A Single-center, Pilot, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Ensifentrine in the Recovery of Hospitalized Patients With COVID-19
Phase: PHASE2
Conditions: Coronavirus Infection, Covid-19, SARS-CoV-2
Sponsor: Verona Pharma Inc

 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Protocol Title: 
A SINGLE-CENTER, PILOT, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF ENSIFENTRINE IN THE RECOVERY 
OF HOSPITALIZED PATIENTS WITH COVID-19. 
 
Protocol Number: 
RPL554-COV-201 
Version: 
4.0 
Amendment Number: 
3.0 
Investigational Product: 
Ensifentrine 
Short Title: 
Ensifentrine therapy for COVID-19. 
Study Phase: 
II 
Sponsor Name: 
Verona Pharma Inc 
 
Legal Registered Address 
8045 Arco Corporate Drive | Suite 130 
Raleigh, NC 27617 
Regulatory Agency 
Identifying Number(s): 
US IND Number: 150701 
Date of Protocol: 
13 October 2020 (replaces Version 3.0, dated 16 July 
2020)  
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 3 of 73 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Table 1 Document History 
Document 
Date 
Substantial 
Region 
Amendment 1.0 
14-July-2020 
Yes 
US 
Amendment 2.0 
16-July-2020 
Yes 
US 
Amendment 3.0 
13-October-2020 
Yes 
US 
 
Amendment 1.0: 14-July-2020 
Overall Rationale for Amendment 1.0: 
The protocol is amended to revise collection and reporting of AEs to include all AEs and 
SAEs, not only Grade 3 and 4, and to clarify that worsening of underlying disease that is 
judged by the investigator to be more severe than expected should be reported as an AE 
or SAE. 
Amendment 2.0: 16-July-2020 
Overall Rationale for Amendment 2.0: 
The protocol is amended to revise the definition of Adverse Events to include collection 
of adverse events associated with the underlying disease, not only those judged by the 
Investigator to be more severe than expected for the patient’s condition. 
Amendment 3.0: 13-October-2020 
Overall Rationale for Amendment 3.0: 
The protocol is amended to revise the inclusion criteria to include an anticipated hospital 
stay of at least 72 hours (following randomization).  A stay of 24 or 48 hours is not 
sufficient time to provide meaningful data due to the limited number of doses of study 
medication received by the patient. 
The Discharge Safety Laboratory Tests will be changed from a requirement to at the 
discretion of the treating physician, and if performed, may be completed within 24 hours 
of discharge.  This is a real-life study, therefore, additional lab tests at or prior to 
discharge may not be medically necessary according to the patient’s treating physician.

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 4 of 73 
Table 2 Description of Changes in the Amendment 
Amendment 1.0 
Section # and Name 
Description of Change 
Brief Rationale 
Table numbering 
Table numbers all shifted by 2 to 
accommodate 2 Tables added for 
the Amendment information. 
Administrative 
change to 
accommodate 
Amendment 
Section. 
Section 8.6, Adverse 
Events 
Section 8.6.1, time period 
and frequency for 
collecting AE and SAE 
information 
The following statement was 
deleted: “Given the nature of 
severity of the underlying illness, 
subjects will have many symptoms 
and abnormalities in vital signs 
and laboratory values. All Grade 3 
and 4 AEs will be captured as AEs 
in this trial.” 
Text was modified to clarify that 
collection of AE information 
would include all AEs and SAEs, 
not only grade 3 and 4. 
Substantial change 
to collect 
information on all 
AEs and SAEs, not 
just Grades 3 and 4. 
Section 8.6.7, Disease-
related events and/or 
disease related outcomes 
not qualifying as AEs or 
SAEs 
This section including the 
following language was deleted. 
“Clinical worsening of COVID-19 
symptoms is an expected disease-
related outcome and should be 
captured as part of the daily 
assessments.” 
 
Section 10.5, Safety 
The sentence “Safety endpoints 
include SAEs and Grade 3 and 4 
AEs” was revised to “Safety 
endpoints include SAEs and AEs” 
Substantial change 
to report summary 
data on all AEs and 
SAEs, not just 
grades 3 and 4. 
Appendix 4, Definition of 
AE 
 
 
The 4th bullet was deleted: “Given 
the nature of severity of the 
underlying illness, subjects will 
have many symptoms and 
abnormalities in vitals and 
laboratory. All Grade 3 and 4 AEs 
Substantial change 
to collect 
information on all 
AEs and SAEs, not 
just Grades 3 and 4, 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 5 of 73 
 
 
Events Meeting the AE 
Definition 
 
will be captured as AEs in this 
trial.” 
The 7th bullet was deleted due to 
redundancy and clarification: “The 
signs, symptoms, and/or clinical 
sequelae resulting from lack of 
efficacy will be reported as AE or 
SAE if they fulfil the definition of 
an AE or SAE. Also, “lack of 
efficacy” or “failure of expected 
pharmacological action” also 
constitutes and AE or SAE.” 
and to clarify a 
redundant bullet. 
Section 6.3.1, Study 
Medication Dispensing 
Language referring to “kit 
medication ID number” and “kit 
lists” was removed. 
Administrative 
change for 
clarification. 
 
 
 
Amendment 2.0 
Section # and Name 
Description of Change 
Brief Rationale 
Appendix 4, Events 
meeting the definition of an 
AE 
 
 
 
 
 
Events NOT meeting the 
definition of an AE 
 
 
 
Bullet 1: the following text was 
deleted “(ie, not related to 
progression of underlying 
disease).” 
Bullet 3: the following language 
was added “or those associated 
with underlying disease including 
expected progression, signs, or 
symptoms of the disease/disorder 
being studied.” 
 
Bullet 1: the following language 
was deleted “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 
Substantial change 
to collect AEs 
associated with 
underlying disease. 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 6 of 73 
 
 
 
 
 
Definition of SAE 
more severe than expected for the 
patient’s condition.”  
Bullet 2: the following language 
was deleted “or expected 
progression, signs, or symptoms of 
the disease/disorder being studied, 
unless more severe than expected 
for the patient’s condition.” 
 
