subjects with or without 
additional bronchodilator background therapy. Two Pphase III 3 studies, 
RPL554-CO-301 and RPL554-CO-302 confirmed the efficacy and safety of 
3 mg ensifentrine BID in subjects with COPD. Ensifentrine 3 mg twice 
daily (OHTUVAYRE) is the approved dose and regimen for the 
maintenance treatment of COPD in adult patients (OHTUVAYRE 
Prescribing Information). 
A review of safety and tolerability across all COPD studies including over 
24 and 48 weeks has shown a safety profile similar to placebo, even when 
added on top of other bronchodilator therapies, including LAMA and LABA 
therapies with or without ICS. 
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 subjects with COPD. 
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 subjects after 4 weeks. 
24-hour Holter monitoring in 324 subjects 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. 
and is marketed 
as Ohtuvayre by 
the FDA. 
Section 6.0. Study 
Treatment. 
In this protocol the terms ‘investigational product,’ and ‘study medication’ 
are the same and refer to the nebulized ensifentrine (3 mg) or 
OHTUVAYRE 
Ensifentrine 
was approved 
and is marketed 
as Ohtuvayre by 
the FDA. 
Appendix 2.  
Regulatory, Ethical, 
and Study Oversight 
Consideration 
Table 6: Study Administrative Structure 
Added via email or fax to UBC information 
Administrative 
change. 
Appendix 3. Adverse 
Events: Definitions 
and Procedures for 
Recording, 
Evaluating, Follow-
up and Reporting 
The section entitled Assessment of Causality was updated to read as 
follows: All efforts should be made to classify the AE according to the 
above categories. 
The section entitled SAE Reporting to Sponsor/ Sponsor’s Designee via 
Paper Form was updated to read as follows: 
 
The Medical Monitor contact information can be found in 
Appendix 2 (Table 7). 
 
The primary mechanism for reporting an SAE to the 
Sponsor/Sponsor’s designee will be the paper SAE reporting form. 
 
The SAE reporting form should be sent by fax to the fax number 
which appears on the form.  As an alternative, the completed SAE 
reporting form can be scanned and sent as an attachment via email 
to: VeronaSafety@ubc.com.   
 
In rare circumstances and in the absence of facsimile or scanning 
equipment, notification by telephone is acceptable with a copy of 
the SAE data collection forms sent by overnight mail or courier 
service to UBC. The address is listed in Appendix 2 (Table 6). 
 
Initial notification via telephone or email does not replace the need 
for the Investigator to complete and sign the SAE pages within the 
designated reporting time frames. 
Administrative 
change. 
 


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Protocol Version 4.0, Amendment 3.0: 19 August 2024 
Overall Rationale for the Amendment: 
The protocol is amended to increase the number of enrolled subjects from 7 to 10 taking 
triple COPD maintenance therapy (LAMA+LABA+ICS).  
Changes are reflected in the Synopsis and in Section 5.1, Inclusion Criteria #9:  
 Demonstrates stable use of dual (LAMA+LABA) or triple (LAMA+LABA+ICS) 
maintenance therapy, in any form (except nebulized) for at least 8 weeks prior to 
screening and agrees to continue use for the duration of the study. Note: The 
number taking LAMA+LABA+ICS will be capped at seven (7) ten (10). The use of 
LAMA or LABA alone or with ICS is not permitted (e.g., LABA+ICS, LAMA). 
 
 


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1.0   PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title 
A Study Assessing the Effect of Ensifentrine on COPD Assessment Test (CAT™) Scores 
over 12 Weeks in Subjects with Moderate to Severe COPD. 
Short Title 
Ensifentrine CAT study. 
Rationale 
Ensifentrine is a selective dual inhibitor of PDE3 and PDE4 which has demonstrated 
pronounced bronchodilation in subjects with chronic obstructive pulmonary disease 
(COPD) as well as anti-inflammatory effects in healthy subjects in clinical studies. 
Ensifentrine inhalation suspension 3 mg twice daily was recently approved in the United 
States (US) for the maintenance treatment of COPD in adult patients and is marketed 
under the tradename OHTUVAYRE™ (NDA 217389). 
The primary goals of pharmacological treatment of COPD are to reduce symptoms, 
exacerbation frequency, and exacerbation severity as well as to improve overall quality of 
life in patients with COPD.1  Tools to assess if treatment goals are attained include 
several patient-reported outcome questionnaires to assist in communications between the 
patient and physician.  However, the uptake of these questionnaires into routine clinical 
practice is integral to the assessment of individualized treatment regimens.2 
The COPD Assessment Test (CAT™; CAT)3–5 is a validated, short, and simple patient 
completed questionnaire.  The CAT is often used in a clinical setting to assess further the 
COPD symptoms and impact of a patient’s well-being. This study will assess the effect of 
ensifentrine on CAT scores in patients with moderate to severe COPD when added to 
standard of care in routine clinical practice. 
Objectives 
Efficacy 
 Primary: To assess the proportion of responders to treatment with ensifentrine 
based on the improvement in individual CAT scores when added to standard of 
care in symptomatic subjects with moderate to severe COPD in routine clinical 
practice.  
 Secondary: To investigate the effects of ensifentrine on COPD symptoms, as 
measured by the CAT in symptomatic subjects with moderate to severe COPD 
when added to standard of care in routine clinical practice.   
 


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Safety 
 Safety of ensifentrine. 
Endpoints 
Efficacy 
 Primary: The proportion of CAT score responders, defined as an improvement 
 
 Secondary:  
o The proportion of CAT score responders, defined as an improvement from 
.  
o CAT score at Week 6 and Week 12 (change from baseline).  
o CAT score at Week 6 and Week 12 (item-level change from baseline). 
Safety 
 Incidence and proportion of AEs. 
 Change from baseline in vital signs (blood pressure and pulse rate). 
Overall Design 
This is a Phase IIIb, single-center, open-label study investigating the effect of treatment 
with twice daily nebulized ensifentrine (3 mg) over 12 weeks on CAT scores in subjects 
with moderate to severe COPD when added to standard of care in routine clinical 
practice.  
At Visit 1, potential subjects will be provided with the informed consent for participation 
in the study.  Following signature on the informed consent, the following information will 
be collected, and procedures performed to confirm subject eligibility for participation in 
the study in the following sequence: 
 CAT Training followed by subject completion of the CAT on paper  
 Modified Medical Research Council Dyspnea Scale (mMRC) 
 Collect and record demographic data 
 Eligibility review (inclusion and exclusion criteria) 
 Review and record medical, surgical, COPD and smoking history 
 Review of prior and concomitant medication  
At Visit 2, subject eligibility will be confirmed (screening tests will be verified, and it 
will be assured that the subject meets all inclusion criteria and no exclusion criteria). 
Spirometry will be performed, a physical examination completed, and vital signs will be 
assessed. Eligible subjects will receive a nebulizer and compressor and will be 
administered their first dose of ensifentrine (3 mg) in-clinic during training on nebulizer 
use. Adverse events will be assessed. Subjects will receive a 6-week supply of 
ensifentrine (3 mg) to be administered twice-daily (BID) with a standard jet nebulizer. 
Ensifentrine will be administered BID for a total of 12 weeks.  


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At Visit 3 (Week 6), subjects will return and complete the CAT, their concomitant 
medication reviewed, their vital signs and safety will be assessed. Subjects will receive a 
6-week supply of ensifentrine (3 mg) administered BID.  
At Visit 4 (Week 12), subjects will complete the CAT, their concomitant medication 
reviewed, their vital signs and safety will be assessed. After 12 weeks, treatment with 
nebulized ensifentrine (3 mg) will end.  
The CAT will be completed on paper at Visits 1, 3 and 4 prior to any 
study procedures to avoid influencing the subject’s response.  All 
questions must be answered. Answers to each question will be 
logged into the eCRF by the study team.  
A follow-up phone call will be made to the subject approximately one week after the end 
of treatment. 
Subjects may remain on prescribed short- and long-acting COPD medications throughout 
participation provided they are not included in the prohibited medication list. COPD 
exacerbations should be treated at physician’s discretion as per usual practice.  
Investigators and Study Centers 
One Investigator and study center is expected to participate in this study. 
Subjects 
Approximately 20 subjects are planned to be enrolled in and complete this study. 
Potential subjects will be included if the following criteria are met: aged 40 – 80 years 
with a clinical diagnosis of stable, moderate-to-severe COPD (forced expiratory volume 
in 1 second [FEV1] 
75
l);  spirometry-confirmed airflow 
obstruction (pre- and post-bronchodilator FEV1/FVC <0.70), 
CAT™; a score of 
; taking inhaled (but not nebulized) LAMA+LABA 
or LAMA+LABA+ICS (capped at 10 subjects) for at least 8 weeks, and are able to use 
the standard jet nebulizer correctly. 
Potential subjects with asthma or other significant lung disease, recent hospitalizations, or 
serious infections; are pregnant or breastfeeding; or are unsuitable to participate, as 
judged by the Investigator, will be excluded. 
Refer to the complete eligibility list in Section 5.0.  
Treatment Groups and Duration 
All subjects meeting eligibility criteria and consenting to participation in the study will 
receive nebulized ensifentrine (3 mg) BID with a standard jet nebulizer for 12 weeks.  
Total duration of subject participation is approximately 14 weeks. 


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Recruitment is anticipated to take 3 months. 
Statistical Methods 
In general, unless stated otherwise, continuous variables will be summarized using 
descriptive statistics (number of subjects, mean, standard deviation, median, minimum, 
and maximum values) and for categorical (nominal) variables, the number and percentage 
of subjects will be used.  
Continuous endpoints will be summarized as change from baseline using a mixed model 
for repeated measures with model terms for time and background therapy, and with 
baseline included as a covariate. Within subject error will be modeled using an 
unstructured covariance matrix, and Kenward-Roger method will be used to estimate 
degrees of freedom. 
confidence limits will be presented at each post-treatment time of assessment. 
Response frequencies will be summarized by negative binomial regression with model 
terms for time and background therapy, and with baseline included as a covariate. 
generated from estimated frequencies and presented for each post-treatment time of 
assessment.  Within subject correlation in responder status will be modeled using an 
unstructured covariance matrix. 
Sample Size 
A sample size of approximately 20 subjects provides the ability to demonstrate a 
responder proportion estimate statistically differs from zero.  Assuming a 30 percent 
response rate in the study population, 20 subjects provides the ability to demonstrate the 
derived proportion differs from zero determined by the lower two-
limit derived from the estimated count using a normal approximation and a standard error 
equal to square root of 6.   
Twenty subjects also provides the ability to demonstrate the estimates of mean change 
from baseline does not extend to the clinically meaningful deterioration limit of (+2 
units). Assuming estimated mean improvement of 1 unit with a corresponding standard 
deviation equal to 4.5, 20 
confidence interval for a mean change from baseline estimate does not exceed 2 units.


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1.2
Schema
Figure 1: Study Schematic
Note: Once treatment with study medication ends, there will be a follow-up telephone call, regardless of study completion or early discontinuation of study medication.
Abbreviations: EW/T = early withdrawal or termination from study.


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1.3 
Schedule of Activities 
Table 1: Schedule of Assessments and Procedures 
 
Study Start 
Treatment Period 
Study End 
 
Early Withdrawal / 
Termination¥ 
 
Screening 
Day 1 
 
Week 6 
(42 ± 3 days) 
Week 12 
(42 ± 3 days) 
7 ± 3 days 
after Visit 4 
 
As Soon as 
Possible after 
EW/T 
7 ± 3 days 
after EW/T 
Visit 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 (EOT) 
Follow-up 
 
EW/T Visit 
Follow-Up 
Informed consentA 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria (eligibility 
review) 
X 
Review, Update 
 
 
 
 
 
 
Demographics (date of birth, age, gender, 
race, ethnicity) 
X 
 
 
 
 
 
 
 
CAT™ training 
X 
 
 
 
 
 
 
 
CAT™B 
X* 
 
X* 
X* 
 
 
 
 
mMRC (administered by study team) 
X 
 
 
 
 
 
 
 
Medical, surgical, smoking history 
X 
Review, Update 
 
 
 
 
 
 
Prior and concomitant medication 
X 
 
 
 
 
 
 
 
Vital signs (blood pressure and pulse rate)  
 
X 
X 
X 
 
 
X 
 
Height and Weight; BMI calculated 
 
X 
 
 
 
 
 
 
Brief physical examC 
 
X 
 
 
 
 
 
 
Urine pregnancy testD 
 
X 
X 
X 
 
 
 
 
Pre- and post-bronchodilator SpirometryE 
 
X 
 
 
 
 
 
 
Nebulizer equipment materials dispensing, 
review, and training; collection at endF 
 
X 
X 
X 
 
 
X 
 
Study medication dispensingG  
 
X 
X 
 
 
 
 
 
In clinic study medication dosing 
 
X 
 
 
 
 
 
 
Concomitant medication review 
 
X 
X 
X 
X 
 
X 
X 
Study medication compliance 
 
 
X 
X 
 
 
X 
 
AE and SAE recording 
 
X 
X 
X 
X 
 
X 
X 
Phone call to subject 
 
 
 
 
X 
 
 
X 


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Note: Information and details on most of the Study Assessments and Procedures can be found in Section 8.0.  *The CAT™ is completed by the 
subject on paper first before any procedures and assessments.  ¥ The early withdrawal / termination visit should be conducted as soon as possible. 
If possible, subjects should remain on study medication through the early termination visit (Section 7.2). 
A. Informed consent must be obtained by the process described in Appendix 2. Consent must be obtained prior to any study procedures being 
performed. 
B. Following informed consent, the CAT™ is performed first before any procedures and assessments. 
C. Assessments of the Cardiovascular, Respiratory, Gastrointestinal, and Neurological systems.  
D. Pregnancy Testing: Pregnancy testing will be conducted on women of childbearing potential only (refer to Appendix 4).  
E. Spirometry:  Pre-bronchodilator testing will be conducted prior to dosing with albuterol. Post-bronchodilator testing should be conducted 
between 15- and 30-minutes following administration of 4 puffs of albuterol. 
F. Collect study supplied compressor if allowed per local site practices. 
G. Information on study medication, dosing and compliance, nebulizers and compressor can be found in Section 6.0.  
 