This section states “If an event is 
not an AE per definition above, 
then it cannot be an SAE even if 
serious conditions are met.” 
The following example was 
deleted “(e.g., hospitalization for 
signs/symptoms of the disease 
under study, death due to 
progression of disease).” 
Amendment 3.0 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities 
In Study Treatment Period column 
for Safety Laboratory Tests, 
clarified with the symbol β and 
added this statement in the notes 
section of the table “Discharge 
safety laboratory tests may be 
completed at the discretion of 
the treating physician and, if 
completed, may be completed 
within 24 hours of the patient’s 
discharge from the hospital.” 
The treating 
physician may not 
deem it necessary to 
have additional 
hematology or 
blood chemistry 
tests ordered prior 
to discharge 
Section 5.1 Inclusion 
Criteria # 4 
Clarified inclusion criteria #4 to 
read as follows: 
Patient with a clinical status 
consistent with 3, 4 or 5 on the 
Ordinal scale and for whom the 
anticipated hospitalization is at 
least 72 hours (after 
randomization). 
Patients with 24-48 
hours in the hospital 
are unlikely to 
provide enough data 
due to the small 
number of doses of 
study medication. 
Section 10.5 Safety 
Added the term “Available” at the 
start of the second paragraph. 
Not all patients will 
have discharge 
safety laboratory 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 7 of 73 
values since these 
may now be 
performed at the 
discretion of the 
treating physician. 
Appendix 3. Laboratory 
Tests 
Added the language in bold to the 
second paragraph. 
“The following safety laboratory 
tests are required for eligibility 
verification and upon discharge at 
the discretion of the treating 
physician and, if completed, may 
be completed within 24 hours of 
the patient’s discharge from the 
hospital if not already conducted 
as part of standard of care:” 
The Investigator 
and the Treating 
Physician are not 
the same.   
This is a real-life 
study and, as such, 
the treating 
physician may not 
deem it necessary to 
have additional 
hematology or 
blood chemistry 
tests ordered prior 
to discharge. 
 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 8 of 73 
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ...................... 3 
TABLE OF CONTENTS ............................................................................... 8 
1 
PROTOCOL SUMMARY ............................................................... 13 
1.1 
Synopsis .................................................................................. 13 
1.2 
Schema ................................................................................... 17 
1.3 
Schedule of Activities ............................................................ 18 
2 
INTRODUCTION............................................................................. 20 
2.1 
Study Rationale ..................................................................... 20 
2.2 
Ensifentrine Background ..................................................... 20 
2.3 
Benefit/Risk Assessment ....................................................... 22 
3 
OBJECTIVES AND ENDPOINTS ................................................. 24 
3.1 
Objectives............................................................................... 24 
3.1.1 
Primary objective ...................................................... 24 
3.1.2 
Secondary objectives ................................................ 24 
3.1.3 
Safety objective ........................................................ 24 
3.2 
Endpoints ............................................................................... 24 
3.2.1 
Primary endpoint ...................................................... 24 
3.2.2 
Secondary endpoints ................................................. 24 
3.2.3 
Safety Endpoints ....................................................... 25 
4 
STUDY DESIGN ............................................................................... 26 
4.1 
Overall Design ....................................................................... 26 
4.2 
Scientific Rationale for Study Design .................................. 26 
4.2.1 
Rationale for ensifentrine in treatment of COVID-19
 .................................................................................. 27 
4.3 
Justification for Design ......................................................... 28 
4.4 
Justification for Dose ............................................................ 29 
4.5 
End of Study Definition ........................................................ 29 
5 
STUDY POPULATION ................................................................... 30 
5.1 
Inclusion Criteria .................................................................. 30 
5.2 
Exclusion Criteria ................................................................. 31 
5.3 
Screen Failures ...................................................................... 31 
6 
STUDY TREATMENT .................................................................... 32 
6.1 
Treatment Assignment ......................................................... 32 
6.2 
Administration of Study Medication ................................... 32 
6.3 
Investigational Product/Study Medication ......................... 33 
6.3.1 
Study medication dispensing .................................... 33 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 9 of 73 
6.3.2 
Identity, preparation and labelling of study 
medication ................................................................ 33 
6.3.3 
Formulation information .......................................... 33 
6.3.4 
Preparation/Handling/Storage/Accountability ......... 33 
6.4 
Emergency Unblinding ......................................................... 34 
6.5 
Concomitant & Prohibited Medications ............................. 34 
6.5.1 
Recording use of concomitant medications .............. 35 
7 
DISCONTINUATION/WITHDRAWAL OF PATIENTS OR 
STUDY TERMINATION ................................................................ 36 
7.1 
Discontinuation of Study Medication .................................. 36 
7.1.1 
Study specific discontinuation of study medication 
criteria ....................................................................... 36 
7.2 
Patient Discontinuation/Withdrawal from the Study ........ 37 
7.3 
Lost to Follow-up .................................................................. 37 
7.4 
Termination of the Study ..................................................... 37 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................... 39 
8.1 
Collection of Data .................................................................. 39 
8.1.1 
7-point ordinal scale of clinical improvement .......... 41 
8.1.2 
Categorizing COVID-19 disease severity ................ 41 
8.1.3 
Vital sign assessment ................................................ 42 
8.1.4 
Recording SoC medications, treatments & laboratory 
test results ................................................................. 42 
8.2 
Screening/baseline and Day 1 .............................................. 43 
8.3 
Study Treatment & Day of Discharge from Hospital ........ 45 
8.4 
Discharge Activities .............................................................. 46 
8.5 
Post Discharge/Day 29 Contacts .......................................... 46 
8.6 
Adverse Events ...................................................................... 47 
8.6.1 
Time period and frequency for collecting AE and 
SAE information ....................................................... 47 
8.6.2 
Method of detecting AEs and SAEs ......................... 48 
8.6.3 
Follow-up of AEs and SAEs .................................... 48 
8.6.4 
Regulatory reporting requirements for SAEs ........... 48 
8.6.5 
Pregnancy ................................................................. 48 
8.6.6 
Adverse Events of special interest ............................ 49 
8.7 
Treatment of Overdose ......................................................... 49 
9 
PROTOCOL EXEMPTIONS/WAIVERS...................................... 50 
10 
STATISTICAL CONSIDERATIONS ............................................ 51 
10.1 
Statistical Hypotheses ........................................................... 51 
10.2 
Study Populations ................................................................. 51 
10.3 
Sample Size Determination .................................................. 51 
10.4 
Efficacy................................................................................... 51 
10.5 
Safety ...................................................................................... 52 
10.5.1 
Missing Data ............................................................. 52 
10.6 
Interim Analyses ................................................................... 52 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 10 of 73 
11 
DATA MONITORING COMMITTEE .......................................... 53 
12 
REFERENCE LIST .......................................................................... 54 
13 
APPENDICES ................................................................................... 56 
Appendix 1: Abbreviations .............................................................. 57 
Appendix 2: Regulatory, Ethical, and Study Oversight 
Consideration ........................................................................ 59 
Appendix 3: Laboratory Tests ......................................................... 64 
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ............. 65 
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information for Patients ....................................................... 71 
Appendix 6: Signature of Investigator ............................................ 73 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 11 of 73 
LIST OF IN-TEXT TABLES 
Table 1 Document History ................................................................................ 3 
Table 2 Description of Changes in the Amendment ......................................... 4 
Table 3. Schedule of activities. ....................................................................... 18 
Table 4. Inclusion criteria. .............................................................................. 30 
Table 5. Exclusion criteria. ............................................................................. 31 
Table 6. Treatment arms. ................................................................................ 32 
Table 7. Study medication dosing. .................................................................. 32 
Table 8. Study medication composition. ......................................................... 33 
Table 9. Prohibited concomitant medications. ................................................ 35 
Table 10. 7-point ordinal scale........................................................................ 41 
Table 11. Screening/baseline visit activities. .................................................. 43 
Table 12. Day 1 visit activities. ...................................................................... 44 
Table 13.  Days 2-29 or until discharge daily activities. ................................ 45 
Table 14.  Day of discharge activities. ............................................................ 46 
Table 15.  Post-discharge follow-up activities. ............................................... 47 
Table 16. Study administrative structure. ....................................................... 61 
Table 17. Medical monitor. ............................................................................. 62 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 12 of 73 
LIST OF IN-TEXT FIGURES 
Figure 1. Study schematic. .............................................................................. 17 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 13 of 73 
1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: 
A single-center, pilot randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of ensifentrine in the recovery of hospitalized patients with COVID-
19. 
Short Title: 
Ensifentrine therapy for COVID-19. 
Rationale 
Verona Pharma is developing inhaled nebulized ensifentrine for the maintenance 
treatment of Chronic Obstructive Pulmonary Disease (COPD).  
Ensifentrine is a dual inhibitor of Phosphodiesterase 3 (PDE3) and PDE4 which has 
demonstrated both bronchodilator and anti-inflammatory effects in clinical studies (Singh, 
2018; Singh, 2020; Franciosi, 2013). Ensifentrine has been studied in patients with COPD 
as a nebulized suspension, dry powder inhaler (DPI) and pressurized metered dose inhaler 
(pMDI). Overall, ensifentrine was well tolerated in 17 clinical studies conducted to date, 
with adverse event incidence and severity generally similar to those in the placebo-treated 
group. Verona Pharma is entering Phase III clinical development with nebulized 
suspension ensifentrine as a maintenance therapy for patients with COPD. 
It is postulated that inhaled ensifentrine treatment in patients with COVID-19 will 
effectively bronchodilate patients, reducing symptoms of dyspnea and improve the 
patient’s oxygen levels thus reducing the need for supplemental oxygen. Activity of 
ensifentrine related to reduction of viral-induced inflammation and CFTR stimulation 
may help patients clear the virus more rapidly and help prevent further clinical 
deterioration resulting from reduced oxygenation and secondary infections related to 
mucus hypersecretion. As such, the goal of ensifentrine treatment in patients with 
COVID-19 is to improve clinical status, facilitate recovery and prevent the progression of 
the disease leading to mechanical ventilation by allowing the patient to breath better 
during the infection, to reduce the inflammation in the lung and facilitate patient recovery 
from COVID-19. 
Objectives and Endpoints  
Primary  
The primary objective is to evaluate the effect of ensifentrine on the proportion of patients 
with recovery from COVID-19 over 29 days. 
The primary endpoint is to evaluate the effect of ensifentrine on the proportion of patients 
with recovery (Day 29). 
• Day of recovery is defined as the first day on which subjects satisfies one of the 
following two categories from the 7-point ordinal scale:  
o not hospitalized, no limitations of activities; 
o not hospitalized, limitation of activities, home oxygen requirement, or both. 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 14 of 73 
Secondary  
Secondary objectives include the evaluation of: 
• the effect of ensifentrine on COVID-19 related time to recovery, clinical status 
and risk of deterioration and  
• the effect of ensifentrine on hospitalization, non-invasive and invasive ventilation 
and oxygen use. 
Secondary endpoints include: 
• Time to recovery defined as satisfying one of the following two categories from 
the 7-point ordinal scale (Day 1-Day 29):  
o not hospitalized, no limitations of activities; 
o not hospitalized, limitation of activities, home oxygen requirement, or both. 
• Proportion of patients with recovery at day 60. 
• Proportion of patients with improvement (from Day 1) of one category using the 
7-point ordinal scale (Days 7, 14 and 29). 
• Proportion of patients with improvement of two categories using the 7-point 
ordinal scale (Days 7, 14 and 29). 
• All-cause mortality at Days 29 and 60. 
• Proportion of patients alive and not in respiratory failure (invasive mechanical 
ventilation or extracorporeal membrane oxygenation (ECMO)) at Day 29. 
• Proportion of patients needing re-hospitalization over 60 days. 
• Duration of hospitalization from Day 1 (Day 1 - Day 29; measured in days). 
• Mean change from baseline in 7-point ordinal scale (Days 7, 14 and 29). 
• Total time on supplemental oxygen (Day 1 - Day 29; measured in days). 
• Incidence and duration of new non-invasive ventilation or high flow oxygen use 
(Day 1 - Day 29; measured in days). 
• Incidence and duration of new oxygen use (Day 1 - Day 29; measured in days). 
• Incidence and duration of new mechanical ventilator use (Day 1 - Day 29; 
measured in days). 
• Proportion of patients receiving invasive mechanical ventilation or extracorporeal 
membrane oxygenation (ECMO) at Days 7, 14 and 29 (7-point ordinal scale 
criteria #6).  
Safety  
Safety objectives include the evaluation of the safety and tolerability of ensifentrine in 
patients with COVID-19. 
Safety endpoints include: 
• The incidence of adverse events (AEs) 
• Vital signs. 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 15 of 73 
Overall Design 
The purpose of this study is to evaluate the effect of ensifentrine in patients hospitalized 
with COVID-19 infection in terms of the proportion of patients in recovery from COVID-
19 at Day 29.  
This is a single center, randomized, double-blind, parallel group, placebo-controlled study 
to determine the efficacy and safety of ensifentrine 2 mg twice daily (BID) administered 
via pressurized metered dose inhaler (pMDI) added on to standard of care (SoC) 
treatment for COVID-19 infection compared to subjects receiving SoC plus placebo. 
Patients 18 to 80 years of age must be hospitalized with a confirmed diagnosis of Severe 
Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection confirmed by 
polymerase chain reaction (PCR) test and displays at least one of the following: 
Respiratory rate greater than 24, new cough, new atypical chest pain, new dyspnea, 
oxygen saturation <97% at rest, chest x-ray with new changes consistent with COVID- 
related airspace disease. 
Patients meeting criteria for inclusion and none of the criteria for exclusion at 
randomization will be randomized to receive study medication in the study until hospital 
discharge or up to 29 days of treatment, whichever comes first. Patients will be 
randomized 2:1 to receive one of the following study treatments:   
• Treatment Arm 1 (n=30): Blinded ensifentrine (2 mg) pMDI BID + Standard of 
Care treatment for COVID-19 infection 
• Treatment Arm 2 (n=15): Blinded placebo pMDI BID + Standard of Care 
treatment for COVID-19 infection 
Randomized patients will receive blinded ensifentrine or placebo twice daily, 
approximately 12 hours apart in the morning and evening, through 29 days or until 
discharge from hospital, whichever is first. Patients will self-administer 4 actuations 
(puffs) pMDI observed by study staff at each dosing event. 
During the treatment period, patients will undergo all assessments and procedures as 
outlined in the Schedule of Activities (SoA) until hospital discharge. Patients completing 
treatment will complete a study contact (telephone or visit as required) within 4 to 10 
days of discharge or early withdrawal. All enrolled patients will complete a telephone 
contact 26 to 32 days and 55-65 days following receipt of 1st dose of study medication for 
assessment of clinical status via the ordinal scale, need for re-hospitalization and vital 
status. 
The study design is displayed in Figure 1 and the SoA is in Table 3. 
Number of Investigators and Study Centers 
This is a single-site study conducted at the University of Alabama at Birmingham 
Hospital (UAB).  The principle investigator is Dr. J. Michael Wells, Division of 
Pulmonary, Allergy, and Critical Care Medicine. 
Number of Patients 
Approximately 45 randomized patients are planned. 
Treatment Groups and Duration 
Every patient enrolled will receive UAB’s SoC treatment for COVID-19 infection.   

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 16 of 73 
Upon enrollment, patients will be randomized 2:1 to receive blinded ensifentrine via 
pMDI BID + SoC or placebo pMDI BID + SoC over 29 days or until discharge from 
hospital, whichever is first. 
• Treatment Arm 1 (n=30): Blinded ensifentrine (2 mg) pMDI BID + Standard of 
Care treatment for COVID-19 infection 
• Treatment Arm 2 (n=15): Blinded placebo pMDI BID + Standard of Care 
treatment for COVID-19 infection 
Statistical Methods 
All analyses are considered exploratory and hypothesis-generating. 
Sample Size 
This is a pilot study and it is not formally powered based on any specific endpoint. 
Sample size has been set to minimize the number of patients exposed, but still large 
enough to give reliable estimates on the efficacy and safety of ensifentrine in the target 
population. 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 17 of 73 
1.2 
Schema 
 
Figure 1. Study schematic. 
 
R 
Treatment Arm 2 (N=15): 
Blinded placebo pMDI BID + SoC 
Treatment Arm 1 (N=30): 
Blinded ensifentrine (2 mg) pMDI BID + SoC 
Discharge 
Contact 
7 ± 3 days after 
discharge 
Screening 
Period 
0 to 4 
days 
Telephone 
Discharge 
Follow-up 
Screening 
Day 1 
29-days or  
Discharge 
Study Treatment  
Daily until Day 29 or Discharge, whichever is first 
Telephone 
60 day Follow-
up  
or Vital Records 
Day 60 
Follow-up 
60 ± 5 days 
after 1
st dose 
Abbreviations - BID: twice daily; SoC: standard of care treatment for COVID-19 infection; mg: milligrams; n: number of patients; pMDI: pressurized metered dose 
inhaler; R: randomization. 
Telephone 
29 day 
Follow-up  
Day 29 
Contact 
29 ± 3 days 
after 1
st dose 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 18 of 73 
1.3 
Schedule of Activities 
Table 3. Schedule of activities. 
 
Procedures for Patients Completing the Study 
Procedures for Early Termination or Withdrawal 
Tests and Procedures 
Screening / 
Baseline 
Day 1† 
Study Treatment Period  
(Days 2 – 29) 
Discharge 
contact‡ 
Day 29 
contact‡‡ 
Day 60 
Follow-
up‡‡‡ 
Early 
Termination / 
Withdrawal 
Discharge 
contact‡ 
Day 29 
contact‡‡ 
Day 60 
Follow-up‡‡‡ 
0 to 4 days 
before Day 1 
(Visit 1) all 
pre-dose 
 Daily until hospital discharge 
or Day 29, whichever is first (or 
as noted) 
(7 + 3 
days) 
(29 + 3 
days) 
(60 + 5 
days) 
  
(7 + 3 days) 
(29 + 3 
days) 
(60 + 5 
days) 
Written Informed Consent 
X 
  
  
  
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
  
  
  
Record medical history and hospital 
admission data 
X 
  
  
  
  
  
  
  
  
  
Brief physical exam*    
X 
  
  
  
  
  
  
  
  
  
Safety laboratory tests hematology, 
chemistry (non-fasting), urinalysis, 
serology, pregnancy test (as 
applicable)Ω 
X 
  
At discharge or on Day 29β 
  
  
  
X 
  
  
  
Review Inclusion/Exclusion criteria 
and categorize disease severity 
X 
  
  
  
  
  
  
  
  
  
Randomization 
  
X 
  
  
  
  
  
  
  
  
Vital signs including oxygen 
saturation¥ 
X 
X 
X1 
  
  
  
X1 
  
  
  
7-point ordinal scale assessmentβ 
X 
X 
X1 
X 
X 
X 
X1 
X 
X 
X 
Record SoC concomitant medication 
and treatments 
X 
X 
X 
  
  
  
X 
  
  
  
Record SoC laboratory test results 
(e.g., hematology, chemistry, 
serology, pathology, radiology, 
urinalysis, etc.)^ 
X 
X 
X 
  
  
  
X 
  
  
  
Adverse Events assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense blinded study medication 
and record 
  
X 
 On Days 12 and 24 
  
  
  
  
  
  
  
Collect used, blinded study 
medication and record 
  
  
 On Days 12, 24 and 29 (or 
discharge) 
  
  
  
X 
  
  
  
Study medication training and 
observation and record 
  
X 
  
  
  
  
  
  
  
  

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 19 of 73 
 
Procedures for Patients Completing the Study 
Procedures for Early Termination or Withdrawal 
Tests and Procedures 
Screening / 
Baseline 
Day 1† 
Study Treatment Period  
(Days 2 – 29) 
Discharge 
contact‡ 
Day 29 
contact‡‡ 
Day 60 
Follow-
up‡‡‡ 
Early 
Termination / 
Withdrawal 
Discharge 
contact‡ 
Day 29 
contact‡‡ 
Day 60 
Follow-up‡‡‡ 
0 to 4 days 
before Day 1 
(Visit 1) all 
pre-dose 
 Daily until hospital discharge 
or Day 29, whichever is first (or 
as noted) 
(7 + 3 
days) 
(29 + 3 
days) 
(60 + 5 
days) 
  
(7 + 3 days) 
(29 + 3 
days) 
(60 + 5 
days) 
Dose blinded study medication with 
study staff and record∑ 
  
X 
twice daily (morning and 
evening) until discharge or Day 
292 
  
  
  
X2 
  
  
  
Follow-up vital status 
  
  
  
X 
X 
X 
  
X 
X 
X 
Re-hospitalization/Still in hospital 
status 
  
  
  
X 
X 
X 
  
X 
X 
X 
Vital records search, if needed 
  
  
  
  
  
X 
  
  
  
X 
† 
Day 1 may take place on the same day as the screening/baseline visit, if appropriate.  If Day 1 activities take place on the same day as screening/baseline visit, only 1 ordinal scale assessment and vital sign 
assessment are necessary, but they must be completed prior to dosing. 
‡ 
Discharge Contact: contact with the patient will take place 4 to 10 days after discharge from hospital within the 29-day treatment period. If the patient remains hospitalized after Day 29, contact with the 
patient will take place 4 to 10 days after receipt of last dose of study medication on Day 29. 
‡‡ 
Day 29 Contact (if patient discharged prior to Day 29): contact with the patient will take place 26 to 32 days after first dose of study medication.  If the Discharge Contact and Day 29 Contact fall within 
same window, this contact will be combined as the Day 29 Contact. 
‡‡‡ 
Day 60 Follow-up: contact with the patient will take place 55 to 65 days after first dose of study medication. 
* 
Record the physical exam documented by the treating team on the day of screening, and verify key parts (heart, lung). 
Ω 
If kidney (creatinine), liver (alanine aminotransferase or aspartate aminotransferase) and pregnancy (if applicable, via serum) were not run prior, they are required during the screening process. Refer to 
exclusion criteria in Section 5.2 and Appendix 3. 
β 
Discharge safety laboratory tests may be completed at the discretion of the treating physician and, if completed, may be completed within 24 hours of the patient’s discharge from the hospital. 
¥ 
Vital signs should be recorded each morning at approximately the same time of a given study day. Variables: Respiration rate (per minute), Oxygen saturation (SpO2), Any supplemental oxygen (yes/no), 
Body temperature, Systolic blood pressure, Heart rate (pulse rate per minute); and Level of consciousness graded on the AVPU scale (Alert, Verbal = voice response present, Pain = pain response present, 
Unresponsive).  Refer to Section 8.1.3. 
1 
These assessments are not required to be completed prior to morning blinded study medication dosing. 
β 
Ordinal scale clinical improvement assessed and recorded each morning at approximately the same time.  The categories are as follows: 1=not hospitalized, no limitations of activities; 2=not hospitalized, 
limitation of activities, home oxygen requirement, or both; 3=hospitalized, not requiring supplemental oxygen but requiring ongoing medical care; 4=hospitalized, requiring any supplemental oxygen; 
5=hospitalized, requiring non-invasive ventilation or use of high-flow oxygen devices; 6=hospitalized, receiving invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); and 
7=death. Refer to Section 8.1.1. 
^ 
Laboratory results performed as recommended by UAB treating physician: Record daily (or as performed) WBC, neutrophil count, lymphocyte count, creatinine values.  Record every 2-3 days (or as 
performed) a) Inflammatory markers and b) LFTs.  Those recommended for UAB staff include: BMP, CBC w/ diff, LFT, IL-6, ferritin, D-dimer every three days. See Section 8.1.4 and Appendix 3. 
∑ 
Study staff, nursing and/or respiratory therapy to administer.  The person administering and observing cannot be the unblinded pharmacist. 
2 
Blinded study medication may be dosed as deemed appropriate by Investigator on day of discharge. 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 20 of 73 
2 
INTRODUCTION 
2.1 
Study Rationale 
According to the US Centers for Disease Control and Prevention, most patients with 
COVID-19 will experience signs and symptoms including fever, cough, shortness of 
breath, and sputum production. Most patients (81%) have what is considered mild to 
moderate illness (mild symptoms up to mild pneumonia), with approximately 14% 
experiencing severe effects (dyspnea, hypoxia, or >50% lung involvement from 
pneumonia on imaging). Clinical goals for patients hospitalized with COVID-19 include 
preventing clinical deterioration (including progression to mechanical ventilation), 
improving dyspnea and reducing hypoxia, and clearing the infection from the lungs. An 
intervention that could improve clinical status and facilitate recovery while minimizing 
progression to mechanical ventilation in patients hospitalized with COVID-19 is urgently 
needed.  
Bronchodilators have been used extensively in COVID-19 patients to alleviate respiratory 
symptoms leading to an albuterol (salbutamol) metered dose inhaler (MDI) shortage. In 
addition to experimental anti-viral therapies, anti-inflammatory agents such as IL-6, 
monoclonal antibodies are also under evaluation for the treatment of patients with 
COVID-19. It was recently reported that elevated inflammatory cells and markers such as 
TNFα and IL-6 have been shown to be associated with COVID-19 severity in patients, 
indicating an inflammatory hyper-response akin to a cytokine storm that is associated 
with poor outcomes (Gong, 2020). As such, agents that target these inflammatory 
mediators, such as inhibitors of phosphodiesterase (PDE) 3 and PDE4, are potential 
therapeutic interventions of significant interest. 
The purpose of this study is to evaluate the efficacy and safety of, ensifentrine (RPL554), 
in combination with SoC treatment for COVID-19 infection for hospitalized patients. 
 