Abbreviations: AE=Adverse Event; BMI= Body Mass Index; CAT™ = COPD Assessment Test™, COPD=Chronic Obstructive Pulmonary 
Disease; EOT=End of Treatment; mMRC=Modified Medical Research Council Dyspnea Scale; SAE=Serious Adverse Event; V=Visit; 
WOCBP=Women of Child-bearing Potential. 
 


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2.0 INTRODUCTION 
2.1
Study Rationale
Ensifentrine inhalation suspension 3 mg twice daily was recently approved in the United 
States (US) for the maintenance treatment of COPD in adult patients and is marketed 
under the tradename OHTUVAYRE™ (NDA 217389, “OHTUVAYRE”).  
The COPD Assessment Test [CAT™; CAT]3–5 is a validated, short, and simple patient 
completed questionnaire. The CAT is often used in a clinical setting to assess further the 
COPD symptoms and impact of a patient’s well-being. This study will assess the effect of 
ensifentrine on CAT scores in subjects with moderate to severe COPD when added to
standard of care in routine clinical practice.
2.2 
Background 
2.2.1 
Chronic Obstructive Pulmonary Disease
COPD is characterized by progressive airflow obstruction which is largely irreversible. 
Chronic inflammation of the respiratory tract, acute exacerbations primarily caused by 
viral and/or bacterial infections, airway remodeling, and excessive mucus production are 
believed to contribute to the airflow obstruction and lung parenchymal destruction. COPD 
is predicted to be the third leading cause of death and fourth most common cause of 
disability worldwide by 2030, and chronic tobacco smoke exposure is believed to be a 
key etiological factor.6
The primary goals of pharmacological treatment of COPD are to reduce symptoms, 
exacerbation frequency and exacerbation severity as well as to improve overall quality of 
life in patients with COPD and current standard-of-care treatments include inhaled short- 
and long-acting bronchodilators (i.e., muscarinic antagonists [LAMA] and 2 agonists
[LABA]) and inhaled corticosteroids (ICS) are utilized to manage symptoms of COPD.1 
2.2.2 
COPD Assessment Test™ (CAT™)
Tools to assess if treatment goals are attained include several patient-reported outcome 
questionnaires to assist in communications between the patient and physician. However, 
the uptake of these questionnaires into routine clinical practice is integral to the 
assessment of individualized treatment regimens.2 
The CAT™ (CAT) is a validated, short, simple questionnaire that permits the evaluation 
and monitoring over time of COPD disease burden in routine clinical practice. The aim of 
the CAT is to aid health status assessment and communication between the patient and 
physician.3,7 


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Results can be viewed immediately since only the sum of the answers is needed to see the
total score, in which the ranges correspond to the impact of COPD on the well-being and 
daily life of the patient. The ranges include 0-9 (mild impact), 10–20 (moderate impact), 
21–30 (severe impact), and 31–40 (very severe impact). There are 8 subdomains, each 
having only one question, and these include Cough, Mucus, Chest Tight, Breathless, 
Limited Activities, Confident, Sleep and Energy.  Patients rate their experience on a 6-
point scale, ranging from 0 (no impairment) to 5 (maximum impairment).  
2.2.3 
Ensifentrine 
Ensifentrine is a novel, small molecule, and is a potent, selective dual inhibitor of 
Phosphodiesterase 3 (PDE3) and PDE4. This novel mechanism of action leads to 
downstream bronchodilatory and anti-inflammatory effects, and represents an important 
potential additional treatment option for patients with moderate to severe COPD, and 
other respiratory indications such as non-cystic fibrosis bronchiectasis (NCFBE), asthma  
and cystic fibrosis whose disease is manifest by airways obstruction and/or inflammation. 
Ensifentrine inhalation suspension 3 mg twice daily was recently approved in the US for 
the maintenance treatment of COPD in adult patients and is marketed under the 
tradename OHTUVAYRE for use with a standard jet nebulizer. As a new treatment for 
COPD, this new mechanism of action allows ensifentrine to 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.8 
Ensifentrine has been evaluated in 22 completed clinical studies involving approximately 
3,000 subjects, of which 16 studies involving over 2,800 subjects comprise the COPD 
development program including pharmacokinetic, pharmacodynamic, phase IIb, and 
phase III studies.  
In one Phase IIb dose-ranging study (RPL554-CO-205) where subjects were dosed with 
ensifentrine (3 mg arm n=82) or placebo (n=84) BID in addition to once-daily tiotropium 
(5 mg), the CAT score was assessed at baseline, following a 2-week run in on tiotropium, 
and after 2 and 4 weeks after treatment.  Results in the 3 mg arm demonstrated a larger 
score reduction from baseline than placebo at both time points and the pattern of 
improvement in the CAT score at Weeks 2 and 4 was similar to the improvement pattern 
observed with COPD symptoms and quality of life.  
In two Phase III studies (RPL554-CO-301 [n=760] and RPL554-CO-302 [n=791]) 
ensifentrine (3 mg) treatment consistently demonstrated the bronchodilator profile of 
ensifentrine in subjects with moderate to severe COPD over 12 weeks.9  Significant 
effects were shown across all key FEV1 endpoints in both studies.  Furthermore, 
ensifentrine-treated subjects showed significant improvements in dyspnea measured via 
Transition Dyspnea Index at Weeks 6, 12 and 24 and subjects also experienced 
improvements in COPD symptoms and quality of life in both studies. Over 24 weeks of 
treatment, ensifentrine-treated subjects demonstrated a substantial reduction in the 
frequency of moderate/severe exacerbations (RPL554 CO-301: 
 reduction, p=0.050; 


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RPL554 CO-302: 
reduction, p=0.009) compared to placebo-treated subjects. There 
was also a reduction in the risk of moderate/severe exacerbations compared to placebo 
observed in both studies (RPL554 CO-301: 
, p=0.038; RPL554 CO-302: 
, p=0.009).9
Overall, ensifentrine was well-tolerated with a low incidence of adverse events (AEs), 
with rates generally similar to placebo (refer to the Investigator’s Brochure [IB] for 
further detail). 
2.3 
Benefit/Risk Assessment 
Non-clinical and clinical data to date do not indicate any areas of medical safety concern 
considered related to ensifentrine treatment. Hypertension may be a potential risk due to 
 in both 
phase III studies, RPL554-CO-301 and RPL554-CO-
reactions were reported with use of ensifentrine. The most commonly reported psychiatric 
adverse reactions in the pooled 24-week safety population from the phase III studies were 
insomnia (6 subject
subject
subject
subject 
-related 
subjects receiving ensifentrine and no subjects receiving placebo. One subject who 
received ensifentrine in the pooled 24-week safety population experienced a suicide-
related adverse reaction (suicide attempt), and in Phase IIb study RPL554-CO-203, one 
subject who received ensifentrine 1.5 mg experienced a suicide-related adverse reaction 
(suicide). A causal relationship between ensifentrine and increased rates of psychiatric 
events could not be established. 
In a reproductive toxicity study, decreased sperm counts in the testis were observed in 
male rats at all doses. The clinical relevance of this observation is undetermined.  
Ensifentrine has demonstrated statistically and clinically significant bronchodilator as 
well as anti-inflammatory effects in non-clinical models and clinical studies with the 
potential to treat obstructive and inflammatory diseases of the respiratory tract, such as 
COPD, non-CF bronchiectasis, CF, and asthma. Ensifentrine has been assessed in clinical 
studies to date in COPD, CF, hospitalized COVID-19 and asthmatic subjects. Considering 
the consistent improvements in lung function in subjects with COPD, asthma and CF, and 
improvements in symptoms, and health-related quality of life across multiple studies in 
subjects with COPD, and substantial reduction in the rate and risk of moderate/severe 
COPD exacerbations along with the overall favorable safety profile in studies to date, the 
benefit-risk profile of ensifentrine is considered positive.  
As always, Investigators should remain alert to the possibility of AEs manifesting in their 
subjects and should handle these in accordance with protocol requirements.  


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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. 


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3.0 OBJECTIVES AND ENDPOINTS 
3.1
Objectives
Efficacy 
Primary: To assess the proportion of responders to treatment with ensifentrine 
based on the improvement in individual CAT scores when added to standard of 
care in symptomatic subjects with moderate to severe COPD in routine clinical 
practice.  
 Secondary: To investigate the effects of ensifentrine on COPD symptoms, as 
measured by the CAT in symptomatic subjects with moderate to severe COPD 
when added to standard of care in routine clinical practice.  
Safety 
 Safety of ensifentrine. 
3.2 
Endpoints 
Efficacy 
 Primary: The proportion of CAT score responders, defined as an improvement 
at Week 12.  
 Secondary: 
o The proportion of CAT score responders, defined as an improvement from 
.  
o CAT score at Week 6 and Week 12 (change from baseline). 
o CAT score at Week 6 and Week 12 (item-level change from baseline).
Safety 
 Incidence and proportion of AEs. 
 Change from baseline in vital signs (blood pressure and pulse rate). 


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4.0 STUDY DESIGN 
4.1
Overall Design
This is a Phase IIIb, single-center, open-label study investigating the effect of treatment 
with twice daily nebulized ensifentrine (3 mg) over 12 weeks on CAT scores in subjects 
with moderate to severe COPD when added to standard of care in routine clinical 
practice. The CAT is a validated, short, and simple patient completed questionnaire which 
has been developed for use in routine clinical practice to measure the health status of 
patients with COPD. 
At Visit 1, potential subjects will be provided with the informed consent for participation 
in the study.  Following signature on the informed consent, the following information will 
be collected, and procedures performed to confirm subject eligibility for participation in 
the study in the following sequence: 
 CAT Training followed by subject completion of the CAT on paper 
 Modified Medical Research Council Dyspnea Scale (mMRC) 
 Collect and record demographic data 
 Eligibility review (inclusion and exclusion criteria) 
 Review and record medical, surgical, COPD and smoking history 
 Review of prior and concomitant medication (refer to Table 5 for Prohibited 
Medications)
At Visit 2, subject eligibility will be confirmed (screening tests will be verified, and it 
will be assured that the subject meets all inclusion criteria and no exclusion criteria). 
Spirometry will be performed, a physical examination completed, and vital signs will be 
assessed. Eligible subjects will receive a nebulizer and compressor and will be 
administered their first dose of ensifentrine (3 mg) in-clinic during training on nebulizer 
use. Adverse events will be assessed. Subjects will receive a 6-week supply of 
ensifentrine (3 mg) to be administered twice-daily (BID) with a standard jet nebulizer. 
Ensifentrine will be administered BID for a total of 12 weeks.   
At Visit 3 (Week 6), subjects will return and complete the CAT first, their concomitant 
medication will be reviewed, their vital signs and safety will be assessed. Subjects will 
receive a 6-week supply of ensifentrine (3 mg) administered BID.  
At Visit 4 (Week 12), subjects will complete the CAT first, their concomitant medication 
will be reviewed, their vital signs and safety will be assessed. After 12 weeks, treatment 
with nebulized ensifentrine (3 mg) will end.  
The CAT will be completed on paper at Visits 1, 3 and 4 prior to any 
study procedures to avoid influencing the subject’s response.  All 
questions must be answered. Answers to each question will be 
logged into the eCRF by the study team.  


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A follow-up phone call will be made to the subject approximately one week after the end 
of treatment.
Subjects may remain on prescribed short- and long-acting COPD medications throughout 
participation provided they are not included in the prohibited medication list. COPD 
exacerbations should be treated at physician’s discretion as per usual practice.  
4.2 
Justification for Dose 
A 3 mg twice daily dose was selected as the phase III dose for the COPD clinical trials 
based on data from two 4-week Phase IIb studies RPL554-CO-203 and RPL554-CO-205 
which showed clinically meaningful and statistically significant improvements in 
pulmonary function with the 3 mg dose over the 12-hour dosing interval, in subjects with 
or without additional bronchodilator background therapy. Two Phase III studies, RPL554-
CO-301 and RPL554-CO-302 confirmed the efficacy and safety of 3 mg ensifentrine BID 
in subjects with COPD. Ensifentrine 3 mg twice daily (OHTUVAYRE) is the approved 
dose and regimen for the maintenance treatment of COPD in adult patients 
(OHTUVAYRE Prescribing Information). 
4.3 
End of Study Definition 
A subject is considered to have completed the study if he/she has successfully completed 
all scheduled visits and completed follow-up contact. With no rescheduled visits, the 
study should last approximately 14 weeks. 
The end of the study is defined as the date of the last follow-up contact of the last subject 
in the study. 


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5.0 STUDY POPULATION 
Prospective approvals of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, are not permitted.
5.1 
Inclusion Criteria 
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 ICF and in this protocol. 
2. Aged 40 to 80 years of age inclusive, at the time of screening. 
3. Sex:
 Males are eligible to participate if they agree to use contraception as described 
in the contraceptive guidance (Appendix 4) from screening and throughout the 
study and for at least 30 days after the last dose of study medication. 
 Females are eligible to participate if they are not pregnant, not breastfeeding, 
and  1 of the following conditions apply: 
a) Not a woman of childbearing potential (WOCBP) as defined in 
Appendix 4. 
OR 
b) A WOCBP who agrees to follow the contraceptive guidance in 
Appendix 4 from screening and throughout the study and for at least 
30 days after the last dose of study medication. 
4. 
 10 pack 
years. Note: Pipe and/or cigar use cannot be used to calculate pack-year history. 
Former smokers are defined as those who have stopped smoking at least 6 months 
prior to screening. Smoking cessation programs are permitted during the study.
5. An established clinical history of COPD as defined by the American Thoracic 
Society (ATS)/European Respiratory Society (ERS) guidelines10 with symptoms 
compatible with COPD.
6. Pre- and post-bronchodilator (4 puffs of albuterol) spirometry at Visit 2 
demonstrating the following:
 Pre- and post-albuterol FEV1/forced vital capacity (FVC) ratio of < 0.70. 
 Post-albuterol FEV1
3
75
.11 
7. 
 2 on the modified Medical Research Council Dyspnea Scale at Visit 
1. 
8. A score of  10 on the COPD Assessment Test™ at Visit 1. 
9. Demonstrates stable use of dual (LAMA+LABA) or triple (LAMA+LABA+ICS) 
maintenance therapy, in any form (except nebulized) for at least 8 weeks prior to 
screening and agrees to continue use for the duration of the study. Note: The 


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number taking LAMA+LABA+ICS will be capped at ten (10). The use of LAMA or 
LABA alone or with ICS is not permitted (e.g., LABA+ICS, LAMA).
10. Capable of withholding short-acting rescue medications for 4 hours, Twice-Daily 
maintenance therapy for 24 hours or Once-Daily maintenance therapy for 48 
hours prior to Visit 2.
11. Capable of using the study nebulizer correctly.
12. Ability to perform acceptable spirometry in accordance with ATS/ERS 
guidelines.12 
13. Willing and able to attend all study visits and adhere to all study assessments and 
procedures.
5.2 
Exclusion Criteria 
1. Hospitalizations for COPD (or COPD exacerbation), pneumonia, or other serious 
infection or treatment with oral or parenteral (oral, intravenous, or intramuscular)
glucocorticoids within the past 12 weeks. 
2. Lower respiratory tract infection within the past 6 weeks or an active infection at 
screening.
3. History of life-threatening COPD, including Intensive Care Unit admission and/or 
requiring intubation within 1-year of screening. 
4. Major surgery (requiring general anesthesia) within the past 6 weeks, lack of full 
recovery from surgery at screening, or planned surgery through the end of the 
study. 
5. Concomitant clinically significant pulmonary disease other than COPD (e.g., 
asthma, tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, 
interstitial lung diseases, sleep apnea (unless controlled with stable continuous 
positive airway pressure [CPAP] use), known alpha-1 antitrypsin deficiency, core 
pulmonale or other non-specific pulmonary disease).
6. Severe comorbidities including unstable cardiac, (e.g., myocardial infarction 
within 1 year prior to screening, unstable angina within 6 months prior to 
screening, or unstable or life-threatening arrhythmia requiring intervention within 
3 months prior to screening) or any other clinically significant medical conditions 
including uncontrolled diseases (e.g., endocrine, neurological, hepatic, 
gastrointestinal, renal, hematological, urological, immunological, psychiatric or 
ophthalmic diseases) that would, in the opinion of the Investigator, preclude the 
subject from safely completing the required tests or the study, or is likely to result 
in disease progression that would require withdrawal of the subject. 
7. HIV infection or other immunodeficiency. 
8. Previous lung resection or lung reduction surgery within 1-year. 
9. Long term oxygen use defined as oxygen therapy prescribed for greater than 12 
hours per day. Note: 
exclusionary. 


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10. Pulmonary rehabilitation unless such treatment has been stable from 4 weeks prior 
to screening and remains stable during the study. Note: Pulmonary rehabilitation 
programs should not be started or completed during participation in the study. 
11. 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. 
12. Significant psychiatric disease that would likely result in the subject not being 
able to complete the study, in the opinion of the Investigator. 
13. Findings on physical examination that an investigator considers to be clinically 
significant. 
14. Known a
 
15. Known diagnosis of severe chronic kidney disease.13
16. Any other known abnormal clinical, cardiac or laboratory (hematology, 
biochemistry or viral) findings, deemed by an investigator to be clinically 
significant. Note: Clinically significant abnormal chemistry and/or hematology 
may be repeated during the screening process.
17. Use of prohibited medications within the time intervals defined in Section 6.7.2. 
18. Current or history of drug or alcohol abuse within the past 5 years. 
19. Women who are breast feeding.
20. Use of an experimental drug within 30 days or 5 half-lives of screening, 
whichever is longer, and/or participation in a study treatment-free follow-up phase 
of a clinical study within 30 days prior to screening. 
21. Use of an experimental medical device or participation in a follow-up phase of an 
experimental medical device clinical study within 30 days prior to screening. 
22. 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. 
23. A disclosed history or one known to the Investigator of significant noncompliance 
in previous investigational studies or with prescribed medications. 
24. Any other reason that the Investigator considers makes the subject unsuitable to 
participate. 
5.3 
Rescreening 
Subjects who are screen failures (Section 5.4) may be rescreened with approval from the 
Medical Monitor. Rescreened subjects should be assigned a new subject number different 
from the initial screening event.  
Rescreening due to failure to meet the following Inclusion Criteria is not allowed for 
Inclusion Criteria # 5, 6, 7, or 8. 


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5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but 
did not receive study medication. See Section 7.1.1 for instructions on managing subjects 
who did not meet the eligibility criteria but received study medication in error.
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure subjects to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAEs.


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6.0 STUDY TREATMENT 
Subjects will receive ensifentrine administered using the inhaled route via a standard jet 
nebulizer supplied by the Sponsor.
In this protocol the terms ‘investigational product,’ and ‘study medication’ are the same 
and refer to the nebulized ensifentrine (3 mg) or OHTUVAYRE. 
6.1 
Dispensing of Medical Devices 
Subjects will be dispensed study supplied medical devices as per the schedule outlined in 
the Schedule of Activities (SoA) (Table 1). 
No Sponsor manufactured medical device is used in this study.
Each eligible subject will be dispensed a study supplied nebulizer, with a compressor: 
 PARI LC ®Sprint nebulizer
 PARI PRONEB ®Max Aerosol Delivery System or equivalent 
At Visit 3, a new PARI LC Sprint® nebulizer will be supplied, if needed. Instructions for 
medical device use are provided in the package insert. 
The study medication should only be administered with the study provided nebulizer. No 
medications other than the study medication should be administered with the study 
provided nebulizer. 
6.2 
Dispensing of Study Medication  
Subjects will be dispensed study medication kit(s) as per the schedule outlined in the 
Schedule of Activities (SoA) (Table 1). 
6.3 
Administration of Study Medication  
Study medication will be administered by inhalation of an aerosol generated by the study 
supplied reusable nebulizer attached to the compressor. 
6.3.1 
Dosing in the Clinic 
At Visit 2, the first dose of study medication will be administered in-clinic with the study 
supplied nebulizer and compressor.  
 Following informed consent and eligibility confirmation, study medication will be 
administered by inhalation of an aerosol generated by the reusable study supplied 
nebulizer attached to a study supplied compressor. 
 The site staff member will need to follow the nebulizer Set-Up instructions 
provided with the nebulizer and the Pharmacy Manual to prepare and administer 
study medication. 


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Administration of nebulized study medication will be observed by the site staff 
member from start of nebulization until end time of nebulization. The site staff 
member MUST administer and observe study medication.  
 Study medication nebulization time should be approximately 5 to 10 minutes. 
 The end time of study medication nebulization is when a slight sputtering sound 
from the nebulizer is heard.  
 The date, the start time, and the end time of study medication nebulization will be 
recorded by the site staff member in the subject source document and the 
electronic case report form (eCRF). 
6.3.2 
Dosing at Home 
Subjects will take their study supplied nebulizer and compressor as well as instructions 
home for use during the study. 
Following Visit 2, subjects will self-administer their daily morning and evening doses of 
study medication at home at approximately the same times each day, approximately 12 
hours apart, for 12 weeks.  
 Prior to dosing at home, subjects must take their background maintenance COPD 
medication approximately 2 minutes prior to taking study medication. 
 The morning doses of COPD maintenance medication and study medication must 
be taken at home in the morning prior to Visit 3 and Visit 4. 
 Each subject will follow the Nebulizer Set-Up instructions and study medication 
label to prepare and self-administer the study medication by inhalation using the 
reusable study supplied nebulizer attached to the study supplied compressor. 
 Study medication nebulization time should be approximately 5 to 10 minutes; 
until a slight sputtering sound from the nebulizer is heard.   
 
Subjects will be instructed as follows:  
 Only a study supplied nebulizer and compressor may be used to administer study 
medication. Only study medication may be used in the study supplied nebulizer 
and compressor. 
 Discard used study medication ampules and open foil pouches of used study 
medication at home. 
 Return unused study medication ampules to the clinic at Visit 3 and Visit 4 for 
collection, and assessment of medication compliance by a site staff member 
(Section 6.6). 
6.4 
Investigational Product/ Study Medication 
Investigational product/study medication is described in Table 2. 


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Table 2: Investigational Product/Study Medication Details 
 
 
 
 
 
  
The ensifentrine formulation 
 
, and supplied 
as a 2.5 mL nominal fill in single unit-dose low density polyethylene (LDPE) translucent 
ampule overwrapped in a foil pouch.  
Ensifentrine is manufactured using aseptic manufacturing techniques in accordance with 
Good Manufacturing Practice guidelines and will be provided to the site as subject kits to 
be dispensed at Visit 2 and Visit 3. 
6.4.1 
Study Medication Formulation Information 
The study medication formulation constituent and concentrations are described in Table 3. 
6.5 
Preparation/Handling/Storage/Accountability 
Study medication should be stored below 25°C (77°F) at controlled room temperature and 
should not be frozen. 
An investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study medication received and any discrepancies are 
reported and resolved before use of the study medication.
All study medication must be stored in a secure, environmentally controlled, limited 
access, monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the Investigator and authorized study center staff.


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The temperature should be monitored, and logs maintained in areas where study 
medication is stored. If temperature conditions have been compromised or any study 
medication has not been stored appropriately, this should be documented, and the study 
medication quarantined until the Sponsor has been notified and confirmed whether it may 
be used. 
Only subjects meeting the eligibility criteria in the study may receive study medication 
and only authorized study center staff may supply or administer study medication.  
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study medication accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study medication are 
provided in the Pharmacy Manual. 
The Investigator, a member of the study center staff, the site pharmacist, or pharmacy 
team member must maintain an adequate record of the receipt and distribution of all study 
medication using the Drug Accountability Form. These forms must be available for 
inspection at any time.
6.6 
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 Visit 3 (Week 6), prior to dispensing study medication, previously dispensed/unused 
study medication will be retrieved, and compliance assessed by the site staff member. 
Subjects exhibiting poor compliance, as assessed by the number of ampule/foil pouch 
counts dispensed and returned, should be counseled on the importance of good 
compliance to the study dosing regimen and this counseling should be documented in the 
subject source document.  
At Visit 4 (Week 12), previously dispensed/unused study medication will be retrieved,
and compliance assessed by the site staff member.  
Non-
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 (Table 7). 


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6.7.1 
Permitted Medications/Therapy 
Permitted COPD rescue and maintenance medications are provided in Table 4. Subjects 
must demonstrate stable use of prescribed long-acting maintenance medications for at 
least 8 weeks prior to screening.
Subjects may continue use of their prescribed inhaled short-acting muscarinic antagonists 
(SAMA), short-
SABA), LABA+LAMA or LABA+LAMA+ICS in any 
form (except nebulized) while participating. Changes in any of these treatments should 
not occur during participation, except in the case of a safety issue. New medications or 
treatments should not be started during participation unless necessary for safety reasons. 
Table 4: Permitted Rescue and Background Medications 
Medication
Condition 
SABA and/or SAMA 
(e.g., albuterol, 
ipratropium) 
For use as rescue medication only during the study, on an as needed 
basis. 
Must withhold prior to Visit 2 spirometry: 4 hours.
LAMA+LABA ± ICS
Subjects will be required to remain on their maintenance COPD 
treatment inhaler(s) at a stable dose for the duration of the study.  
Must withhold prior to Visit 2 spirometry: 48 (once-daily) or 24 
(twice-daily) hours. 
Only approved COPD doses of ICS are permitted for enrollment and 
during study participation (e.g., Trelegy containing 100 mcg FF). 
Maintenance therapy should resume once Visit 2 has been completed. 
Abbreviations: COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroids; 
LAMA = long-acting muscarinic antagonist; LABA = long-
 = short-
acting muscarinic antagonists; SABA = short-
6.7.2 
Prohibited Medications/Therapy 
Prohibited medications and therapies are provided in Table 5. Prohibited medications are 
not to be taken during study conduct. 


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Table 5: Prohibited Medications/Therapy 
Medication
Time interval withheld prior to Visit 2
Oral, systemic or parenteral steroid 
therapies 
3 months prior and prohibited during the study. 
Antibiotics for lower respiratory tract 
infection or chronic use of antibiotics
6 weeks prior and prohibited during the study.
Inhaled Corticosteroids (e.g., ICS 
monotherapy, high dose inhaled 
corticosteroids) 
IF taking LAMA+LABA, the use of ICS is prohibited 
at least 8 weeks prior and prohibited during the study.  
IF taking LAMA+LABA+ICS, the use of ICS must be 
at a stable dose for at least 8 weeks prior and continue 
for the duration of the study.  
IF taking LAMA+LABA+ICS, ICS doses not 
approved for COPD are prohibited for 8 week prior 
and during study participation (e.g., > 100 mcg/day). 
ICS monotherapy is not permitted. 
ICS should not be initiated, dose changed, or 
discontinued during the study except for safety 
reasons.
Oral leukotriene inhibitors (i.e., 
montelukast, zafirlukast, zileuton) 
48 hours prior and prohibited during the study.
Theophylline and PDE4 inhibitors 
(e.g., roflumilast, apremilast, 
crisaborole) 
8 weeks prior and prohibited during the study. 
Terbutaline 
24 hours prior and prohibited during the study.
Nebulized SABA, SAMA, LAMA, 
LABA or ICS 
8 weeks prior and prohibited during the study. 
Oral beta2-agonists 
1 week prior and prohibited during the study. 
Abbreviations: COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroids; 
LAMA = long-acting muscarinic antagonist; LABA = long-
SAMA = short-
acting muscarinic antagonists; SABA = short-
.
6.7.3 
Recording Use of Concomitant Medications 
Information on all medications and therapies the subject takes other than the study 
medication, including over-the-counter drugs, must be collected, and recorded. 
All COPD medications used within the past 3 months 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).  
 Documentation of background maintenance medications (LAMA+LABA or 
LABA+LAMA+ ICS) use prior to and during the study should be recorded on the 
concomitant medication page of the eCRF along with reason for use, dates of 
administration (start date), and dosing information (dose and frequency). End date 
should be documented as “Ongoing.”
 Documentation of rescue medication use prior to and during the study should be 
recorded on the concomitant medication page of the eCRF along with reason for 
use, dates of administration (start and end dates), and dosing information (dose 
and frequency). End date should be documented as “Ongoing.” 


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Any vaccine that is recommended by the subject’s healthcare provider is permitted during 
the study and should be collected and recorded.
All non-COPD medications will be recorded in the eCRF at Visit 1 and changes recorded 
during the study. Information recorded will include, but may not be limited to items such 
as: 
 Reason for use. 
 Dates of administration including start and end dates. 
 Dosage information including route, dose, and frequency. 
6.8 
End of Study Procedures 
Seven ± 3 days after Visit 4 (or Early Withdrawal/Termination) (Table 1), the site should 
contact the subject by telephone to complete the following assessments:
Concomitant medications
 AEs and SAEs 
6.9 
Treatment After the End of Study 
There are no plans to provide post-study treatment, including study medication for 
compassionate use, following study completion. 
After the End of Study Follow-up phone call (Table 1), subjects may resume conventional 
COPD therapy as prescribed by the investigator or other physician. 
Medications initiated after the end of study treatment should not be entered into the eCRF 
except for those given for a SAE. 