2.2 
Ensifentrine Background 
PDEs are enzymes that impact a range of cellular functions within the airways and the 
lungs by modulating levels of cyclic nucleotides. PDEs 3 and 4 are known to play key 
roles in important cellular function related to airways disease, such as smooth muscle 
relaxation, mucus production, ciliary beat frequency, airway re-modeling and 
inflammatory mediator release (Zuo, 2019; Boswell-Smith, 2006; Abbott-Banner, 2014; 
Matera, 2014). Thus, selective PDE inhibition, specifically PDE3 and PDE4, may be 
useful in the treatment of respiratory disease.  
Ensifentrine is an investigational, inhaled, dual inhibitor of PDE3 and PDE4 which has 
demonstrated both bronchodilator and anti-inflammatory effects in clinical studies in 
healthy individuals as well as those with asthma, allergic rhinitis and COPD (Singh, 
2018; Singh, 2020; Franciosi, 2013). Ensifentrine has been studied in patients with COPD 
as a nebulized suspension therapy, DPI and pMDI. Overall, ensifentrine was well 
tolerated in 17 clinical studies conducted to date, with adverse event incidence and 
severity generally similar to those in the placebo-treated group. Verona Pharma is 
entering Phase III clinical development with nebulized ensifentrine as a maintenance 
therapy for patients with COPD. 
It is postulated that ensifentrine treatment in patients with COVID-19 will effectively 
bronchodilate patients, reducing symptoms of dyspnea and improve the patient’s oxygen 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 21 of 73 
levels thus reducing the need for supplemental oxygen. Activity of ensifentrine related to 
reduction of viral-induced inflammation and CFTR stimulation may help patients clear 
the virus more rapidly and help prevent further clinical deterioration resulting from 
reduced oxygenation and secondary infections related to mucus hypersecretion. As such, 
the goal of ensifentrine treatment in patients with COVID-19 is to improve clinical status, 
facilitate recovery and prevent the progression of the disease leading to mechanical 
ventilation by allowing the patient the patient to breath better during the infection, to 
reduce the inflammation in the lung and facilitate patient recovery from COVID-19. 
The safety, bronchodilator, bronchoprotective and anti-inflammatory activities of 
ensifentrine have been evaluated in 17 clinical trials involving more than 1300 subjects. 
In the clinical studies performed to date, nebulized ensifentrine has demonstrated 
pronounced bronchodilator effects in healthy subjects and in patients with COPD or 
asthma. Nebulized ensifentrine has demonstrated bronchodilator and anti-inflammatory 
effects in proof of concept studies in healthy patients, and those with asthma or COPD 
(Franciosi, 2013; Singh, 2018; Singh, 2020; Bjermer, 2019). Additionally, anti-
inflammatory effects have been observed in a model of COPD-like inflammation in 
healthy subjects (Franciosi, 2013). A Phase II single and repeat dose study with 
ensifentrine in a dry powder inhaler (DPI) format up to 3 mg in 37 patients with COPD 
showed that single and repeat doses of twice daily ensifentrine over one week had a rapid, 
dose-dependent, and statistically significant bronchodilatory effect up level over 12 hours. 
A new formulation was developed to allow for delivery of ensifentrine using a 
convenient, hand-held pMDI. In Part A of a two-part Phase 2 study, ensifentrine delivered 
via pMDI was evaluated as a single dose in patients with COPD. Part B of this study is on 
hold pending resolution of COVID-related impacts on patients and sites.  The active 
pharmaceutical ingredient used in the pMDI formulation is the identical physical form 
and morphology as that used in the nebulizer suspension product in previous studies. 
Furthermore, a non-clinical assessment of local and systemic toxic potential of a dry 
powder inhaler (DPI) formulation of ensifentrine (of the identical physical form and 
morphology) blended with lactose was conducted in a 2-week inhalation study in Han 
Wistar rats. The purpose of this non-clinical study was to support single and repeat dose 
clinical studies with both a DPI as well as a pMDI formulation, consisting of ensifentrine 
suspended in hydrofluoroalkane (HFA)-134a propellant only. Results from this initial 
bridging toxicology study with an ensifentrine lactose dry powder blend showed no new 
findings when this vehicle formulation is used at similar exposure levels, and this body of 
data supports clinical evaluation of both the DPI and pMDI formulations. Finally, single 
dose pharmacokinetic data from the ensifentrine pMDI in patients with COPD dosed from 
0.1 mg to 3 mg was analogous to that observed following a single dose with ensifentrine 
DPI in COPD patients regarding both Cmax and AUC0-12h. 
Overall, ensifentrine was well tolerated in all clinical studies completed to date, with 
adverse event (AE) incidence and severity generally similar to those in the placebo-
treated group. Serious adverse events (SAEs) have been uncommon and there is no 
apparent pattern in the SAEs reported to date.  
Information on the background of ensifentrine as described in this section can be found in 
the Verona Pharma plc. Ensifentrine Clinical Investigators Brochure v. 19, 20th May 
2020, unless otherwise cited. 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 22 of 73 
2.3 
Benefit/Risk Assessment 
No significant medical risks to patients have been identified from studies conducted to 
date with ensifentrine administered in the nebulized, dry powder or metered dose 
inhalation formulations. With all formulations of inhaled ensifentrine studied to date (17 
studies, n > 1300 patients), including nebulized suspension (15), DPI (1) and pMDI (1), 
including 2 x 4-week, 400-patient studies with nebulized ensifentrine in COPD patients 
up to twice daily doses of 6 mg, ensifentrine has been well tolerated to date, with adverse 
event (AE) incidence and severity generally similar to those in the placebo-treated group. 
In studies with COPD patients, this included patients with many underlying co-
morbidities including cardiovascular disease, diabetes, hypertension and underlying renal 
dysfunction.  Adverse events related to cardiovascular or gastrointestinal systems have 
not been associated with ensifentrine treatment. Serious adverse events (SAEs) have been 
uncommon and there is no apparent pattern in the SAEs reported to date. The risk of 
drug-drug interactions with ensifentrine is very low. 
A small, transient increase in peak heart rate (HR) of 3 bpm was observed with the 6 mg 
nebulized dose after 4 weeks of twice daily treatment in patients with COPD, an increase 
in peak pulse rate (but not HR) of 6 bpm was observed with the 3 mg dose after 7 days of 
twice daily DPI treatment in patients with COPD, and an increase in peak heart rate was 
observed with the 3 mg and 6 mg single dose of pMDI of 7 beats per minute (bpm) and 
11 bpm, respectively, in patients with COPD, but no corresponding increase in pulse rate 
was observed for the 3 mg dose. In healthy volunteers, a single dose of 6 mg nebulized 
ensifentrine showed an increase in peak HR of 12 bpm at supratherapeutic exposures.  
These small, transient increases in peak heart rate are not considered clinically 
meaningful and have not been associated with adverse clinical outcomes.  
Ensifentrine has been demonstrated to have favorable non-clinical toxicology and PK 
profiles when delivered via the inhaled route as both a nebulized suspension and as a DPI. 
Following single dosing, the PK profiles from ensifentrine DPI and MDI are similar in 
patients with COPD. 
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 AUC). There were no effects on embryo-fetal survival and development in 
either rats or rabbits in the main embryo-fetal development studies. The effects of 
ensifentrine on fertility and reproductive performance in female rats have not yet been 
assessed. 
Ensifentrine has statistically and clinically significant bronchodilator as well as 
anti-inflammatory effects. As such, the clinical development of ensifentrine is focused on 
the treatment of obstructive and inflammatory lung diseases, including COPD. 
Considering the consistent improvements in lung function, symptoms and health-related 
quality of life across multiple studies in patients with COPD and the overall favorable 
safety profile in studies to date, the benefit/risk profile of ensifentrine in patients with 
COVID-19 is considered positive.  

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 23 of 73 
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 Investigators Brochure v. 19, 20th May 2020.  

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 24 of 73 
3 
OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
3.1.1 Primary objective 
The primary objective is to evaluate the effect of ensifentrine on the proportion of patients 
with recovery from COVID-19 over 29 days. 
3.1.2 Secondary objectives 
• To evaluate the effect of ensifentrine on COVID-19 related time to recovery, 
clinical status and risk of deterioration,  
• To evaluate the effect of ensifentrine on hospitalization, non-invasive and invasive 
ventilation and oxygen use. 
3.1.3 Safety objective 
• To evaluate the safety and tolerability of ensifentrine in patients with COVID-19. 
 
3.2 
Endpoints 
3.2.1 Primary endpoint 
The primary endpoint is to evaluate the effect of ensifentrine on the proportion of patients 
with recovery (Day 29). 
• Day of recovery is defined as the first day on which subjects satisfies one of the 
following two categories from the 7-point ordinal scale:  
o not hospitalized, no limitations of activities; 
o not hospitalized, limitation of activities, home oxygen requirement, or both. 
3.2.2 Secondary endpoints 
• Time to recovery defined as satisfying one of the following two categories from 
the 7-point ordinal scale (Day 1-Day 29):  
o not hospitalized, no limitations of activities; 
o not hospitalized, limitation of activities, home oxygen requirement, or both. 
• Proportion of patients with recovery at Days 7, 14, 29 and 60. 
• Proportion of patients with improvement (from Day 1) of one category using the 
7-point ordinal scale at Days 7, 14 and 29. 
• Proportion of patients with improvement (from Day 1) of two categories using the 
7-point ordinal scale at Days 7, 14 and 29. 
• All-cause mortality at Days 29 and 60. 
• Proportion of patients alive and not in with respiratory failure (invasive 
mechanical ventilation or extracorporeal membrane oxygenation [ECMO]) at Day 
29. 
• Proportion of patients needing re-hospitalization over 60 days. 
• Duration of hospitalization from Day 1 (Day 1 - Day 29; measured in days). 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 25 of 73 
• Mean change from baseline in 7-point ordinal scale (Days 7, 14 and 29). 
• Total time on supplemental oxygen (Day 1 - Day 29; measured in days). 
• Incidence and duration of new non-invasive ventilation or high flow oxygen use 
(Day 1 - Day 29; measured in days). 
• Incidence and duration of new oxygen use (Day 1 - Day 29; measured in days). 
• Incidence and duration of new mechanical ventilator use (Day 1 - Day 29; 
measured in days). 
• Proportion of patients receiving invasive mechanical ventilation or extracorporeal 
membrane oxygenation (ECMO) at Days 7, 14 and 29 (7-point ordinal scale 
criteria #6).  
 
3.2.3 Safety Endpoints 
• Incidence of Adverse Events (AEs) 
• Vital Signs 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 26 of 73 
4 
STUDY DESIGN 
4.1 
Overall Design 
The purpose of this study is to evaluate the effect of ensifentrine on the proportion of 
patients hospitalized with COVID-19 infection with recovery over 29 days.  
This is a single center, randomized, double-blind, parallel group, placebo-controlled study 
to determine the efficacy and safety of ensifentrine 2 mg BID administered via pMDI 
added on to SoC treatment for COVID-19 infection compared to subjects receiving SoC 
plus placebo. 
Patients 18 to 80 years of age must be hospitalized with a confirmed diagnosis of SARS-
CoV-2 infection confirmed by PCR test and displays at least one of the following: 
Respiratory rate greater than 24, new cough, new atypical chest pain, new dyspnea, 
oxygen saturation <97% at rest, chest x-ray with new changes consistent with COVID-19 
related airspace disease. 
Patients meeting criteria for inclusion and none of the criteria for exclusion at 
randomization will be randomized to receive study medication until to hospital discharge 
or up to 29 days of treatment, whichever comes first. Patients will be randomized 2:1 to 
receive one of the following study treatments:   
• Treatment Arm 1 (n=30): Blinded ensifentrine (2 mg) pMDI BID + Standard of 
Care treatment for COVID-19 infection 
• Treatment Arm 2 (n=15): Blinded placebo pMDI BID + Standard of Care 
treatment for COVID-19 infection 
Randomized patients will receive blinded ensifentrine or placebo twice daily, 
approximately 12 hours apart in the morning and evening, through 29 days or until 
discharge from hospital, whichever is first. Patients will self-administer 4 actuations 
(puffs) pMDI observed by study staff at each dosing event. 
During the treatment period, patients will undergo all assessments and procedures as 
outlined in the SoA until hospital discharge. Patients completing treatment will complete 
a study contact (telephone or visit as required) within 4 to 10 days of discharge or early 
withdrawal. All enrolled patients will complete a telephone contact 26 to 32 days and 55-
65 days following receipt of 1st dose of study medication for assessment of clinical status 
via the ordinal scale, need for re-hospitalization and vital status. 
 