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7.0 DISCONTINUATION OF STUDY MEDICATION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Medication 
Subjects may permanently discontinue study medication before the end of the study if 
they choose to or at the Investigator’s discretion. Subjects who permanently discontinue 
study medication are required to withdraw from the study after completion of the Early 
Withdrawal/Termination procedures described in Table 1 and Section 7.2 as soon as
possible.  
Circumstances potentially requiring or actually resulting in discontinuation of study 
medication are described below. 
7.1.1 
Does Not Meet Criteria  
A subject who does not meet the Eligibility Criteria (Section 5.0) should not receive study 
medication, will be considered a screen failure (Section 5.4), and may be eligible for 
rescreening (Section 5.3). 
If a subject who does not meet the Eligibility Criteria inadvertently receives study 
medication, the Medical Monitor must be contacted and will consult with the Sponsor to 
determine if the subject may continue, must be discontinued from study medication,
and/or discontinued from the study. Such subjects, if discontinued, may be replaced, but 
are not eligible for rescreening (Section 7.1.1). 
7.1.2 
Positive Pregnancy Test in Females 
Women who are pregnant or breastfeeding are not eligible to participate. Pregnancy 
testing will be conducted in women of childbearing potential during screening and at 
other times specified in the SoA (Table 1). 
Women exhibiting a positive pregnancy test during the study will be discontinued from 
study medication and followed-up per the Collection of Pregnancy Information guidelines 
in Section 8.4.5 and Appendix 4. 
7.1.3 
COPD Exacerbation Withdrawal Criteria 
A subject that experiences a COPD exacerbation during participation may be withdrawn 
from the study if requested by the subject or at the discretion of investigator.
7.1.4 
Liver Chemistry Stopping Criteria
Subjects may be withdrawn for abnormal liver function as considered by the investigator 
if it is in best interest of the subject.
If any of these criteria are met, immediately discontinue study medication, and contact the 
Medical Monitor: 


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1. 
x
 x 
 x 
ULN and INR > 1.5, if INR measured. INR measurement is not required, and the 
threshold value stated will not apply to subjects receiving anticoagulants), termed 
‘Hy’s Law’ must be reported as an SAE. 
a. Note: 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. 
b. The following are required if this criterion is met: 
i. Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 
anti-liver kidney microsomal antibodies and quantitative total 
immunoglobulin G (IgG or gamma globulins). 
ii. Serum acetaminophen adduct HPLC assay (quantifies potential 
acetaminophen contribution to liver injury in subjects with definite 
or likely acetaminophen use in the preceding week).13
iii. 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.14
2. 
 x ULN. 
3. 
 x ULN but < < 8 x 
 
4. 
x ULN if associated with symptoms (new or worsening) believed to be 
related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, or jaundice) or hypersensitivity (such as fever, rash, or eosinophilia). 
5. 
x ULN but < 8 x 
 
7.1.5 
Other Criteria
Other criteria that may or may not require permanent discontinuation of study medication 
include but are not limited to AE, lack of efficacy, protocol deviation, non-compliance, 
study, or site closed/terminated, investigator discretion, or subject withdrawal of consent.
7.1.6 
Discontinuation of the Study 
If the Sponsor discontinues or terminates the study, all subjects will be permanently 
discontinued from study medication and should complete the Early 
Withdrawal/Termination procedures described in Table 1 and Section 7.2 as soon as 
possible. 


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7.2 
Subject Discontinuation/Withdrawal from the Study 
A subject may withdraw from the study at any time at his/her own request or may be 
withdrawn from administration of study medication and from all study participation at the 
discretion of the Investigator at any time for safety, behavioral, compliance, or 
administrative reasons. See the SoA (Table 1) for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
 If the subject withdraws consent for disclosure of future information, the Sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
 If a subject withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the Investigator must document this in the study 
center study records. 
If a subject is withdrawn prior to completion of the study, every attempt should be made 
to have the subject complete the Early Withdrawal/Termination procedures in the SoA 
(Table 1) as soon as possible and the End of Study follow-up phone call (Section 6.8). 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she fails to return for scheduled 
visits and is unable to be contacted by the study center. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 The study center must attempt to contact the subject and reschedule the missed 
visit as soon as possible and counsel the subject on the importance of maintaining 
the assigned visit schedule and ascertain whether the subject wishes to and/or 
should continue in the study. 
 Before a subject is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the subject (where possible, 3 telephone 
calls and, if necessary, a certified letter to the subject’s last known mailing address 
or local equivalent methods).  These contact attempts should be documented in the 
subject’s medical record. 
 Should the subject continue to be unreachable, he/she will be considered to be lost 
to follow-up and will be discontinued from the study. 


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8.0 STUDY ASSESSMENTS AND PROCEDURES 
Subjects may not complete any screening procedures unless all prohibited 
medications/therapy described in Section 6.7.2 have been withheld for the defined time 
interval.
Study procedures and their timing are summarized in the SoA (Table 1). 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue study 
medication. 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The Investigator will maintain a Screening Log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screen failure, as applicable. 
Procedures conducted as part of the subject’s routine clinical and obtained before signing 
of the ICF may be utilized for the screening process or baseline purposes provided the 
procedures met the protocol-specified criteria and were performed within the time frame 
defined in the SoA (Table 1). 
See Section 5.4 for specific information to be collected for screen failures. 
8.1 
Visits 
Planned timepoints for all assessments are provided in the SoA (Table 1). 
8.1.1 
Visit 1  
8.1.1.1
Informed Consent 
Informed consent must be obtained according to the informed consent process described 
in Appendix 2.
8.1.1.2
Demographic Variables 
Demographic variables will be recorded. These include date of birth, age, gender, race, 
ethnicity.
8.1.1.3
COPD Assessment Test (CAT™) 
Site staff will review the CAT form and provide instructions to the subject. The CAT will 
be completed on paper by the subject per the instructions in Section 8.2. The completed 
CAT will be logged into the eCRF by the study team.


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The order should be CAT followed by the mMRC.
8.1.1.4
Modified Medical Research Council Dyspnea Scale (mMRC)
The mMRC dyspnea scale is a questionnaire that measures COPD symptoms and defines 
symptom burden (refer to Appendix 5).15  Site staff will administer/interview the subject 
to complete the mMRC dyspnea scale questionnaire and record the score in the eCRF.
8.1.1.5
Medical, Medication and Smoking History
A history of relevant current or past medical conditions, surgical history, COPD history, 
and smoking history will be obtained:
Medical history, relevant surgical history and medical conditions will be recorded. 
Note: Minor surgical procedures (e.g., tonsillectomy, appendectomy) performed 
more than 5 years prior to screening do not need to be recorded. 
 COPD history will be recorded and includes COPD diagnosis history and COPD 
exacerbation history. 
 Current and prior medications will be recorded (Section 6.7.3). 
 COPD type (emphysema and/or chronic bronchitis), as assessed by the 
investigator or medical professional). Chronic bronchitis is defined as “regular 
production of sputum for 3 or more months in 2 consecutive years (in the absence 
of other conditions that may explain it)”.1 
 Smoking history (current or former) will be recorded. Former smokers are defined 
as those who have stopped smoking for at least 6 months. Pack years calculation: 
smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 
years)] 
Note: Medical and COPD condition(s) identified during screening will be documented as 
medical history and not as an AE(s) unless the condition worsens during the study and 
meets the definition of an AE. 
8.1.1.6
Eligibility Criteria 
Subject eligibility will be assessed for all inclusion criteria (Section 5.1) and exclusion 
criteria (Section 5.2). 
8.1.2 
Visit 2 
Medical and COPD history and concomitant medications will be reviewed, and any 
changes recorded. It will be confirmed that each subject meets all inclusion criteria and 
no exclusion criteria prior to the dispensing of study equipment and study medication.
8.1.2.1 
Vital Signs 
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. 


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Supine blood pressure and pulse measurements should be obtained after the subject has 
been at rest for at least 5 minutes in the supine position and located in a quiet setting 
without distractions (e.g., television, cell phones). 
8.1.2.2
Height and Weight 
Height in centimeters (cm), weight in kilograms (kg), and body mass index will be 
measured and recorded.
8.1.2.3
Physical Examination 
A physical examination will include assessments of the Cardiovascular, Respiratory, 
Gastrointestinal, and Neurological systems. 
Investigators should pay special attention to clinical signs to ensure subjects have had no 
previous serious physical or mental illness(es). Refer to Note at the end of Section 
8.1.1.5.
8.1.2.4
Urine Pregnancy Test 
A urine pregnancy test will be conducted only on women of childbearing potential (refer 
to Appendix 4). 
8.1.2.5
Spirometry Assessment 
Pre-bronchodilator testing will be conducted prior to dosing with albuterol. Post-
bronchodilator testing should be conducted between 15- and 30-minutes following 
administration of 4 puffs of albuterol.  
Spirometry will be obtained that meets or exceeds the ATS minimal performance 
recommendations.12 
 Prior to the spirometry measurement, the site staff will train each subject on how 
to perform acceptable spirometry maneuvers. 
 Acceptable spirometry efforts should have a satisfactory start of test and end of 
forced expiration (plateau in the volume-time curve) and be free from artifacts due 
to cough, glottic closure, early termination, poor effort, obstructed mouthpiece, 
equipment malfunction, or other reason.12 
 For FEV1 and FVC determinations, at least 3 but no more than 8 acceptable 
spirometry efforts should be obtained. 
 The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even 
if they do not come from the same effort. 
Subjects should refrain from smoking and/or caffeinated beverages prior to spirometry as 
follows:  
 No smoking for at least 1-hour prior to spirometry assessment. 
 Abstain from drinking caffeinated beverages (e.g., tea, coffee) for 2 hours prior to 
spirometry assessment. 


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8.1.2.6
Study Equipment Dispensed 
Subjects will be trained in the use of the PARI LC Sprint nebulizer and PARI PRONEB 
Max Aerosol Delivery System (compressor), which will be used for inhalation of study 
medication during treatment (Section 6.1).  
Site staff will review the nebulizer information and instructions provided by the 
manufacturer with the subject (e.g., Instructions for Use, located in the Pharmacy 
Manual). The subject will receive hands on training on the use of the nebulizer which will 
coincide with administering of the first dose of study medication (Section 6.3.1). The 
nebulizer and equipment will be taken home (Section 6.1). 
8.1.2.7 
Study Medication Dispensed 
Study Medication will be dispensed (Sections 6.2 and 6.3.2): 6 weeks supply of 
ensifentrine (3 mg).  
8.1.2.8 
Study Medication Dosed (in-clinic) 
Subject will be administered first dose of Study Medication in-clinic during training on 
the use of the nebulizer and compressor (Section 6.3.1). 
8.1.2.9 
Safety Assessment
Subjects will be assessed for any adverse events per instructions in Section 8.3.2. 
8.1.3 
Visit 3 
Visit 3 will take place at Week 6 (42 ± 3 days after Visit 2). The following will occur: 
 The CAT will be completed on paper (Section 8.2), concomitant medication 
reviewed and any changes recorded, and vital signs will be taken 
(Section 8.1.2.1).  
 Unused Study Medication will be collected and assessed for compliance per 
Section 6.6. 
 Study Medication will be dispensed: 6 weeks supply of ensifentrine (3 mg). A 
new nebulizer cup may be dispensed, if needed.
 Subjects will be assessed for any adverse events per instructions in Section 8.3.2. 
8.1.4 
Visit 4 
Visit 4 will take place at Week 12 (42 ± 3 days after Visit 3). The following will occur: 
 The CAT will be completed on paper (Section 8.2), concomitant medication 
reviewed and any changes recorded, and vital signs will be taken 
(Section 8.1.2.1).  
 Unused Study Medication will be collected and assessed for compliance per 
Section 6.6. 
 Study equipment (Section 6.1) will be collected. 


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Subjects will be assessed for any adverse events per instructions in Section 8.3.2.
8.1.5
Telephone Follow-up
The final study contact is a follow-up telephone call 7 ± 3 days after Visit 4 (or EW/T). 
The following will occur:
 Concomitant medication will be reviewed, and any changes recorded. 
 Subjects will be asked about any adverse events per instructions in Section 8.3.2. 
8.2 
Efficacy Assessment 
Planned timepoints for all efficacy assessments are provided in the SoA (Table 1).
The CAT™ is a one-page, 8-item questionnaire suitable for completion by patients 
diagnosed with COPD. When completing the questionnaire, individuals rate their 
experience on a 6-point scale, ranging from 0 (no impairment) to 5 (maximum 
impairment) with a scoring range of 0-40. Higher scores indicate greater disease impact. 
Refer to Appendix 5.  
The CAT will be completed on paper and must be the first assessment completed at Visits 
1, 3 and 4 to avoid influencing the subject’s response.  At Visit 1, the order should be 
CAT followed by the mMRC.
All questions must be answered, and the subject should not be told their results. It is 
recommended that the questionnaire be administered at the same time of day at each visit. 
Answers to each question will be logged into the eCRF by the study team. 
Adequate time must be allowed to complete all items on the questionnaire; the 
questionnaire must be reviewed for completeness and, if necessary, the subject should be 
encouraged to complete any missing items. 
8.3
Safety Assessments
Planned timepoints for all safety assessments are provided in the SoA (Table 1).
8.3.1 
Vital Signs 
Vital signs should be obtained prior to study medication dosing, as applicable. 
Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
Supine blood pressure and pulse measurements should be obtained after the subject has 
been at rest for at least 5 minutes in the supine position and located in a quiet setting 
without distractions (e.g., television, cell phones).


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8.3.2 
Adverse Event Assessment 
The method of detecting AEs will be performed as described in Section 8.4 and 
Appendix 3. 
8.4 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
AEs will be reported by the subject. 
The Investigator and any designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study medication or study 
procedures, or that caused the subject to discontinue the study (Appendix 3). 
As stated in Section 8.1.1.5, medical and COPD condition(s) identified during screening 
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. 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information 
AEs and SAEs will be collected from time of first dose of study medication through the 
follow-up contact.  
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix 3. The Investigator will submit any updated SAE data to the 
Sponsor designee within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the event to 
be reasonably related to the study medication or study participation, the Investigator must 
promptly notify the Sponsor.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
8.4.2
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.