4.2 
Scientific Rationale for Study Design 
Inhaled ensifentrine has three main pillars of pharmacology relevant to treatment of 
patients with COVID-19: 1) bronchodilation 2) anti-inflammatory effects and 3) CFTR 
stimulation.  
1) Bronchodilation: In patients experiencing acute symptoms of shortness of breath and 
cough, acute treatment with ensifentrine can be used to improve oxygenation, alleviate 
symptoms, improve shortness of breath and reduce the work of breathing. Ensifentrine 
could be used as monotherapy or added on to short acting or long-acting beta2-agonists or 
muscarinic antagonists (SABA, LABA, SAMA, LAMA or SABA/SAMA, LABA/LAMA 
combinations) providing immediate bronchodilation (≤ 5 minutes) to patients who are 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 27 of 73 
having trouble breathing and/or with excessive cough. Clinical effects of ensifentrine on 
lung function are described in detail in the Investigator Brochure. 
2) Anti-Inflammatory effects: It is expected that ensifentrine will help clear the virus-
induced lung inflammation via reduction in local inflammatory cell numbers such as 
neutrophils, eosinophils, lymphocytes, macrophages and pro-inflammatory mediators 
such as TNFα and IL-6. 
Inhaled ensifentrine has demonstrated anti-inflammatory effects in a model of COPD-like 
inflammation in healthy subjects. In healthy subjects dosed with a nebulized solution of 
ensifentrine (0.018 mg/kg, approximately 1 mg dose) once daily for 6 days, induced 
sputum 6 hours after a lipopolysaccharide challenge showed a reduction in absolute 
numbers of neutrophils (p = 0.002), macrophages (p = 0.044), eosinophils (p = 0.001), 
lymphocytes (p = 0.001) and total cells (p = 0.002) (Franciosi, 2013).  
In vitro, ensifentrine has demonstrated functional inhibition of PDE4 via inhibition of 
TNFα production in LPS-stimulated human monocytes (520 nM) and inhibition of 
proliferation of human mononuclear cells stimulated with PHA (460 nM) (Boswell-
Smith, 2006) Additional work in animal models has shown that ensifentrine reduces 
inflammatory cell recruitment (eosinophil) following antigen challenge in guinea pigs.  
Other inhibitors of PDE4 have shown additional anti-inflammatory effects in assays 
where ensifentrine has not yet been tested, although it is expected that the pharmacology 
should be analogous or enhanced through inhibition of both PDE3 and PDE4: the PDE4 
inhibitor CHF-6001 reduced IL-6 in vitro in dendritic cells (Gianello, 2019) and 
roflumilast reduced IL-6 in bronchoalveolar lavage  fluid in COPD patients (Savelikhina, 
2018). Furthermore, these inhibitors of PDE4, CHF-6001 and roflumilast have also been 
shown in vitro to reduce in viral-induced inflammation in human bronchial epithelial 
(HBE) cells infected with rhinovirus (RV) and respiratory syncytial virus (RSV), 
respectively (Edwards, 2016; Mata, 2013). Roflumilast has also shown that the PDE4 
inhibitory mechanism may reduce viral load as shown with roflumilast in HBE infected 
with RSV over 10 days (Mata, 2013). It should be noted that selective inhibitors of PDE4 
such as roflumilast and CHF-6001 do not have bronchodilatory activity, and use of 
roflumilast, an oral inhibitor of PDE4, is limited by significant gastrointestinal effects.  
Ensifentrine is delivered via the inhalation route and gastrointestinal effects observed 
with other PDE4 inhibitors have not been observed in ensifentrine studies.   
3) CFTR Stimulation: Ensifentrine may also facilitate mucociliary clearance in patients 
via stimulation of CFTR, often found to be downregulated or functionally impaired in 
patients with pneumonia. In vitro evaluation of ensifentrine in human bronchial epithelial 
cells demonstrated that ensifentrine stimulates CFTR-dependent ion secretion across 
bronchial epithelial cells isolated from patients carrying the R117H/F508del cystic 
fibrosis genotype (Turner, 2016). Ensifentrine also significantly increased ciliary beat 
frequency in primary human bronchial epithelial cells at a similar magnitude to what was 
observed with PDE4 control, roflumilast. 
4.2.1 Rationale for ensifentrine in treatment of COVID-19 
In terms of clinical outcomes, Verona Pharma hypothesizes that ensifentrine treatment of 
patients with COVID-19 will effectively result in bronchodilation in patients, reducing 
symptoms of dyspnea and improve the patient’s oxygen levels thus reducing the need for 
supplemental oxygen. Activity of ensifentrine related to reduction of viral-induced 
inflammation and CFTR stimulation may facilitate viral clearance more rapidly and help 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 28 of 73 
prevent further clinical deterioration resulting from reduced oxygenation and secondary 
infections related to mucus hypersecretion. As such, the goal of ensifentrine treatment in 
patients with COVID-19 is to improve clinical status, facilitate recovery and prevent the 
progression of the disease leading to mechanical ventilation by allowing the patient to 
breathe better during the infection, to reduce the inflammation in the lung and facilitate 
patient recovery from COVID-19 infection.   
Because ensifentrine provides bronchodilation via its inhibition of PDE3 and PDE4, anti-
inflammatory effects following inhaled administration including the potential to 
decreased viral-induced inflammation, and bronchial cell CFTR stimulation, this 
pharmacologic therapy, delivered via pMDI, may serve as an innovative treatment for 
patients with COVID-19. 
This study will expand our knowledge and understanding about how ensifentrine can be 
used to facilitate recovery or prevent deterioration in hospitalized, COVID-19 patients.  
 
4.3 
Justification for Design 
This study is designed as a randomized, double-blind parallel group study evaluating 
impactful outcomes to patients, treating physicians, and healthcare facilities. As a small, 
unpowered pilot study, Verona Pharma aims to quickly collect data informing on the 
potential utility of inhaled ensifentrine pMDI in patients with COVID-19 by evaluation of 
trends across key independent endpoints. 
The study is randomized 2:1 to ensifentrine:placebo in order to minimize the number of 
patients exposed to placebo during the study. A treatment duration of up to 29 days was 
selected to ensure that most hospitalized patients could receive study treatment during 
their full course of hospitalization, as the CDC has recently reported the median duration 
of hospitalization in patients who survived to be 10 to 13 days and median range of viral 
shedding among hospitalized patients to be 12–20 days (CDC Interim Clinical Guidance 
for Management of Patients with Confirmed Coronavirus Disease (COVID-19), June 2, 
2020). 
The patient population includes hospitalized patients with moderate to severe COVID-19, 
as we anticipate ensifentrine benefit including preventing progression to respiratory 
failure or other clinical conditions defined as Critical COVID-19 (FDA COVID-19: 
Developing Drugs and Biological Products for Treatment or Prevention Guidance for 
Industry).  
Ensifentrine has not shown evidence of liver injury in trials including over 1300 patients. 
Nonclinical data indicate that circulating ensifentrine is rapidly and extensively 
metabolized. At physiologically relevant concentrations (approximately 3 nM), 
metabolism is primarily mediated by cytochrome P-450 (CYP) 2C9 (93%); and to a lesser 
extent CYP2D6 (24%) and CYP3A4 (less than 5%). A drug-drug interaction study in 
healthy volunteers has shown that concomitant dosing of nebulized ensifentrine 3 mg 
with steady state fluconazole, an inhibitor of CYP2C9 and CYP3A4, resulted in an 
increase in Cmax and AUC0-inf of 41% and 63% when compared with ensifentrine alone 
(RPL554-PK-102; IBv19). This less than 2-fold increase is not considered clinically 
meaningful, as ensifentrine of up to 6 mg twice daily was found to be well tolerated with 
a comparable adverse event profile to placebo for over 4 weeks of dosing (Study 
RPL554-CO-203, IBv19). Because of this data, patients with some level of liver enzyme 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 29 of 73 
elevation may be recruited into the study as it is not expected to have a meaningful impact 
on exposures (UAB is reporting that approximately 8% of patients hospitalized with 
COVID-19 have ALT >2x ULN and approximately 19% have AST >2x ULN). Analysis 
of urine samples in clinical study RPL554-PK-102 showed that after a 3 mg nebulized 
dose, urinary elimination of unchanged ensifentrine was negligible (<0.3% of the dose 
from RPL554-PK-102; IBv19). An analysis of trough plasma concentrations, Cmax and 
AUC0-12h in 127 patients enrolled in Phase 2 studies with mild and moderate renal 
impairment (GFR 30 to 90 mL/min) compared with patients with normal renal function 
(GFR ≥90 mL/min) did not show evidence of increased exposures in patients with 
reduced renal function. Patients with significant hepatic impairment/hepatic failure, renal 
failure or multiorgan failure will be withdrawn from study treatment. Ensifentrine has 
been shown to be a likely substrate for BCRP in vitro. A review of steady state exposure 
from Phase 2b studies RPL554-CO-203 and RPL554-CO-205 including 128 patients 
taking concomitant BCRP inhibitors (e.g. proton pump inhibitors, pravastatin) has shown 
that there is no increase in exposure compared to patients not taking these classes of 
medications, therefore, concomitant use of BCRP inhibitors is not excluded. 
 
4.4 
Justification for Dose 
Ensifentrine has been well-tolerated in clinical studies to date. The dose for this study (2 
mg) was selected based on analysis of pharmacokinetic (PK) and pharmacodynamic (PD) 
data (lung function improvement) from single dose study with pMDI, combined with 
what is known about PK/PD from multiple studies with a nebulized suspension of 
ensifentrine in healthy volunteers and patients with COPD, and a clinical study using 
ensifentrine in dry powder inhaler format. 
The dose was selected based on analysis of fine particle dose comparing the pMDI with a 
DPI and nebulized suspension of ensifentrine, along with pharmacokinetic (PK) and 
pharmacodynamic (PD) data (lung function improvement) from single dose study with 
pMDI RPL554-MD-201, combined with what is known about PK/PD from multiple 
studies with a nebulized suspension of ensifentrine in patients with COPD, and a clinical 
study using ensifentrine in dry powder inhaler format (RPL554-DP-201). These data 
support that a 2 mg twice daily dose of ensifentrine pMDI should provide equivalent fine 
particle dose, PK and lung function improvement as that observed from a twice daily 3 
mg nebulized dose, which has shown to be efficacious and well-tolerated over 4 weeks in 
patients with COPD. 
 
4.5 
End of Study Definition 
A patient is considered to have completed the study if he/she has successfully completed 
all visits during their treatment period while hospitalized and completed the Day 29 and 
Day 60 follow-up contacts.  
The end of the study is defined as the date of the last follow-up visit of the last patient in 
the study. 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 30 of 73 
5 
STUDY POPULATION 
Approximately 45 male and non-pregnant female adults hospitalized with COVID-19 and 
who meet all eligibility criteria will be enrolled at one site. The inclusion and exclusion 
criteria are listed in Table 4 and Table 5, respectively. 
 
5.1 
Inclusion Criteria 
Table 4. Inclusion criteria. 
1 
Capable of giving informed consent indicating that they understand the purpose 
of the study and study procedures and agree to comply with the requirements and 
restrictions listed in the informed consent form and in this protocol. 
2 
Age: Patient must be at least 18 years of age and less than or equal to 80 years of 
age at the time of informed consent. 
3 
Sex: Males are eligible to participate or females of non-childbearing potential or 
WOCBP who have a negative pregnancy test at screening are eligible to 
participate. WOCBP and female partners of male participants agree to either 
abstinence or use at least one primary form of highly effective contraception not 
including hormonal contraception from the time of screening through Day 60 
following the first dose of study medication. Refer to Appendix 5. 
4 
Patient with a clinical status consistent with 3, 4 or 5 on the Ordinal scale and for 
whom the anticipated hospitalization is at least 72 hours (after randomization). 
• Hospitalized, not requiring supplemental oxygen, but requiring ongoing 
medical care  
• Hospitalized, requiring any supplemental oxygen  
• Hospitalized, requiring non-invasive ventilation or use of high flow 
oxygen devices  
5 
Admission to hospital AND have a confirmed diagnosis of severe acute 
respiratory syndrome coronavirus (SARS-COV-2) infection confirmed by 
polymerase chain reaction (PCR) test AND displays at least one of the 
following: 
a. Respiratory rate > 24 breaths per minute, 
b. new cough,  
c. new atypical chest pain,  
d. new dyspnea,  
e. oxygen saturation < 97% at rest,  
f. chest x-ray with new changes consistent with COVID- related airspace 
disease. 
6 
Capable of complying with all study restrictions and procedures including ability 
to use the pMDI correctly. 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 31 of 73 
5.2 
Exclusion Criteria 
Table 5. Exclusion criteria. 
1 
Participation in any other clinical trial of an experimental treatment for COVID-
19, unless related to an expanded access program as part of Standard of Care. 
2 
Evidence of multiorgan failure. 
3 
Requiring mechanical ventilation at screening. 
4 
Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 X 
upper limit of normal (ULN) at screening. 
5 
Creatinine clearance < 30 mL/min at screening. 
6 
Pregnancy or lactation at screening. 
7 
Allergy or other contraindication or one of ensifentrine. 
8 
In the opinion of the clinical team, progression to death is imminent and 
inevitable within the next 24 hours, irrespective of the provision of treatments. 
9 
Use of prohibited medications (Section 6.5). 
10 
Any other reason that the Investigator considers makes the patient unsuitable to 
participate. 
 
 
5.3 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but 
were not randomized to receive blinded study medication. Patients randomized in error 
but not treated should be withdrawn.  
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure patients to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAE.  
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 32 of 73 
6 
STUDY TREATMENT 
6.1 
Treatment Assignment 
All patients consented will be assigned a patient identification number upon signing of 
the informed consent using the following convention: XXX-YYY where XXX is UAB’s 
center number and YYY is the patient number (001, 002, etc.). 
Once eligibility is confirmed, patients will be randomized in a 2:1 ratio to one of two 
treatment arms listed below (Table 6).  
 