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8.4.3 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a 
study medication under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study medication under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators, as necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate
according to local requirements. 
8.4.4 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, through the follow-up contact, or the 
subject is lost to follow-up (as defined in Section 7.3).  Further information on follow-up 
of AEs and SAEs is given in Appendix 3. 
8.4.5 
Pregnancy 
Details of all pregnancies in female subjects will be collected after the start of study 
medication and until 30 days after the last dose of study medication.
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.4.6 
Adverse Events of Special Interest 
Adverse events of special interest have not been identified for ensifentrine. 
8.4.7 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs 
Disease-related events and/or disease-related outcomes should generally not be recorded 
or reported as an adverse event.  


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COPD exacerbations are an expected disease-related outcome, unless the exacerbations 
manifest in an unusual or uncharacteristic manner. COPD exacerbations including daily 
expected COPD symptoms (e.g., dyspnea, chest tightness, wheezing, cough, sputum, that 
are not associated with the dosing event) will not be collected as an AE unless they meet 
the definition of an SAE. 
8.4.8 
Device Incidents 
The Investigator, or responsible person according to local requirements (e.g., the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of device incidents to the IRB/IEC, device manufacturer, or 
regulatory authorities, as required. 
A device incident is defined as an incident related to the failure of a medical device, 
deterioration in its effectiveness, or inadequacy in its labeling or directions that led to the 
death or serious deterioration in health of a subject, user, or other person, or could do so 
were it to recur. 
8.5 
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.  
8.6 
Data Monitoring Committee  
There are no plans to include a Data Monitoring Committee for this study. Ensifentrine 
has demonstrated to have a safety profile similar to placebo in subjects with COPD.  


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9.0 STATISTICAL CONSIDERATIONS 
Further details of the analyses to be performed can be found in the Statistical Analysis 
Plan (SAP).
9.1 
Statistical Hypotheses 
The aim of this study is to quantify both improvement CAT scores and responder 
proportions in subjects with moderate/severe COPD treated with ensifentrine (3 mg) for 
12-weeks. No formal statistical tests will be performed. Study conclusions will be based 
on two-
proportions.  
9.2
Sample Size Determination
A sample size of approximately 20 subjects provides the ability to demonstrate a 
responder proportion estimate statistically differs from zero.  Assuming a 30 percent 
response rate in the study population, 20 subjects provides the ability to demonstrate the 
derived proportion differs from zero determined by the lower two-
limit derived from the estimated count using a normal approximation assuming a standard 
error equal to the square root of 6.   
Twenty subjects also provides the ability to demonstrate the estimates of mean change 
from baseline does not extend to the clinically meaningful deterioration limit of (+2 
units).  Assuming estimated mean improvement of 1 unit with a corresponding standard 
deviation equal to 4.5, 20 
confidence interval for a mean change from baseline estimate does not exceed 2 units. 
9.3 
Statistical Methods 
In general, unless stated otherwise, continuous variables will be summarized using 
descriptive statistics (number of subjects, mean, standard deviation [SD], median, 
minimum, and maximum values) and for categorical (nominal) variables, the number and 
percentage of subjects will be used. 
In general, unless stated otherwise, continuous variables will be summarized using 
descriptive statistics (number of subjects, mean, standard deviation, median, minimum, 
and maximum values) and for categorical (nominal) variables, the number and percentage 
of subjects will be used.  
9.3.1 
Populations for Analyses 
Allocation of subjects to the analysis populations (and whether any subjects or specific 
data from a subject will be excluded) will be determined prior to database lock. 


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The Full Analysis Set (FAS) will consist of all subjects that were administered the study 
medication at Visit 2 and have a CAT completed at baseline and from at least one post-
treatment visit.  
The Safety Analysis Set (SAS) will consist of all subjects who were administered the 
study medication at Visit 2. 
9.3.2 
Statistical Analyses 
Continuous endpoints will be summarized as change from baseline using a mixed model 
for repeated measures with model terms for time and background therapy, and with 
baseline included as a covariate. Within subject error will be modeled using an 
unstructured covariance matrix, and Kenward-Roger method will be used to estimate 
degrees of freedom. 
confidence limits will be presented at each post-treatment time of assessment.  
Response frequencies will be summarized by negative binomial regression with model 
terms for time and background therapy, and with baseline included as a covariate. Within 
subject correlation in responder status will be modeled using an unstructured covariance 
matrix. 
will be generated from estimated frequencies and presented for each post-treatment time 
of assessment.  
9.3.3 
Efficacy Analyses 
Analysis will be based on the FAS.  
Continuous variables will be summarized both for the absolute value and for change from 
baseline using descriptive statistics (N, mean, median, SD, minimum, and maximum), 
generated separately as well as overall.  
Results will provide the number of subjects included in each analysis, estimated least 
square means and corresponding standard errors and 95
 confidence intervals (CIs).  
Total score data will be used for the change from baseline CAT analysis and the 
responder analysis. 
Individual CAT item score (8-items) will be used for the change from baseline item-level 
analysis. 
An analysis of the proportion of subjects with an improvement from baseline in CAT 
score of 2 or more will be summarized by visit and analyzed using negative binomial 
regression.  
CAT total score and the individual item scores will be listed for each visit (items: Cough, 
Mucus, Chest Tight, Breathless, Limited Activities, Confident, Sleep and Energy). A plot 
of the least square means change from baseline in total score over time will be presented 
(based on the MMRM analysis). 


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Additional details will be provided in the SAP. 
9.3.4
Safety Analyses
Safety analysis will be descriptive and based on the SAS including all treated subjects.  
AEs will be analyzed using quantitative and qualitative measures. Treatment emergent 
adverse events (TEAEs) will be summarized by treatment for all AEs, related AEs, SAEs, 
deaths, AEs leading to discontinuation of study medication or to withdrawal from study, 
AEs of different severity and AEs of different chronicity.  
TEAEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and summarized by system organ class (SOC) and preferred term (PT) for each treatment. 
Adverse events will be included in subject listings. Seriousness, relatedness, and outcome 
will be identified in subject listings.  
Vital signs will be summarized as change from baseline values for each parameter. Vital 
signs will be included in subject listings. Abnormal values and marked abnormalities will 
be identified in subject listings.  
9.3.5 
Other Analyses 
Subject disposition including total number of screened subjects, number of completers, 
withdrawn subjects (including reason for withdrawal) and subjects included in each 
analysis set will be summarized overall. Subject disposition will be included in subject 
listings. 
The number of subjects with major protocol deviations will be summarized by type and 
category of violation overall. Major protocol deviations will be included in subject 
listings. 
Demographic and baseline characteristics will be summarized using descriptive statistics 
overall. Demographic and baseline characteristics will be included in subject listings.  
Medical history will be coded using MedDRA and summarized by SOC and PT for each 
sequence and overall. Medical history will be provided in subject listings. 
Prior medications will denote medications used prior to the first dose of study medication. 
Prior medications will be summarized and provided in subject listings. Prior medications 
will be provided in subject listings. 
Concomitant medications will denote medications started prior to but continuing after 
receipt of study medication. Concomitant medications will be summarized separately by 
Anatomical Therapeutic Chemical (ATC) levels 2 and 4.  Concomitant medications will 
be included in subject listings. 
Compliance to study medication will be computed based on the number of ampules/foil 
pouch count dispensed and unused ampules/foil pouches returned. Non-compliance will 


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be defined as a
. Compliance 
will be summarized overall.  
9.3.6 
Missing Data 
As discontinuation of study medication will result in subject withdrawal, data collected 
after treatment withdrawal will not be included in the analyses, and missing data will not 
be imputed. 
9.4 
Interim Analyses 
There will be no formal interim analysis in the study. 
 


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10.0 REFERENCE LIST 
[1] GOLD. 
.; 
2024. https://goldcopd.org/2024-gold-report/. Accessed February 8, 2024 
[2] Stanford RH, Tabberer M, Kosinski M, Johnson PT, White J, Carlyle M, et al. 
Assessment of the COPD Assessment Test Within U.S. Primary Care. Chronic Obstr 
Pulm Dis J Copd Found. 2020;7(1):26-37. doi:10.15326/jcopdf.7.1.2019.0135
[3] Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Leidy NK. Development and 
first validation of the COPD Assessment Test. Eur Respir J. 2009;34(3):648-654. 
doi:10.1183/09031936.00102509 
[4] Jones P, Harding G, Wiklund I, Berry P, Leidy N. Improving the process and outcome 
of care in COPD: development of a standardised assessment tool. Prim Care Respir J. 
2009;18(3):208-215. doi:10.4104/pcrj.2009.00053 
[5] Jones PW, Harding G, Wiklund I, Berry P, Tabberer M, Yu R, et al. Tests of the 
Responsiveness of the COPD Assessment Test Following Acute Exacerbation and 
Pulmonary Rehabilitation. Chest. 2012;142(1):134-140. doi:10.1378/chest.11-0309
[6] STUCKLER D. Population Causes and Consequences of Leading Chronic Diseases: 
A Comparative Analysis of Prevailing Explanations. Milbank Q. 2008;86(2):273-326. 
doi:10.1111/j.1468-0009.2008.00522.x 
[7] Gruffydd-Jones K, Brusselle G, Jones R, Miravitlles M, Baldwin M, Stewart R, et al. 
Changes in initial COPD treatment choice over time and factors influencing prescribing 
decisions in UK primary care: In UK primary care: A real-world, retrospective, 
observational. npj Primary Care Respiratory Medicine. 2016;26. 
doi:10.1038/npjpcrm.2016.2 
[8] Donohue JF, Rheault T, MacDonald-Berko M, Bengtsson T, Rickard K. Ensifentrine 
as a Novel, Inhaled Treatment for Patients with COPD. Int J Chronic Obstr Pulm Dis. 
2023;Volume 18:1611-1622. doi:10.2147/copd.s413436 
[9] Anzueto A, Barjaktarevic IZ, Siler TM, Rheault T, Bengtsson T, Rickard K, et al. 
Ensifentrine, a Novel PDE3 and PDE4 Inhibitor for the Treatment of COPD: 
Randomized, Double-Blind, Placebo-controlled, Multicenter, Phase III Trials (The 
ENHANCE Trials). Am J Respir Crit Care Med. Published online 2023. 
doi:10.1164/rccm.202306-0944oc 
[10] Celli BR, MacNee W, Agusti A, Anzueto A, Berg B, Buist AS, et al. Standards for 
the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position 
paper. European Respiratory Journal. 2004;23:932-946. 
doi:10.1183/09031936.04.00014304 
[11] Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: The global lung function 2012 
equations. European Respiratory Journal. 2012;40:1324-1343. 
doi:10.1183/09031936.00080312 


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[12] Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et 
al. Standardization of Spirometry 2019 Update. An Official American Thoracic Society 
and European Respiratory Society Technical Statement. Am J Resp Crit Care. 
2019;200(8):e70-e88. doi:10.1164/rccm.201908-1590st 
[13] Inker LA, Titan S. Measurement and Estimation of GFR for Use in Clinical Practice: 
Core Curriculum 2021. Am J Kidney Dis. 2021;78(5):736-749. 
doi:10.1053/j.ajkd.2021.04.016 
[14] Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS, Committee GS. Global 
Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive 
Pulmonary Disease: NHLBI/WHO Global Initiative for Chronic Obstructive Lung 
Disease (GOLD) Workshop Summary. Am J Respir Crit Care Med. 2001;163(5):1256-
1276. doi:10.1164/ajrccm.163.5.2101039 
[15] Mahler DA, Wells CK. Evaluation of Clinical Methods for Rating Dyspnea. Chest. 
1988;93(3):580-586. doi:10.1378/chest.93.3.580 
[16] Standardized Questionaries on Respiratory Symptoms. BMJ. 1960;2(5213):1665-
1665. doi:10.1136/bmj.2.5213.1665 
  
 


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Appendix 1 
Abbreviations 
AE 
Adverse event 
ALT 
Alanine aminotransferase
ATS 
American Thoracic Society 
BID 
Twice daily 
CI 
Confidence interval 
COPD
Chronic obstructive pulmonary disease 
CV 
Coefficient of variation 
eCRF 
Electronic case report form 
ERS 
European Respiratory Society 
FAS 
Full analysis set 
FDA 
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease
IB 
Investigator’s brochure
ICF
Informed consent form 
ICS
Inhaled corticosteroid(s) 
IEC 
Independent Ethics Committee
IRB 
Institutional Review Board 
LABA
Long-
-agonist 
LAMA 
Long-acting muscarinic antagonist 
LDPE 
Low-density polyethylene
MedDRA 
Medical Dictionary for Regulatory Activities 
PDE 
Phosphodiesterase 
PT 
Preferred term 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula
SAE 
Serious adverse event 
SAP 
Statistical analysis plan
SAS 
Safety analysis set
SD 
Standard deviation 
SoA
Schedule of Activities
SOC
System organ class
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
US 
United States
Verona 
Verona Pharma plc. 
WOCBP
Women of Childbearing Potential


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Appendix 2 
Regulatory, Ethical, and Study Oversight 
Consideration 
Regulatory and Ethical Considerations 
 
This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
o Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
o Applicable laws and regulations. 
 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the Investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
 
Any amendments to the protocol will require IRB/IEC and regulatory authority approval, 
when applicable, before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to subjects. 
 
The Investigator will be responsible for the following: 
o 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. 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
o Providing oversight of the conduct of the study at the study center and adherence 
to requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, EU Clinical Trials Directive 2001/20/EC (if applicable), and all other 
applicable local regulations. 
 
After reading the protocol, the Principal Investigator will sign the protocol signature page 
and send a copy of the signed page to the Sponsor or designee. 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. 
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 


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


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Documentation of the method the new information was presented to the subject along with the 
name of the site staff member and date the new information was presented to the subject must be 
documented in the subject’s source document. 
Data Protection 
 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred. 
 
The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. 
 
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy 
legislation. 
Administrative Structure 
The study administration structure is in Table 6. Medical Monitor and 24-hour urgent medical 
contact information is in Table 7. 
Table 6: Study Administrative Structure 


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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 
clinicaltrials.gov no later than 1 year after the primary completion date of the clinical study, 
which is defined as the date of final data collection for the primary outcome measure. 
Data Quality Assurance 
 
All subject data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct for each 
subject by physically or electronically signing the eCRF. 
 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered into the eCRF. 
 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized study center personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor. 


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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 subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, should not obscure the original entry, and should be explained if 
necessary (e.g., via an audit trail). 
 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s study 
center. 
 
Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
 
Definition of what constitutes source data can be found in ICH E6(R2) Section 1.51. 
Study and Study Center Closure 
The Sponsor reserves the right to close the study center or terminate the study at any time for any 
reason at the sole discretion of the Sponsor. Study centers will be closed upon study completion. 
A study center is considered closed when all required documents and study supplies have been 
collected and a study center closure visit has been performed. 
The Investigator may initiate study center closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study center by the Sponsor or Investigator may include but are 
not limited to: 
 
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
 
Inadequate recruitment of subjects by the Investigator. 
 
Discontinuation of further study medication development. 
Publication Policy 
The data generated by this study are the confidential information of the Sponsor. 


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Appendix 3 
Adverse Events: Definitions and Procedures 
for Recording, Evaluating, Follow-up and Reporting 
Definition of AE 
 
An AE is any untoward medical occurrence in a subject or subject, temporally associated 
with the use of study medication, whether or not considered related to the study 
medication. 
 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study medication. 
Events Meeting the AE Definition 
 
Any abnormal laboratory test results (e.g., hematology, clinical chemistry) or other safety 
assessments (e.g., ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the Investigator (i.e., not related to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study medication administration even though 
it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
medication or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms and/or clinical sequelae resulting from lack of efficacy 
will be reported as an AE or SAE if they fulfil the definition of an AE or SAE. 
Events NOT Meeting the AE Definition 
 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the subject’s condition. 
 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 


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Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads 
to the procedure should be assessed using the AE/SAE definitions. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death. 
b) Is life-threatening. 
The term ‘life-threatening’ in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization. 
In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent disability/incapacity. 
 
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 


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f)
Other situations:
 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
Recording and Follow-up of AE and/or SAE 
AE and SAE Recording 
 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
 
The Investigator will then record all relevant AE/SAE information in the eCRF. Each 
event must be recorded separately. 
 
It is not acceptable for the Investigator to send photocopies of the subject’s medical 
records to Sponsor/Sponsor’s designee in lieu of completion of the Verona Pharma 
/AE/SAE eCRF page. 
 
There may be instances when copies of medical records for certain cases are requested by 
groups such as the Sponsor/Sponsor’s designee, Health Authority, or Ethics Committee. 
In this case, all subject identifiers, with the exception of the subject/patient number, will 
be redacted on the copies of the medical records before submission to records to the 
Sponsor/Sponsor’s designee. 
 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to one of the following categories: 
 
Mild: An event that is easily tolerated by the subject, causing minimal discomfort, and not 
interfering with everyday activities. 
 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 


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Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Chronicity 
 
Single occasion: Single event with limited duration. 
 
Intermittent: Several episodes of an event, each of limited duration 
 
Persistent: Event which remained indefinitely. 
Assessment of Causality 
The Investigator is obligated to assess the relationship between study medication and each 
occurrence of each AE/SAE. The AE must be characterized as either 1) a reasonable possibility of 
causality or 2) no reasonable possibility of causality: 
 
Reasonable possibility:  There is a clear temporal relationship between the study 
intervention and the event onset; and the event is known to occur with the study 
intervention or there is a reasonable possibility that the study intervention caused the 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study intervention and the event. 
 
No reasonable possibility:  There is no evidence suggesting that the study intervention 
caused the event, there is no temporal relationship between the study intervention and 
event onset, or an alternate etiology has been established (e.g., event is consistent with 
medical history). 
All efforts should be made to classify the AE according to the above categories. 
The Investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study medication administration will be 
considered and investigated. 
The Investigator will also consult the Investigator’s Brochure (IB) in his/her assessment. 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the Sponsor/Sponsor’s designee. However, it is very 
important that the Investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor/Sponsor’s designee. 


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


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Reporting of SAEs
SAE Reporting to Sponsor/ Sponsor’s Designee via Paper Form  
 
The Medical Monitor contact information can be found in Appendix 2 (Table 7). 
 
The primary mechanism for reporting an SAE to the Sponsor/Sponsor’s designee will be 
the paper SAE reporting form. 
 
The SAE reporting form should be sent by fax to the fax number which appears on the 
form.  As an alternative, the completed SAE reporting form can be scanned and sent as an 
attachment via email to: VeronaSafety@ubc.com.   
 
Initial notification via telephone or email does not replace the need for the Investigator to 
complete and sign the SAE pages within the designated reporting time frames. 


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Appendix 4 
Contraceptive Guidance and Collection of 
Pregnancy Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenopausal female with 1 of the following: 
a) Documented hysterectomy. 
b) Documented bilateral salpingectomy. 
c) Documented bilateral oophorectomy. Note: Documentation can come from the study center 
personnel’s: review of the subject’s medical records, medical examination, or medical history 
interview. 
2. Postmenopausal female: 
a) Postmenopausal females are defined as amenorrhoeic for greater than 1 year with an 
appropriate clinical profile, e.g., age appropriate, > 45 years, in the absence of hormone 
replacement therapy. 
Contraception Guidance 
Male Subjects 
 
Male subjects with female partners of childbearing potential are eligible to participate if 
they agree to ONE of the following from the first dose up to 30 days after the last dose of 
study medication: 
- Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 
- Agree to use a male condom plus partner use of a contraceptive method with a 
failure rate of < 
 Table 8 when having penile-vaginal 
intercourse with a woman of childbearing potential who is not currently pregnant. 
 
In addition, male subjects must refrain from donating sperm for the duration of the study 
and for 30 days after the last dose of study medication. 
 
Male subjects with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration during the study and for 30 days after the last dose of study medication. 


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Female subjects
Female subjects of childbearing potential are eligible to participate if they are not breastfeeding 
and agree to use a highly effective method of contraception consistently and correctly as 
described in the table below, during the study starting at Visit 1 and for at least 30 days after the 
last dose of study treatment. 
Table 8: Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of < 1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb
 
Oral 
 
Intravaginal 
 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
 
Oral 
 
Injectable 
Highly Effective Contraceptive Methods That Are User Independent a 
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb
 
Intrauterine device (IUD) 
 
Intrauterine hormone-releasing system (IUS) 
Bilateral tubal occlusion. 
Vasectomized partner
A vasectomized partner is a highly effective birth control method provided that the partner is 
the sole male sexual partner of the WOCBP, and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. 
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the subject. 
NOTES:
a Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
subjects participating in clinical studies. 
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: 
 
WOCBP should only be included after a negative pregnancy test during screening is 
conducted prior to study medication dispensing. 
 
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. 


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Collection of Pregnancy Information
Male subjects with partners who become pregnant 
The Investigator will attempt to collect pregnancy information on any male subject’s female 
partner who becomes pregnant while the male subject is in the study. 
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 subjects who become pregnant 
 
The Investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor/Sponsor Designee within 24 hours of learning of a 
subject’s pregnancy. 
o The Medical Monitor contact information can be found in Appendix 2 (Table 7). 
o The primary mechanism for reporting Pregnancy to the Sponsor/Sponsor’s designee will 
be the paper Pregnancy reporting form. 
o The Pregnancy reporting form should be sent by fax to the fax number which appears on 
the form.  As an alternative, the completed form can be scanned and sent as an 
attachment via email to: VeronaSafety@ubc.com.   
 
Any female subject who becomes pregnant while participating in the study will discontinue 
study medication. The subject will be approached and asked to consent to being followed to 
determine the outcome of the pregnancy. The Investigator will collect follow-up information 
on the subject and the neonate, and the information will be forwarded to the Sponsor. 
Generally, follow-up will be no longer than 6 to 8 weeks beyond the estimated delivery date. 
Any termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure. 
 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such.  For SAE reporting, 
refer to Appendix 3. 
 
Any post-study pregnancy related SAE considered reasonably related to the study medication 
by the Investigator will be reported to the Sponsor as described in Section 8.4.5. While the 
Investigator is not obligated to actively seek this information in former subjects, he or she 
may learn of an SAE through spontaneous reporting. 
 


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Appendix 5
Questionnaires
The COPD Assessment Test™was developed by a multi-disciplinary group of international 
experts in COPD supported by GSK. The CAT is self-administered on paper. CAT, COPD 
Assessment Test, and the CAT logo are trademarks of the GSK group of companies.
GlaxoSmithKline Services Unlimited. Registered in England.3–5
COPD Assessment Test™(CAT)
https://www.catestonline.org/patient-site-test-page-english.html
Accessed 01April2024.
CAT score
Level of Impact
31 - 40
Very High Impact
21 - 30
High Impact
10 - 20
Medium Impact
< 10
Low Impact


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The modified Medical Research Council (mMRC) Dyspnea Scale (From ATS News 1982; 8:12-
16.8).15  The mMRC is based off the MRC breathlessness score first published by Fletcher, et al.16  
Site staff will administer/interview the subject to complete the mMRC dyspnea scale 
questionnaire. 
mMRC Grade
Description
0
Not troubled with breathlessness except with strenuous exercise 
1
Troubled by shortness of breath when hurrying on the level or walking up 
a slight hill 
2 
Walks slower than people of the same age on the level because of 
breathlessness or has to stop for breath when walking at own pace on the 
level 
3 
Stops for breath after walking about 100 yards or after a few minutes on 
the level
4 
Too breathless to leave the house or breathless when dressing or 
undressing
 


Protocol RPL554-CO-303
Version 4.0; 19 August 2024
Verona Pharma plc 
CONFIDENTIAL 
Page 76 of 76 
Signature of Investigator 
 
PROTOCOL TITLE:
A Study Assessing the Effect of Ensifentrine on CAT™ 
Scores over 12 Weeks in Subjects with Moderate to Severe 
COPD 
PROTOCOL NO:
RPL554-CO-303
VERSION:
4.0
VERSION DATE:  
19 August 2024 
This protocol is a confidential communication of Verona Pharma plc. I confirm that I 
have read this protocol, I understand it, and I will work according to this protocol. I will 
also work consistently with the ethical principles that have their origin in the Declaration 
of Helsinki and that are consistent with Good Clinical Practices and the applicable laws 
and regulations. Acceptance of this document constitutes my agreement that no 
unpublished information contained herein will be published or disclosed without prior 
written approval from the Sponsor.  
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT 
your name, title, and the name of the study center where the study will be conducted. 
Return the signed copy to the Sponsor. 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
Signature of Investigator 
Date 



SAP_001.pdf: 
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Page 1 of 19 
Verona Pharma 
Statistical Analysis Plan: A Study Assessing the Effect of Ensifentrine on 
COPD Assessment Test (CAT
) Scores over 12 Weeks in Subjects with 
Moderate to Severe COPD (Ensifentrine CAT Study) 
Prepared by 
 
Document Revision History: 
Version 
Date 
Content/Modifications 
01
07/30/2024
Initial draft
02 
12/11/2024 
Added additional details for instructions on failed model 
convergence and added SAS platform and version number. 
 
 
 
 


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Statistical Analysis Plan 
Approval  
Signature Page 
 


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Table of Contents 
1 
Abbreviations ........................................................................................................................................ 4 
2 
Introduction ........................................................................................................................................... 4 
2.1
Background .................................................................................................................................. 4 
2.2
Changes to Planned Analyses ...................................................................................................... 5 
3 
Study Objectives ................................................................................................................................... 5 
4 
Investigational Plan and Study Design ................................................................................................. 6 
5 
Sample Size Justification ...................................................................................................................... 7 
6 
Visit Schedule and Visit Windows ....................................................................................................... 8 
7 
Study Populations ............................................................................................................................... 10 
8 
Statistical Methods .............................................................................................................................. 10 
8.1
General Reporting Conventions ................................................................................................ 10 
8.2
Adjustments for Interim Analyses and Multiplicity of Endpoints ............................................. 10 
8.3
Handling of Missing Data.......................................................................................................... 10 
8.4
Evaluations and Statistical Analyses ......................................................................................... 11 
8.4.1 
Subject Disposition ............................................................................................................... 11 
8.4.2 
Demographics and Baseline Characteristics ......................................................................... 11 
8.4.3 
Prior and Concomitant Medications ...................................................................................... 11 
8.4.4 
Treatment Compliance .......................................................................................................... 12 
8.4.5 
Primary Efficacy Endpoint .................................................................................................... 13 
8.4.6 
Secondary Efficacy Endpoint ................................................................................................ 13 
8.4.7 
Safety Evaluations and Analyses .......................................................................................... 14 
9 
References ........................................................................................................................................... 17 
10 
List of Tables, Figures and Listings ............................................................................................... 18 
11 
Table, Figure and Listing Shells .................................................................................................... 19 


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1 Abbreviations 
AE  
Adverse Event  
ATC  
BID 
BMI 
CAT 
Anatomical Therapeutic Chemical  
Twice daily 
Body Mass Index 
COPD Assessment Test 
CI  
COPD 
EOT 
FAS 
FEV1 
GOLD 
 
ICS 
LABA 
LAMA 
LSM 
Confidence Interval  
Chronic Obstructive Pulmonary Disease 
End of Treatment 
Full Analysis Set 
Forced Expiratory Volume in 1 Second 
Global Initiative for Chronic Obstructive Lung 
Disease 
Inhaled Corticosteroid(s) 
Long-A
Agonist 
Long-Acting Muscarinic Antagonist 
Least Square Mean 
MedDRA  
mMRC 
PDE
Medical Dictionary for Regulatory Activities 
Modified Medical Research Council Dyspnea Scale 
Phosphodiesterase
PT 
Preferred Term 
SAE(s)  
SAP 
Serious Adverse Event(s)  
Statistical Analysis Plan 
SAS   
SAS 
SD
Statistical Analysis Software
  
Safety Analysis Set 
Standard Deviation
SOC  
TEAE 
WHO 
WOCBP 
System Organ Class  
Treatment-Emergent Adverse Event(s) 
World Health Organization 
Women of Childbearing Potential 
2 Introduction 
2.1
Background 
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow 
obstruction which is largely irreversible. COPD is predicted to be the third leading cause of death 
and fourth most common cause of disability worldwide by 2030 (Stuckler, 2008). The primary 
goals of pharmacological treatment of COPD are to reduce symptoms, exacerbation frequency 
and exacerbation severity as well as to improve overall quality of life in patients with COPD. 
Current standard-of-care treatments include inhaled short- and long-acting bronchodilators (i.e., 
utilized to manage symptoms of COPD (GOLD, 2024).  