Table 6. Treatment arms. 
Treatment Arm 
n 
Treatment 
Treatment Arm 1 
30 
Blinded ensifentrine (2 mg) pMDI BID + SoC* 
Treatment Arm 2 
15 
Blinded placebo pMDI BID + SoC* 
Abbreviations: SoC= standard of care, pMDI= pressurized metered dose inhaler, BID= 
twice daily 
*SoC treatment for COVID-19 infection based on established practices within UAB 
 
Randomization will take place prior to the first study medication administration in the 
order patients are enrolled and in accordance with a computer-generated randomization 
list supplied by the statistician. Available randomization numbers must be used 
sequentially for the next enrolled patient. Patients will be dosed with either blinded 
ensifentrine or placebo according to the randomization scheme.  
 
6.2 
Administration of Study Medication  
Under the direction of study staff, randomized patients will self-administer 4 actuations 
(puffs) pMDI at each dosing event. Dosing will be performed twice daily approximately 
12 hours apart in the morning and evening at approximately the same time each day 
(Table 7).  
The precise date and time of dose administrations performed in clinic at study visits, and 
in the evening, shall be documented in the eCRF. Information on missing doses will also 
be documented in the eCRF. 
 
Table 7. Study medication dosing. 
Time of day 
Study medication dose 
Morning  
4 puffs via pMDI before noon 
Evening  
4 puffs via pMDI approximately 12 hours later 
Abbreviations: pMDI= pressurized metered dose inhaler 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 33 of 73 
6.3 
Investigational Product/Study Medication  
6.3.1 Study medication dispensing  
Study medication will be shipped to the site unblinded pharmacist from the Sponsor. 
Ensifentrine and placebo pMDIs are supplied as unlabeled, pressurized canisters with 
yellow plastic actuators. Inhalers will be packaged individually at the site in single 
cartons and labelled according to the randomization schedule. Appropriate study center 
personnel will dispense the appropriate double-blind medication. Clinical study labels 
will be added at the site pharmacy. Each inhaler provides approximately 15 days of 
treatment, thus, each patient will require 1 inhaler to be dispensed on Days 1, 12 and 24 to 
complete 29 days of treatment. Detailed dispensing instructions will be provided in the 
study Pharmacy Manual. 
Study medication is kept with the site Pharmacy and not the patient, in accordance with 
site procedures. 
6.3.2 Identity, preparation and labelling of study medication 
The International Union of Pure and Applied Chemistry (IUPAC) name for ensifentrine 
drug substance is 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-
aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one. The ensifentrine 
pMDI is manufactured in accordance with Good Manufacturing Practice (GMP) 
guidelines. 
6.3.3 Formulation information 
The active formulations of ensifentrine and placebo in pMDI will be double-blind. The 
placebo is the same as the ensifentrine active formulation, except that the active 
ingredient is omitted. Each actuation of pMDI containing ensifentrine will deliver 0.5 mg, 
such that 4 puffs will equal a 2 mg dose. 
The formulation constituent and concentrations are described in Table 8. 
 
Table 8. Study medication composition. 
Constituent 
Ensifentrine 
Concentration (% w/w) 
Placebo Concentration 
(% w/w) 
Ensifentrine (micronized) 
0.648 
0 
HFA-134a 
99.352 
99.352 
Abbreviations: HFA=hydrofluoroalkane; w/w = weight per weight 
 
6.3.4 Preparation/Handling/Storage/Accountability 
• Study medication should not be stored above 25°C. Temperature logs should be 
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. 
• Study medication will be stored under the control of the Investigator or designee 
in a secure facility appropriate for the advised storage conditions. Study 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 34 of 73 
medications that are to be returned by the Investigator/staff or have expired must 
be stored separately from the unused study medications. 
• 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. 
• The Investigator will be responsible for the labeling and dispensing, inventory and 
accountability of study medication, exercising accepted medical and 
pharmaceutical practices and ensuring that an accurate, timely record of the 
disposition is maintained.  
o The Investigator must ensure there is at least one unblinded pharmacist to 
label the study medication and perform accountability measures. 
• At the end of the study, the unused study medication can be destroyed locally after 
accountability has been verified and written authorization has been provided by 
the Sponsor.  
 
6.4 
Emergency Unblinding 
The blind will be broken only if specific emergency treatment would require knowing the 
treatment status of the patient or if the protocol review committee (Section 11) 
recommends unblinding data for safety review reasons. If the blind needs to be broken for 
an individual patient, the Investigator will contact the Sponsor as soon as feasible. The 
Investigator may unblind the study medication immediately if he/she feels it is necessary 
prior to contacting the Sponsor. However, the Investigator should promptly document and 
explain to the Sponsor any premature unblinding. Otherwise, all blinding will be 
maintained until all queries are resolved and the database is locked.  
The statistical vendor for this study is the site’s data management group and will have 
access to break the blind, if necessary, but this will be kept in a secure access area. 
 
6.5 
Concomitant & Prohibited Medications 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
• UAB’s standard treatment for COVID-19 infection is permitted, with the 
exception of prohibited medications listed in Table 9. 
• UAB’s standard treatment for COVID-19 infection will be recorded in the eCRF 
from screening to discharge.  
 
 
 
 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 35 of 73 
Table 9. Prohibited concomitant medications. 
Medication 
Time Interval 
Theophylline, PDE4 inhibitors (e.g. 
roflumilast, apremilast, crisaborole) 
48 hours prior to Screening Visit and 
prohibited during the study 
Investigational or experimental 
medication for COVID-19 infection as 
part of a clinical trial that is not 
considered Standard of Care 
During study participation 
Abbreviations: PDE= phosphodiesterase 
 
6.5.1 Recording use of concomitant medications  
• Documentation during screening should be recorded on the concomitant 
medication page 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.” 
• Details (e.g., dose, route, date, and time of administration) will be recorded. 
• All medications for each subject along with the reason for use, time/date of 
administration, dose, route and duration of their administration will be recorded 
starting at screening and changes recorded during the trial. 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 36 of 73 
7 
DISCONTINUATION/WITHDRAWAL OF PATIENTS OR STUDY 
TERMINATION 
7.1 
Discontinuation of Study Medication  
Patients may choose to permanently discontinue study medication before the end of the 
trial.  The Investigator may choose for the patient to permanently discontinue study 
medication before the end of the trial at their discretion. The Investigator must document 
the reason for discontinuation of study medication. 
Study medication discontinuation may occur due to: 
• Unacceptable toxicity related to study treatment 
• Intolerable or persistent adverse events of any severity 
• General or specific changes in the patient's condition rendering the patient 
unacceptable for further treatment in the judgment of the Investigator 
• The request of the patient 
Patients who permanently discontinue study medication are not required to withdraw 
from the study.  Ideally, subjects who have permanently discontinued study medication 
will continue to complete important efficacy and safety assessments through the follow-
up contact.  
• If a patient withdraws from the study and has received at least one dose of the 
study medication they may: 
o continue in the study without taking study medication and complete 
important efficacy and safety assessments through the follow up contact, 
or  
o continue to allow the study to record data associated with their standard 
treatment course without completing any study required assessments with 
the exception of the follow up contact, or  
o participate in the follow up phone calls only approximately 30 and 60 days 
after enrolling in the study 
7.1.1 Study specific discontinuation of study medication criteria 
Patients should be withdrawn from study medication for the following reasons: 
• If they experience a clinically significant progression of disease such as: 
o Kidney or liver or multi-organ failure  
o Need for mechanical ventilation 
o Stage 5, end stage kidney disease (GFR <15 mL/min)  
o ALT and/or AST increases to > 5 times upper limits of normal 
• Pregnancy in a female patient 
• If a patient who does not meet eligibility criteria is inadvertently randomized and 
received study medication 
Other criteria that may or may not require permanent discontinuation of study medication 
include but are not limited to: 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 37 of 73 
Adverse event, lack of efficacy, protocol deviation, non-compliance, study 
closed/terminated, investigator discretion, or patient withdrawal of consent. 
 
7.2 
Patient Discontinuation/Withdrawal from the Study  
A patient may withdraw from the study at any time at his/her own request, may 
permanently discontinue study medication but wish to remain in the study, or may be 
withdrawn from administration of study medication or from all study participation at the 
discretion of the Investigator at any time for safety, behavioral, compliance, or 
administrative reasons.  
Withdrawn patients may need to be replaced, depending on the actual discontinuation 
rate. 
See the SoA (Section 1.3) for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
• If the patient withdraws consent for disclosure of future information, the Sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• If a patient withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the Investigator must document this in the study 
center study records. 
 
7.3 
Lost to Follow-up 
• A patient will be considered lost to follow-up if he or she is unable to be contacted 
by the study center. 
• Before a patient is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the patient. These contact attempts should 
be documented in the patient’s medical record. 
• Should the patient continue to be unreachable, a telephone call to medical contacts 
listed in medical record will be performed to determine vital status.  If dead – 
marked as death and date recorded.  If unreachable, a vital records check may be 
conducted to determine if a death has occurred approximately 60 days following 
the 1st dose of study medication.   
• If no death record is found and the patient or medical contact continues to be 
unreachable approximately 60 days following the 1st dose of study medication, 
he/she will be considered to have been lost to follow-up and withdrawn from the 
study. 
 
7.4 
Termination of the Study 
Given the potential severity of COVID-19 and limited information about the expected 
clinical course, there are no pre-specified study stopping rules. Instead there will be close 
oversight by the protocol team composed of the Sponsor’s Medical Monitor, the 
Investigator and 2 independent physicians, and frequent reviews of the safety data 
(Section 11). 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 38 of 73 
Conditions that may warrant termination of the study include, but are not limited to: 
• The discovery of an unexpected, serious, or unacceptable risk to patients enrolled 
in the study; 
• The decision on the part of the Sponsor to suspend or discontinue testing, 
evaluation, or development of ensifentrine; 
• Serious failure of the Investigator to comply with the International Council on 
Harmonization (ICH) Guidelines on Good Clinical Practice (GCP) or local 
regulations; 
• Submission of knowingly false information from the research facility to the 
Sponsor, the Independent Ethics Committee (IEC) or any national regulatory 
officials; 
• Major, repeated, non-adherence to the protocol. 
The Sponsor must be informed immediately in the event of any major protocol deviation 
or serious breach of ICH GCP. 
Study termination and follow-up will be performed in compliance with the conditions set 
forth in ICH GCP. The decision to discontinue the study is at the discretion of the 
Sponsor, the Investigator, the regulatory authority or IEC and should if possible be taken 
by mutual agreement. A record of such a discussion will be prepared and stored in the 
study file. The Sponsor will ensure the regulatory authorities and IECs are notified.

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 39 of 73 
8 
STUDY ASSESSMENTS AND PROCEDURES 
• The SoA is in Section 1.3. 
• Protocol amendments, waivers or exemptions are discussed in Section 9.  Regulatory, 
ethical and study oversight details are included in Appendix 2. 
• Safety concerns related to use of the study medication should be discussed with the 
Sponsor immediately upon occurrence or awareness to determine if the patient should 
continue or discontinue study medication.  The Investigator may discontinue study 
medication for a patient if deemed necessary.  The treatment of any given subject may 
be stopped for SAEs, clinically significant adverse events, severe laboratory 
abnormalities, or any other medical conditions that indicate to the Investigator that 
continued dosing is not in the best interest of the patient. In addition, a subject in this 
clinical study may discontinue study drug at their request for any reason. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct as well as compliance discussed in Section 9 
and Appendix 2 and regulatory requirements included in Appendix 2. 
• All screening evaluations must be completed and reviewed to confirm that potential 
patients meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the patient’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the SoA.  
• The maximum amount of blood collected for study related procedures from each 
patient, will not exceed 500 mL. Repeat or unscheduled samples may be taken for 
safety reasons or for technical issues with the samples. 
• Should a death occur in a study patient, data should be collected on whether the death 
occurred after withdrawal study medication and, if so, the reason for study drug 
withdrawal.  Withdrawal of care, comfort care, do not resuscitate (DNR) orders will 
be captured in the event of a death. 
• The site will attempt to follow-up on clinical status, but at a minimum the vital status 
of patients that do not have a telephone follow-up approximately 60 days following 
randomization and at least one dose of study medication. 
• See Section 5.3 for specific information to be collected for screen failures. 
 