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Tools to assess if treatment goals are attained include several patient-reported outcome 
questionnaires to assist in communications between the patient and physician. However, the 
uptake of these questionnaires into routine clinical practice is integral to the assessment of 
individualized treatment regimens (Stanford, et al., 2019). The COPD Assessment Test [CAT
; 
CAT] (Jones, et al., 2009) is a validated, short, and simple patient completed questionnaire.  The 
CAT is often used in a clinical setting to assess further the COPD symptoms and impact of a 
-being. 
Verona Pharma plc. is developing inhaled nebulized ensifentrine for the maintenance treatment 
of chronic obstructive pulmonary disease (COPD). Ensifentrine is a novel, small molecule, 
potent, and selective dual inhibitor of Phosphodiesterase 3 (PDE3) and PDE4. The dual 
mechanism of action of ensifentrine has both bronchodilatory and anti-inflammatory effects and 
has the potential to offer an important maintenance treatment option for the treatment of 
obstructive and inflammatory diseases of the respiratory tract, such as COPD, cystic fibrosis, and 
asthma (Donahue et al., 2023). Ensifentrine has been evaluated in 22 completed clinical studies 
involving approximately 3,000 subjects, of which 16 studies involving over 2,800 subjects 
comprise the COPD development program including pharmacokinetic, pharmacodynamic, Phase 
IIb, and Phase III studies. In two Phase III studies (RPL554-CO-301 [n=760] and RPL554-CO-
302 [n=789]) ensifentrine (3 mg) treatment consistently demonstrated the bronchodilator profile 
of ensifentrine in subjects with moderate to severe COPD over 12 weeks while significant effects 
were shown across all key FEV1 endpoints and a significant improvement in exacerbation 
frequency and severity was shown in both studies (Anzueto, et al., 2023). This Phase IIIb study 
will assess the effect of ensifentrine on CAT scores in subjects with moderate to severe COPD 
when added to standard of care in routine clinical practice.  
2.2
Changes to Planned Analyses 
Not applicable as this is the initial version of the SAP.  
3 Study Objectives 
The objectives for this study are as follows:  
Primary Efficacy Objective: The primary efficacy objective for this study is to assess the 
proportion of responders to treatment with ensifentrine, defined as subjects with an improvement 
in individual CAT scores of > 2, when added to standard of care in symptomatic subjects with 
moderate to severe COPD in routine clinical practice.  
Secondary Efficacy Objective: To investigate the effects of ensifentrine on COPD symptoms, as 
measured by the CAT in symptomatic subjects with moderate to severe COPD when added to 
standard of care in routine clinical practice. 
Safety Objective: To summarize the safety profile of subjects treated with ensifentrine.  


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4 Investigational Plan and Study Design 
This is a Phase IIIb, single-center, open-label study investigating the effect of treatment with 
twice daily nebulized ensifentrine (3 mg) over 12 weeks on CAT scores in subjects with 
moderate to severe COPD when added to standard of care in routine clinical practice. 
At Visit 1, potential subjects will be provided with the informed consent for participation in the 
study.  Following signature on the informed consent, the following information will be collected, 
and procedures performed to confirm subject eligibility for participation in the study in the 
following sequence: 
 
CAT Training followed by subject completion of the CAT on paper 
 
Modified Medical Research Council Dyspnea Scale (mMRC) 
 
Collect and record demographic data 
 
Eligibility review (inclusion and exclusion criteria) 
 
Review and record medical, surgical, COPD and smoking history 
 
Review of prior and concomitant medication 
At Visit 2, subject eligibility will be confirmed (screening tests will be verified, and it will be 
assured that the subject meets all inclusion criteria, and no exclusion criteria). Subjects who are 
screen failures may be rescreened with approval from the Medical Monitor. Rescreened subjects 
should be assigned a new subject number different from the initial screening event. Spirometry 
will be performed, a physical examination completed, and vital signs will be assessed. Eligible 
subjects will receive a nebulizer and compressor and will be administered their first dose of 
ensifentrine (3 mg) in-clinic during training on nebulizer use. Adverse events will be assessed. 
Subjects will receive a 6-week supply of ensifentrine (3 mg) to be administered twice-daily 
(BID) with a standard jet nebulizer. Ensifentrine will be administered BID for a total of 12 
weeks.   
At Visit 3 (Week 6), subjects will return and complete the CAT first, their concomitant 
medication will be reviewed, their vital signs and safety will be assessed. Subjects will receive a 
6-week supply of ensifentrine (3 mg) administered BID. 
At Visit 4 (Week 12), subjects will complete the CAT first, their concomitant medication will be 
reviewed, their vital signs and safety will be assessed. After 12 weeks, treatment with nebulized 
ensifentrine (3 mg) will end. 
A follow-up phone call will be made to the subject approximately one week after the end of 
treatment. 
Subjects may remain on prescribed short- and long-acting COPD medications throughout 
participation provided they are not included in the prohibited medication list. COPD 
 
A subject is considered to have completed the study if he/she has successfully completed all 
scheduled visits and completed follow-up contact. With no rescheduled visits, the study should 
last approximately 14 weeks. 


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5 Sample Size Justification 
A sample size of approximately 20 subjects provides the ability to demonstrate a responder 
proportion estimate statistically differs from zero.  Assuming a 30 percent response rate in the 
study population, 20 subjects would provide an expected count of 6 events. The two-sided 95% 
confidence interval for the number of events generated via normal approximation is (1.199, 
10.801). Thus,20 subjects provide the ability to demonstrate the derived proportion differs from 
zero determined by the lower two-sided 95% confidence limit derived from the estimated count 
using a normal approximation assuming a standard error equal to the square root of 6.   
Twenty subjects also provide the ability to demonstrate the estimates of mean change from 
baseline does not extend to the clinically meaningful deterioration limit of (+2 units).  Assuming 
estimated mean improvement of 1 unit with a corresponding standard deviation equal to 4.5, 20 
subjects provide the ability to demonstrate the upper 95% confidence interval for a mean change 
from baseline estimate does not exceed 2 units. 


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6 Visit Schedule and Visit Windows 
Table 1: Schedule of Assessments and Procedures 
 
 
Study 
Start 
Treatment Period 
Study End 
 
Early Withdrawal / 
Termination¥ 
 
Screening 
Day 1 
 
Week 6 
(42 ± 3 days) 
Week 12 
(42 ± 3 days) 
7 ± 3 days 
after Visit 4 
 
As Soon as 
Possible 
after EW/T 
7 ± 3 days 
after EW/T 
Visit 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
(EOT) 
Follow-up 
 
EW/T Visit 
Follow-Up 
Informed consent A 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria (eligibility 
review) 
X 
Review, Update 
 
 
 
 
 
 
Demographics (date of birth, age, gender, 
race, ethnicity) 
X 
 
 
 
 
 
 
 
CAT
 training 
X 
 
 
 
 
 
 
 
CATTM B  
X* 
 
X* 
X* 
 
 
 
 
mMRC (administered by study team) 
X 
 
 
 
 
 
 
 
Medical, surgical, smoking history 
X 
Review, Update 
 
 
 
 
 
 
Prior and concomitant medication 
X 
 
 
 
 
 
 
 
Vital signs (blood pressure and pulse rate)  
 
X 
X 
X 
 
 
X 
 
Height and Weight; BMI calculated 
 
X 
 
 
 
 
 
 
Brief physical exam C 
 
X 
 
 
 
 
 
 
Urine pregnancy test D 
 
X 
X 
X 
 
 
 
 
Pre- and post-bronchodilator Spirometry E 
 
X 
 
 
 
 
 
 
Nebulizer equipment materials dispensing, 
review, and training; collection at end F 
 
X 
 
X 
 
 
 
 
Study medication dispensing G 
 
X 
X 
 
 
 
 
 
In clinic study medication dosing 
 
X 
 
 
 
 
 
 
Concomitant medication review 
 
X 
X 
X 
X 
 
X 
X 
Study medication compliance 
 
 
X 
X 
 
 
X 
 
AE and SAE recording 
 
X 
X 
X 
X 
 
X 
X 
Phone call to subject 
 
 
 
 
X 
 
 
X 


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Note: Information and details on most of the Study Assessments and Procedures can be found in the protocol in Section Error! Reference source not found..  *
The CAT
 is completed by the subject on paper first before any procedures and assessments.  ¥ The early withdrawal / termination visit should be conducted as 
soon as possible. If possible, subjects should remain on study medication through the early termination visit (protocol Section Error! Reference source not f
ound.). 
A.
Informed consent must be obtained by the process described in Error! Reference source not found. of the protocol. Consent must be obtained prior to any s
tudy procedures being performed. 
B.
Following informed consent, the CAT
 is performed first before any procedures and assessments. 
C.
Assessments of the Cardiovascular, Respiratory, Gastrointestinal, and Neurological systems.  
D.
Pregnancy Testing: Pregnancy testing will be conducted on women of childbearing potential only (refer to Error! Reference source not found. of the p
rotocol).  
E.
Spirometry:  Pre-bronchodilator testing will be conducted prior to dosing with albuterol. Post-bronchodilator testing should be conducted between 15- and 
30-minutes following administration of 4 puffs of albuterol. 
F.
Collect study supplied compressor if allowed per local site practices. 
G.
Information on study medication, dosing and compliance, nebulizers and compressor can be found in protocol Section Error! Reference source not found..  
 
Abbreviations: AE=Adverse Event; BMI= Body Mass Index; CAT
 = COPD Assessment Test
, COPD=Chronic Obstructive Pulmonary 
Disease; EOT=End of Treatment; mMRC=Modified Medical Research Council Dyspnea Scale; SAE=Serious Adverse Event; V=Visit; 
WOCBP=Women of Child-bearing Potential. 
s


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7 Study Populations 
Allocation of subjects to the analysis populations (and whether any subjects or specific data from 
a subject will be excluded) will be determined prior to database lock. Study populations will be 
defined as follows:  
Enrolled Analysis Set: The Enrolled Analysis Set (EAS) will consist of all subjects who 
provided informed consent for this study.  Subjects will be classified according to administration 
of study medication at study Day 1, and will be summarized with and without the administration 
of study medication.    
Full Analysis Set: The Full Analysis Set (FAS) will consist of all subjects that were 
administered the study medication at Visit 2 and have a CAT completed at baseline and from at 
least one post-treatment visit. The full analysis set will be used for all efficacy analyses.  
Safety Analysis Set: The Safety Analysis Set (SAS) will consist of all subjects who were 
administered the study medication at Visit 2. The safety analysis set will be used for all safety 
analyses and baseline summaries.  
8 Statistical Methods 
8.1
General Reporting Conventions 
Study data will be made available in listings or electronic format as requested. Study results will 
be reported in tabular form using descriptive and inferential statistics. Standard numeric 
descriptive statistics include number observed (n), mean, standard deviation (SD), median, 
minimum, and maximum values. Standard categorical descriptive statistics include the count and 
percentages of subjects for each level of the variable summarized. Confidence intervals (CIs) 
will be two-sided 95% intervals. Unless specified otherwise, two-sided p-values of less than or 
equal to 0.05 or one-sided p-values of less than or equal to 0.025 will be considered statistically 
significant. All summaries and statistical analyses will be completed using Version 9.4 or later of 
the SAS Statistical Analysis System (SAS Institute, Inc. Cary, NC) for Windows x64. 
8.2
Adjustments for Interim Analyses and Multiplicity of Endpoints 
No interim analyses are planned for this study. As there is only one primary efficacy endpoint, 
no adjustments will be made for multiplicity.  
8.3
Handling of Missing Data 
As discontinuation of study medication will result in subject withdrawal, data collected after 
treatment withdrawal will not be included in the analyses, and missing data will not be imputed. 


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8.4
Evaluations and Statistical Analyses 
8.4.1
Subject Disposition 
Study disposition will be summarized overall and presented in listing format. Disposition and 
baseline information will be summarized using the Enrolled population.  For subjects undergoing 
more than 1 screening assessment, the last screening assessment will be included in disposition 
summaries. Study disposition information will be summarized through: 
Number of subjects screened.  
Number of screen failures and reason for failure.  
Number of subjects in each analysis population (EAS, FAS, and SAS).  
Number of subjects that completed the study.  
Number of subjects that completed each follow-up visit (Day 1, Week 6, Week 12, 
Follow-up phone call) 
Number of discontinued subjects and reason for discontinuation.  
Duration of follow-up in days summarized as a continuous variable.  
Additionally, the number of subjects with major protocol deviations will be summarized by 
deviation type and category of violation overall. Major protocol deviations will also be included 
in subject listings. 
8.4.2
Demographics and Baseline Characteristics 
Demographics and baseline data including age, gender, race, ethnicity, height, weight, and BMI 
will be summarized descriptively overall and presented in listing format for the Safety Analysis 
Set. Medical history will be coded using MedDRA and summarized descriptively by SOC and 
PT for the Safety Analysis Set. Medical history will be provided in subject listings for the Safety 
Analysis Set. COPD history including COPD type, COPD diagnosis history, and COPD 
exacerbation history will be summarized descriptively and presented in listing format for the 
Safety Analysis Set. Smoking history will be summarized descriptively and presented in listing 
format for the Safety Analysis Set. Results from the Modified Medical Research Council 
(mMRC) dyspnea scale questionnaire will be presented in listing format for the Safety Analysis 
Set. 
8.4.3
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using World Health Organization (WHO) drug 
code and summarized separately by Anatomical Therapeutic Chemical (ATC) levels 1, 2 and 4 
for the Safety Analysis Set. Prior medications will denote medications used prior to the first dose 
of study medication. Concomitant medications will denote medications started prior to but 
continuing after receipt of study medication or medications started after receipt of study 
medication. 


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8.4.4
Treatment Compliance 
Compliance to study medication will be based on dispensed and returned unused ampules for the 
safety population. Compliance will be presented for 12 weeks using summary statistics by time 
intervals (Day 1 to Week 6, Weeks 6-Week 12, and full study length), as well as using frequency 
counts by subgroups: <80%, 80-90%, 90-100%, >100%. 
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. Patients should take the study medication twice daily. 
Patients are dispensed ampules at Visit X and return at Visit Y, however in the eCRF returned 
ampules will be recorded under Visit X.  
For time interval compliance to study medication will be calculated as follows:  
 
100 Where Denominator1 is calculated with the following rules:  
N1 = Number of ampules expected. Calculated based on total N of Ampules 
dispensed at Week 6 and at Week 12, considering 2 ampules per day, apart from 
first dose (Week 6) or last dose (Week 12) date for completed patients where we 
would only consider 1 ampule per day calculated: {{[Date of Visit Y] - [Date of 
Dispensing at Visit X] + 1} * 2 - 1}  for Week 6.  Note:  this calculation 
considers the first dose administered on Day 1 at the site is included in the 
number dispensed for Week 6.   
N2= Number of ampules between dispensing and returning visit calculated: 
{{[Date of Visit Y] - [Date of Dispensing at Visit X] + 1} * 2} - 1 for Week 6 and 
= Number of ampules between dispensing and returning visit calculated: {{[Date 
of Visit Y] - [Date of Dispensing at Visit X] + 1} * 2} - 2 for Week 12.  Note:  
this calculation considers the first dose administered on Day 1 at the site is 
included in the number dispensed for Week 6.  
 
Week 6 and Week 12 summaries will use N2 for Denominator 1.   
In overall summaries i
 
In overall summaries if N1<N2 then Denominator1 = N1. 
Overall compliance to study medication will be calculated 100 times (100*) the sum of Week 6 
and Week 12 compliance divided by the sum of Denominator 1 over Week 6 and Week 12. 


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8.4.5
Primary Efficacy Endpoint
8.4.5.1 Primary Efficacy Hypothesis 
The primary efficacy endpoint for this study is the proportion of CAT responders, defined as an 
 2, at Week 12. This will be evaluated for the null hypothesis that 
the proportion is not different than 0:  
H0: p = 0 vs. H1: p > 0 
Where p is the proportion of subjects at Week 12 with an improvement from baseline of at least 
2 in CAT total score. A two-sided unadjusted 95% confidence interval for the proportion will be 
used to determine study success with the lower bound of the CI > 0 indicating success.  
8.4.5.2 Primary Efficacy Analysis 
The FAS population will be used to assess the primary efficacy endpoint of proportion of CAT 
total score 
 2 at Week 12. The proportion of 
subjects classified as responders at week 12, standard errors, and corresponding 95% CI will be 
estimated by negative binomial regression with timepoint and background therapy 
(LABA+LAMA or LABA+LAMA+ICS) included as fixed effects, and with baseline CAT total 
score included as a covariate. The scale parameter in the negative binomial model will be held 
fixed by specifying a noscale option.  
8.4.5.3 Sensitivity and Supporting Analyses 
As a supporting analysis the proportion of CAT total score responders defined as improvement 
 2 will be analyzed at Week 6 in the same manner as the primary efficacy 
analysis. 
As a sensitivity analysis the primary efficacy endpoint analysis will also be analyzed with subject 
included as a repeated measure to provide a robust standard error for the estimated proportion 
and to accommodate model misspecification. The scale parameter in the negative binomial 
model will be held fixed by specifying a noscale option.  
8.4.6
Secondary Efficacy Endpoint 
8.4.6.1 Change from Baseline CAT Total Score 
The secondary endpoint of change from baseline in CAT total score will be evaluated at Week 6 
and Week 12. Scores for the CAT total score ranges from 0-40. CAT total score will be 
summarized descriptively at baseline and each timepoint. A mixed model for repeated measures 
with timepoint and background therapy (LABA+LAMA or LABA+LAMA+ICS) included as 
fixed effects, and with baseline CAT total score included as a covariate. Subject will be included 
as a random effect and an unstructured covariance matrix will be used. The Kenward-Rogers 
approximation will be used for the denominator degrees of freedom. In the event the model fails 
to converge, a compound symmetry covariance structure will be used. Should the model fail to 
converge with a compound symmetry covariance structure, an ANCOVA model at each 
timepoint will be performed with background therapy included as a fixed effect and baseline 


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CAT total score included as a covariate. Least square mean estimates, standard errors, and 
corresponding 95% confidence limits will be presented for each post-treatment time of 
assessment. A plot of the least square means change from baseline in total score over time will 
be presented.  
8.4.6.2 Change from Baseline CAT Individual Item Analyses 
The CAT questionnaire contains 8 individual items with scores ranging from 0-5. Each 
individual item will be summarized at Week 6 and Week 12 in the same manner as the change 
from baseline CAT Total Score secondary efficacy endpoint.  The baseline for individual items 
is the item score at the baseline assessment.  Least square mean estimates, standard errors, and 
corresponding 95% confidence limits will be presented at each post-treatment time of assessment  
8.4.7
Safety Evaluations and Analyses 
All safety evaluations will be conducted on the safety population. Safety analyses will include 
incidence of adverse events and vital sign summaries.  
8.4.7.1 Adverse Events and SAEs 
An adverse event (AE) is any untoward medical occurrence in a subject or subject, temporally 
associated with the use of study medication, whether considered related to the study medication 
or not. AEs will be collected from time of first dose to follow-up contact. Medical and COPD 
condition(s) identified during screening 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. Treatment-
emergent adverse events (TEAE) are any events that occur after the first dose of study treatment. 
Serious adverse events (SAE) include any occurrence defined as an AE that results in any of the 
following:  
Death 
Is life-threatening 
Requires in-patient hospitalization or prolongation of hospitalization 
Results in persistent disability/incapacity 
Is a congenital anomaly/birth defect 
Other 
AEs requiring hospitalization include any events at a hospital or emergency ward for observation 
setting. Complications that occur during hospitalization are AEs. Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not considered an AE. 
whether SAE reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the other outcomes 
listed in the above definition. These events should usually be considered serious. 


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In addition to seriousness, AEs will be classified based on intensity (mild, moderate, severe), and 
relatedness/causality (reasonable possibility or no reasonable possibility). AEs will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by system 
organ class (SOC) and preferred term (PT). TEAEs, for the Safety Analysis Set, will be listed 
and summarized descriptively as the count and percentage of subjects experiencing the event in 
tabular form. Seriousness, relatedness, and outcome will be identified in the listings. AE 
summaries will include the following:  
Overall TEAE Summary 
TEAEs by SOC and PT 
Serious TEAEs by SOC and PT 
Treatment-related TEAEs by SOC and PT 
Serious treatment-related TEAEs by SOC and PT 
TEAEs by Severity and SOC and PT 
TEAEs Resulting in Discontinuation of Study Medication by SOC and PT 
TEAEs Resulting in Withdrawal from Study by SOC and PT 
TEAEs Resulting in Death by SOC and PT 
Listing of all TEAEs 
Listing of all Serious TEAEs 
Listing of all TEAEs Resulting in Death 
Listing of all TEAEs Resulting in Discontinuation of Study Medication  
Listing of all TEAEs Resulting in Withdrawal from Study  
Adverse events will be counted once per patient per SOC and PT.  Incidence of TEAEs will be 
presented by SOC and PT and broken down further by maximum severity and relationship to 
study medication. 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 a 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 
 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.  TEAEs leading to 
t Permanently 
 
8.4.7.2 Vital Signs 
Vital signs will be collected at Day 1, Week 6, and Week 12 visits and will include blood 
pressure and pulse rates. Vital signs, for the Safety Analysis Set, will be summarized 


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descriptively in tabular format as the values at each visit and change from baseline values for 
each parameter. Vital sign measurements will also be included in listing format. Abnormal and 
markedly abnormal values will be identified in the vital sign listings. Markedly abnormal values 
are defined in Table 2.  
Table 2: Markedly Abnormal Post-Baseline Vital Signs 
Variable 
Unit 
Abnormally Low 
Abnormally High 
SBP 
mmHg 
A decrease 
from Baseline 
of  40 
Value 90
An increase 
from Baseline 
of  40 
Value  180 
DBP 
mmHg 
A decrease 
from Baseline 
of  20 
Value  50 
An increase 
from Baseline 
of  20 
Value  105 
Pulse Rate 
Bpm 
A decrease 
from Baseline 
of  30 
Value  50 
An increase 
from Baseline 
of  30 
Value  110 
8.4.7.3 Physical Examination 
A brief physical exam will be conducted on the Day 1 visit and will include assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Physical examination 
results, for the Safety Analysis Set, will be provided in listing format.  
8.4.7.4 Pregnancy Test Results 
Urine pregnancy tests will be conducted at the Day 1, Week 6, and Week 12 visits on women of 
childbearing potential only. Urine pregnancy test results, for the Safety Analysis Set, will be 
provided in listing format.  


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9 References 
Stuckler D. Population Causes and Consequences of Leading Chronic Diseases: A Comparative 
Analysis of Prevailing Explanations. Milbank Q. 2008;86(2):273-326. doi:10.1111/j.1468-
0009.2008.00522.x 
Gold. 2024 Global Strategy for Prevention, Diagnosis and Management of COPD.; 2024. 
https://goldcopd.org/2024-gold-report/. Accessed February 8, 2024 
Stanford RH, Tabberer M, Kosinski M, Johnson PT, White J, Carlyle M, et al. Assessment of the 
COPD Assessment Test Within U.S. Primary Care. Chronic Obstr Pulm Dis J Copd Found. 
2020;7(1):26-37. doi:10.15326/jcopdf.7.1.2019.0135 
Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Leidy NK. Development and first 
validation of the COPD Assessment Test. Eur Respir J. 2009;34(3):648-654. 
doi:10.1183/09031936.00102509 
Donohue JF, Rheault T, MacDonald-Berko M, Bengtsson T, Rickard K. Ensifentrine as a Novel, 
Inhaled Treatment for Patients with COPD. Int J Chronic Obstr Pulm Dis. 2023;Volume 
18:1611-1622. doi:10.2147/copd.s413436 
Anzueto A, Barjaktarevic IZ, Siler TM, Rheault T, Bengtsson T, Rickard K, et al. Ensifentrine, a 
Novel PDE3 and PDE4 Inhibitor for the Treatment of COPD: Randomized, Double-Blind, 
Placebo-controlled, Multicenter, Phase III Trials (The ENHANCE Trials). Am J Respir Crit Care 
Med. Published online 2023. doi:10.1164/rccm.202306-0944oc 


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10 List of Tables, Figures and Listings 
.
Table 
Number 
Title 
Population 
14.1.1
Study Enrollment 
All Subjects
14.1.2
Subject Disposition 
SAS Subjects
14.1.3
Protocol Deviations
SAS Subjects
14.1.3
Demographics and Baseline Characteristics
SAS Subjects
14.1.4
Medical History 
SAS Subjects
14.1.5
Smoking History
SAS Subjects
14.1.6
COPD History
SAS Subjects
14.1.7.1 
Prior Medications by ATC Levels 1, 2, and 4
SAS Subjects
14.1.7.2 
Concomitant Medications by ATC Levels 1, 2, and 4 SAS Subjects
14.1.8
Treatment Compliance 
SAS Subjects
14.2.1.1 
Proportion of CAT Responders at Week 12
FAS Subjects
14.2.1.2 
Analysis of Type 3 Model Effects on CAT 
Responder Status at Week 12
FAS Subjects 
14.2.1.3 
Proportion of CAT Responders at Week 6 
FAS Subjects
14.2.1.4 
Sensitivity Analysis of Proportion of CAT 
Responders at Week 12
FAS Subjects 
14.2.2.1 
Change From Baseline in CAT Total Score by 
Timepoint
FAS Subjects 
14.2.2.2 
Change From Baseline in CAT Individual Item 
Scores by Timepoint
FAS Subjects 
14.3.1.1 
Overall Summary of Treatment-Emergent Adverse 
Events 
SAS Subjects 
14.3.1.2 
Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term
SAS Subjects 
14.3.1.3 
Serious Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
SAS Subjects 
14.3.1.4 
Treatment-Related Treatment-Emergent Adverse 
Events System Organ Class and Preferred Term
SAS Subjects 
14.3.1.5 
Serious Treatment-Related Treatment-Emergent 
Adverse Events by System Organ Class and 
Preferred Term
SAS Subjects 
14.3.1.6 
Treatment-Emergent Adverse Events by Severity 
and System Organ Class and Preferred Term
SAS Subjects 
14.3.1.7 
Treatment-Emergent Adverse Events Resulting in 
Discontinuation of Study Medication by System 
Organ Class and Preferred Term
SAS Subjects 


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14.3.1.8 
Treatment-Emergent Adverse Events Resulting in 
Withdrawal from Study by System Organ Class and 
Preferred Term
SAS Subjects 
14.3.1.9 
Treatment-Emergent Adverse Events Resulting in 
Death by System Organ Class and Preferred Term 
SAS Subjects 
14.3.2 
Summary of Vital Signs Change from Baseline by 
Timepoint
SAS Subjects 
Listing 
Number 
Title 
Population 
16.1.1
Study Enrollment and Disposition 
All Subjects
16.1.2
Screen Failures and Reason for Failure
All Subjects
16.1.3
Major Protocol Deviations 
SAS Subjects
16.1.4
Demographics and Baseline Characteristics
SAS Subjects
16.1.5
Medical History  
SAS Subjects
16.1.6
Smoking History
SAS Subjects
16.1.7
COPD History
SAS Subjects
16.1.8.1 
Prior Medications
SAS Subjects
16.1.8.2 
Concomitant Medications
SAS Subjects
16.1.9
Treatment Compliance 
SAS Subjects
16.1.10 
Modified Medical Research Council (mMRC) 
Dyspnea Scale Results
SAS Subjects 
16.2.1
CAT Total Score Results by Timepoint
FAS Subjects
16.2.2
CAT Individual Item Score Results by Timepoint
FAS Subjects
16.3.1.1 
Treatment-Emergent Adverse Events 
SAS Subjects
16.3.1.2 
Serious Treatment-Emergent Adverse Events
SAS Subjects
16.3.2
Vital Sign Results
SAS Subjects
16.3.3
Physical Exam Results
SAS Subjects
16.3.4
Urine Pregnancy Test Results
SAS Subjects
Figure 
Number 
Title 
Population 
14.2.1 
Plot of CAT Total Score LSM Change from 
Baseline Over Time
FAS Subjects 
11 Table, Figure and Listing Shells 
Output shells will be provided in a separate document.