8.1 
Collection of Data 
Patients will be assessed daily while hospitalized. Clinical data will be recorded using 
eCRFs adapted from the WHO-ISARIC (World Health Organization–International Severe 
Acute Respiratory and Emerging Infections Consortium) case record form 
(https://isaric.tghn.org). 
Screening and baseline information will be collected and recorded on the eCRF.  This 
will include the following information: 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 40 of 73 
• Informed consent review, eligibility review, including screening liver, kidney and 
pregnancy (if applicable) laboratory tests, and categorization of their positive 
COVID-19 disease severity (according to the FDA’s document: COVID-19: 
Developing Drugs and Biological Products for Treatment or Prevention Guidance 
for Industry, May 2020). Refer to Section 8.1.2 for severity definitions. 
• Demographics, hospital admission date (for COVID-19 infection), medical and 
smoking history, standard of care medications and treatments and type of facility 
transferred from. 
• Existing co-morbidities and any medication taken for those listed as well as 
medications taken since admission. 
Randomization information will be recorded on an eCRF.  If study medication is 
dispensed, it will be recorded on this form. 
Starting on Day 1 to discharge, Day 29 or withdrawal of consent, site staff will record on 
an eCRF daily the following information: 
• Clinical status (7-point ordinal scale) each morning (Section 8.1.1). 
• Vital signs each morning at approximately the same time (Section 8.1.3).  
• Concomitant medications taken as part of  SoC for COVID-19 infection treatment 
(Section 6.5.1 and Section 8.1.4). 
• Supportive treatments received as part of SoC for COVID-19 infection treatment 
or new infection that develops while hospitalized (Section 8.1.4).  
• Routine laboratory, infection and imaging test results received as part of SoC 
(Section 8.1.4). 
• Study medication doses taken and when. 
• On the day of discharge or Day 29, safety laboratory tests may be performed at the 
discretion of the treating physician and, if completed, may be completed within 24 
hours of the patient’s discharge from the hospital. 
• Adverse events. 
At discharge site staff will schedule a follow-up and complete an eCRF page including 
the following: 
• Date of discharge and reason (e.g., COVID-19 negative, improved enough for 
discharge, etc.) 
• Where the patient was discharged to (e.g., home, rehab center, etc.) 
• If the patient was COVID-19 positive or negative at discharge (yes/no/unknown) 
• Which medications the patient was discharged with 
• If supplemental oxygen or other supportive treatment was prescribed for treatment 
after discharge 
At the follow-up calls, site staff will complete eCRF pages including the following: 
• Date of follow-up 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 41 of 73 
• How patient is doing, their clinical (7-point ordinal scale) or minimally recording 
their vital status. 
• Whether the patient had been re-hospitalized following discharge. 
• Any adverse events or pregnancy 
• A disposition eCRF for how the patient completed or did not complete (with 
reason) the study. 
8.1.1 7-point ordinal scale of clinical improvement 
Clinical status will be assessed using a 7-point ordinal scale. The ordinal scale is an 
assessment of the clinical status at the first assessment of a given study day. Each day, the 
worse score for the previous day will be recorded (i.e., on Day 3, Day 2 score is obtained 
and recorded as Day 2).  The ordinal scale is adapted from the WHO R&D Blueprint 
expert group which measures illness severity over time 
(https://www.who.int/blueprint/priority-diseases/key-
action/COVID19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.
pdf). The scale is listed in Table 10.  
 
Table 10. 7-point ordinal scale. 
1 
not hospitalized, no limitations of activities 
2 
not hospitalized, limitation of activities, home oxygen requirement, or both 
3 
hospitalized, not requiring supplemental oxygen but requiring ongoing medical 
care 
4 
hospitalized, requiring any supplemental oxygen 
5 
hospitalized, requiring non-invasive ventilation or use of high-flow oxygen 
devices 
6 
hospitalized, receiving invasive mechanical ventilation or extracorporeal 
membrane oxygenation (ECMO); and 
7 
death 
 
8.1.2 Categorizing COVID-19 disease severity 
Categorization of PCR positive COVID-19 disease severity will be in accordance with the 
FDA’s document: COVID-19: Developing Drugs and Biological Products for Treatment 
or Prevention Guidance for Industry (May 2020). Patients with Critical Disease would 
meet exclusion criteria and not eligible for participation. 
• Mild disease (meeting all inclusion and no exclusion criteria): Symptoms of mild 
illness that could include fever, cough, sore throat, malaise, headache, muscle 
pain, gastrointestinal symptoms, without shortness of breath or dyspnea and no 
clinical signs indicative of moderate, severe, or critical severity. 
• Moderate disease (meeting all inclusion and no exclusion criteria): could include 
any symptom of mild illness or shortness of breath with exertion.  Clinical signs 
suggestive of moderate illness, such as respiratory rate ≥ 20 breaths per minute, 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 42 of 73 
saturation of oxygen (SpO2) > 93% on room air at sea level, heart rate ≥ 90 beats 
per minute and no clinical signs indicative of severe or critical severity. 
• Severe disease (meeting all inclusion and no exclusion criteria): could include any 
symptom of moderate illness or shortness of breath at rest, or respiratory distress.  
Clinical signs indicative of severe systemic illness, such as respiratory rate ≥ 30 
per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room air at sea level or 
PaO2/FiO2 < 300 and no criteria of critical severity. 
• Critical disease: evidence of critical illness, defined by at least one of the 
following: 1) respiratory failure defined based on resource utilization requiring at 
least one of the following: endotracheal intubation and mechanical ventilation, 
oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen 
delivered via reinforced nasal cannula at flow rates > 20 L/min with fraction of 
delivered oxygen ≥ 0.5), noninvasive positive pressure ventilation, ECMO, or 
clinical diagnosis of respiratory failure (i.e., clinical need for one of the preceding 
therapies, but preceding therapies not able to be administered in setting of 
resource limitation); 2) shock (defined by systolic blood pressure < 90 mm Hg, or 
diastolic blood pressure < 60 mm Hg or requiring vasopressors); or 3) multi-organ 
dysfunction/failure. 
8.1.3 Vital sign assessment 
Vital signs will be assessed and recorded each morning at approximately the same time of 
a given study day. 
Vital signs to be assessed and recorded include: respiration rate (breaths per minute), 
oxygen saturation, supplemental oxygen use (yes/no), fraction of inhaled oxygen (FiO2), 
sternal capillary refill time, body temperature, dehydration, blood pressure, heart rate 
(beats per minute and level of consciousness graded on the AVPU scale (Alert, Verbal = 
voice response present, Pain = pain response present, Unresponsive) (worst score on the 
assessment day for each).  
8.1.4 Recording SoC medications, treatments & laboratory test results 
Concomitant medications/therapy will be recorded daily (Section 6.5). The list of 
prohibited medications/therapy is provided in Section 6.5.  Concomitant medications 
taken as part of SoC for COVID-19 infection treatment, and which may include: 
angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, antibiotics, 
anti-fungal agents, anti-viral agents (e.g., remdesivir), inhaled or oral corticosteroids, 
immune-suppressant agents, intravenous fluids, non-steroidal anti-inflammatory agents, 
or oral/orogastric fluids, or other medications (as specified). 
Status of supportive treatments received as part of SoC for COVID-19 infection treatment 
will be recorded daily (yes/no and details as applicable in the eCRF). These may include 
treatments such as: oxygen therapy and details, high flow oxygen use, non-invasive 
ventilation, invasive ventilation, prone positioning, inhaled nitric oxide, tracheostomy 
inserted, ECLS/ECMO, renal replacement therapy or dialysis, vasopressor/inotropic agent 
use, use of neuromuscular blocking agents, other interventions or procedures (specified). 
Any blood gas analyses and results and any new infection occurring during participation, 
regardless of organism (i.e. viral or non-viral), should be captured along with the site of 
infection and source of culture (e.g., BAL, tracheal aspirate, sputum, blood, urine etc.). 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 43 of 73 
Routine laboratory and imaging tests performed as recommended by the treating 
physician (refer to Appendix 3) will be recorded as they are performed.  Some tests may 
be recorded more frequently (e.g., white blood cell count, neutrophil count, lymphocyte 
count, creatinine values) than others (e.g., inflammatory markers and liver function tests).   
 
8.2 
Screening/baseline and Day 1  
Activities related to the screening/baseline and Day 1 visits are listed in Table 11 and 
Table 12. The Screening/baseline eCRF and the Daily eCRF must be completed pre-
randomization and pre-study medication dose (if applicable).   
 
Table 11. Screening/baseline visit activities. 
Assessment 
Information 
Informed Consent 
• Informed consent must be obtained according to the 
Informed Consent Process described in Appendix 2. 
• Counsel subjects to use adequate birth control methods 
required during the trial to avoid pregnancy. 
• Women of childbearing potential must agree to 
abstinence or to use at least one primary form of 
contraception for the duration of the study. Patients who 
are randomized must continue this for 60 days 
following the first dose (acceptable methods will be 
determined by the site). 
Demographic variables 
• Document the patient’s demographic variables will 
include items such as age, sex, ethnicity, height, weight, 
body mass index, and race. 
Medical, surgical and 
smoking history 
• Document the patient’s history of relevant current or 
past medical conditions, surgical history, and smoking 
history (current or former [yes or no]) will be obtained. 
Former smokers are defined as those who have stopped 
smoking for at least 6 months prior to Screening.  
• Minor surgical procedures (e.g., tonsillectomy, 
appendectomy) performed more than 5 years prior to 
Screening do not need to be recorded. 
• Medical condition(s) identified during Screening will be 
documented as medical history and not as an adverse 
event(s) unless the condition worsens during the trial 
and meets the definition of an adverse event. 
Hospital admission 
information 
• Document the reason for hospital admission (e.g., 
COVID-19 symptoms and diagnosis). Refer to Inclusion 
criteria in Section 5.1. 
• Document the most recent laboratory and imaging 
(radiology, hematology, chemistry, serology, urine, etc.) 
test results since hospital admission (Section 8.1.4). 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 44 of 73 
SoC concomitant 
medication & supportive 
treatment assessment  
• SoC concomitant medications and administered 
treatments must be recorded (Section 8.1.4). 
• Document the medications taken (for COVID-19 
treatment) since admission along with the time, dose, 
and duration of their administration. 
Brief physical 
examination 
• Document the results of a physical examination 
performed within 4 days of randomization. 
• Assess the patient’s heart and lungs and document. 
Safety laboratory 
assessments 
• Perform Screening Hematology, Chemistry (non-
fasting), Urine Analysis, Serum Pregnancy Test (as 
applicable) and document findings (see Appendix 3 and 
Exclusion criteria in Section 5.2). 
Inclusion/Exclusion 
criteria  
• Assess eligibility of the patient eligibility using the 
Inclusion (Section 5.1) and Exclusion criteria (Section 
5.2). 
• Categorization of disease severity (Section 8.1.2). 
Clinical status 
assessment (7-point 
ordinal scale) 
• Clinical status will be assessed and recorded using the 
7-point ordinal scale at the first assessment of a given 
study day.  
• See Section 8.1.1. 
Vital sign assessment  
• Vital signs will be assessed and recorded each morning 
at approximately the same time of a given study day.  
• See Section 8.1.3. 
 
Day 1 may take place on the same day as the screening/baseline visit, if appropriate.  If 
Day 1 activities take place on the same day as screening/baseline visit, only one 7-point 
ordinal scale assessment and vital signs are necessary, but they must be completed prior 
to dosing, if the patient is randomized to Treatment Arm 1. 
 
Table 12. Day 1 visit activities. 
Assessment 
Information 
Randomization 
• Patients meeting all Inclusion criteria (Section 5.1) and 
none of the Exclusion criteria (Section 5.2) will be 
randomly assigned to one treatment arm prior to study 
medication treatment. 
SoC concomitant 
medication & supportive 
treatment assessment 
• SoC concomitant medications and administered 
treatments must be recorded (Section 8.1.4). 
• Document any care decisions that are made due to 
resource limitation. 
Clinical status 
assessment (7-point 
ordinal scale) 
• Clinical status will be assessed and recorded using the 
7-point ordinal scale at the first assessment of a given 
study day.  
• See Section 8.1.1. 
Vital sign assessment  
• Vital signs will be assessed and recorded each morning 
at approximately the same time of a given study day.  
• See Section 8.1.3. 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 45 of 73 
Blinded study medication 
dispensing  
• Study medication dispensed by study staff. 
Blinded study medication 
training 
• pMDI Observation & Training by study staff. 
Blinded study medication 
dosing  
• Blinded study medication administered via pMDI in the 
morning (4 puffs) and approximately 12 hours later in 
the evening (4 puffs). 
• Document date and time taken. 
Adverse Events 
assessments 
• The method of detecting adverse event will be 
performed as described in Section 8.6 and Appendix 4. 
 
 
8.3 Study Treatment & Day of Discharge from Hospital 
Activities related to Days 2-29 or until discharge are listed in Table 13. At each daily 
visit, the Daily eCRF must be completed.  
 
Table 13.  Days 2-29 or until discharge daily activities.  
Assessment 
Information 
SoC concomitant 
medication & supportive 
treatment assessment 
• Taken as prescribed and recorded daily, as above for 
Day 1. 
• Any new infection occurring during participation, 
regardless of organism (i.e. viral or non-viral), should 
be captured. Additionally, the site of infection and 
source of culture (e.g., BAL, tracheal aspirate, sputum, 
blood, urine etc.) should be recorded. 
SoC laboratory results  
• Routine laboratory and imaging tests performed as 
recommended by the treating physician (Section 8.1.4 
and Appendix 3).   
Clinical status 
assessment (7-point 
ordinal scale) 
• Assessed and documented daily, as above for Day 1. 
Vital sign assessment  
• Assessed and documented daily, as above for Day 1. 
Blinded study medication 
dispensing & collection 
• Blinded study medication dispensed and collected by 
study staff on Days 12 and 24 and discharge. 
• Dispensing and collection data is documented. 
Blinded study medication 
dosing 
• Taken daily, as above for Day 1. On the Day of 
Discharge, study medication may be dosed as deemed 
appropriate by Investigator. 
• Document date and time taken. 
Adverse Events 
assessments 
• Assessed and recorded daily, as above for Day 1. 
 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 46 of 73 
8.4 Discharge Activities 
For the Day of Discharge (Day 29 or the last day in the hospital if discharged before Day 
29), the Daily eCRF will be completed as above (Table 13) as well as a Discharge eCRF 
to document how the patient was discharged (Table 14).  
 
Table 14.  Day of discharge activities. 
Assessment 
Information 
Record discharge 
information 
• 
Discharged (yes/no).*  
• 
If discharged, the Date of discharge and reason (e.g., 
COVID-19 negative, recovered, not discharged 
[remains hospitalized] etc.) is noted. Date of scheduled 
follow-up telephone call. 
• 
Where the patient was discharged to (e.g., home, rehab 
center, etc.). 
• 
If the patient was COVID-19 positive or negative at 
discharge (yes/no/unknown). 
• 
Which medications the patient was discharged with. 
• 
If supplemental oxygen was prescribed for treatment 
after discharge. 
 
* Patients not discharged from the hospital by Day 29 
Some study patients may not be ready for discharge from the hospital by Day 29.  In these 
instances, study treatment and data collection procedures still end on Day 29 (with the 
exception of contacts in the next section).  This information will be noted in the 
Discharge eCRF as “study treatment complete, but patient remains hospitalized.”  This 
would also be captured in the Day 29 Clinical status assessment (7-point ordinal scale).  
Patients that remain hospitalized after Day 29 will be contacted as described in the next 
section. 
 
8.5 
Post Discharge/Day 29 Contacts  
Following Day 29 or discharge from the hospital (if earlier), there will be three points of 
contact with all study patients, regardless of hospitalization status. Each contact will require 
the completion of a Follow-up eCRF (Table 15). 
• Discharge Contact: 4 to 10 days after discharge from hospital, if discharged within the 
29-day treatment period.  
o If the patient remains hospitalized after Day 29, study treatment and data 
collection procedures still end on Day 29 (with the exception of contacts in 
this section) and contact with the patient will take place 4 to 10 days after 
receipt of last dose of study medication (Day 29). 
• Day 29 Contact: 26 to 32 days after first dose of study medication.  If the Discharge 
Contact and Day 29 Contact fall within same window, this contact will be combined to 
the Day 29. 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 47 of 73 
• Day 60 Follow-up: 55 to 65 days after first dose of study medication. 
o Should a patient or their medical contact be unable to be contacted at any 
of these timepoints, a vital records search will be performed to determine 
the patient’s vital status approximately 60 days after first dose of study 
medication. 
 
Table 15.  Post-discharge follow-up activities. 
Assessment 
Information 
Follow-up date 
• Date of follow-up contact 
 
Clinical status 
assessment (7-point 
ordinal scale) 
• Assessed and documented, as above for Day 1  
(clinical and vital status) 
Re-hospitalization status 
or remains in hospital 
• Any incidence of re-admission to the hospital following 
a 24-hour period of discharge (date and duration) that is 
related to COVID-19 
• Date of discharge (if after Day 29) should be noted in 
the Follow-up eCRF. 
Adverse Events 
assessments 
• Documented, as above for Day 1  
 
 
8.6 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 4. The SoA is Table 3 in 
Section 1.3. 
Adverse events will be reported by the patient and/or investigator and recorded on the AE 
CRF.  
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 patient to discontinue the study (Appendix 4).  
As stated in Section 8.6, medical condition(s) identified during the screening visit will be 
documented as medical history and not as an adverse event(s) unless the condition 
worsens during the trial and meets the definition of an adverse event. 
8.6.1 Time period and frequency for collecting AE and SAE information 
For this study, AEs and SAEs will be collected from the time of the first dose of study 
medication through the follow-up (end of study) visit. 
SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests or change in existing therapy) will be collected from the time of 
consent through the follow-up visit. 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 48 of 73 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix 4. The Investigator will submit any updated SAE data to the 
Sponsor designee within 24 hours of it being available.  
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a patient has been discharged from the study, and he/she considers the event to 
be reasonably related to the study medication or study participation, the Investigator must 
promptly notify the Sponsor.  
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4. 
8.6.2 Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.  
8.6.3 Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
patient at subsequent visits/contacts. All SAEs, will be followed until resolution, 
stabilization, the event is otherwise explained, through the follow-up visit, or the patient 
is lost to follow-up (as defined in Section 7.3). Further information on follow-up of AEs 
and SAEs are given in Appendix 4. 
8.6.4 Regulatory reporting requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of patients and the 
safety of a study medication under clinical investigation are met. The Investigator will 
submit any updated SAE data to the Sponsor designee within 24 hours of it being 
available.  
• 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 Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
8.6.5 Pregnancy 
• Details of all pregnancies in female patients will be collected after the start of study 
medication and until 30 days after the last dose of study medication.  

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 49 of 73 
• 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 5. 
• Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.6.6 Adverse Events of special interest 
Adverse events of special interest have not been identified for ensifentrine.  
 
8.7 
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.  
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 50 of 73 
9 
PROTOCOL EXEMPTIONS/WAIVERS 
The investigator should not implement any deviation from, or changes of, the protocol 
without agreement by the sponsor and prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an 
immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or 
administrative aspects of the trial (e.g., change in monitor(s), change of telephone 
number(s)).  
• The investigator, or person designated by the investigator, should document and 
explain any deviation from the approved protocol.  
• The investigator may implement a deviation from, or a change in, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB/IEC 
approval/favorable opinion. As soon as possible, the implemented deviation or 
change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) 
should be submitted:  
(a) To the IRB/IEC for review and approval/favorable opinion;  
(b) To the sponsor for agreement and, if required;  
(c) To the regulatory authority(ies) 
Regulatory, ethical and study oversight details are included in Appendix 2. 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 51 of 73 
10 STATISTICAL CONSIDERATIONS 
10.1 Statistical Hypotheses 
All analyses are considered exploratory and hypothesis-generating. All tests will be two-
sided at 5% significance level. Hypothesis tested for the primary endpoint will be if 
addition of ensifentrine to SoC for up to 29 days could increase the proportion of patients 
with recovery versus standard of care plus placebo. The status according to the 7-point 
ordinal scale of all patients regardless of treatment withdrawal will be followed up during 
the scheduled treatment period (Day 29) and at a follow-up Day 60, or as far as possible. 
Secondary endpoints are tested independently and there will be no adjustment for 
multiple tests. 
Study days for analyses include Day 1 (start dose), Day 7 (6 to 8 days after 1st dose), Day 
14 (13 to 15 days after 1st dose) and Day 29. 
 
10.2 Study Populations 
Modified intent to treat (mITT):  
• Will consist of all randomized and treated patients. Efficacy will be evaluated as 
randomized. 
Per protocol population (PP):  
• Will consist of all patients in mITT without any major protocol deviations deemed to 
have an effect on efficacy analyses. 
Safety set (SS):  
• Will consist of all randomized and treated patients. Safety will be evaluated by actual 
treatment. 
 
10.3 Sample Size Determination 
This is a pilot study and it is not powered based on any specific endpoint. Sample size has 
been set to minimize the number of patients exposed, but still large enough to give 
reliable estimates on the efficacy and safety of ensifentrine in the target population. 
 
10.4 Efficacy 
The proportion of patients with recovery at Day 29 will be compared between treatment 
groups using a logistic regression model adjusting for treatment. The treatment difference 
will be expressed as an odds ratio with 95% confidence intervals and associated two-
sided p-value. Potential stratification variables such as age group and/or gender may be 
considered depending on the randomization outcome, details will be given in the 
Statistical Analysis Plan. 
The time to recovery from Day 1 to Day 29 will be compared between treatment groups 
using a log-rank test; patients not in recovery at end-of study/withdrawal will be censored 
at last observed time point in the treatment period or at last time status was assessed if 
collected post treatment-withdrawal. Patients with death as outcome will be censored at 
the scheduled end-of-study day 29. Data will be illustrated using Kaplan-Meier plots and 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 52 of 73 
the median time to recovery estimated if appropriate. Stratification in the model with 
respect to age group and/or gender may be considered based on the randomization 
outcome.  
Secondary endpoints of survival type will be compared between treatments using the log 
rank test similar to the time to recovery endpoint. Secondary endpoints assessing 
proportion of patients fulfilling an event will be compared between treatments using a 
logistic regression. Continuous outcomes will be compared between treatments using 
ANCOVA models with treatment and stratification groups as factors and baseline as a 
covariate. Estimated treatment difference with 95% confidence intervals and associated 2-
sided p-value will be given. Endpoints assessing duration of (days with) additional 
oxygen use/ventilator need will be compared between treatments using Wilcoxon rank 
sum test.  
 
10.5 Safety  
Safety endpoints include SAEs and AEs (Appendix 4). Adverse events will be analyzed 
using quantitative and qualitative measures. Treatment-emergent adverse events will be 
summarized by treatment group for all AEs, related AEs, serious adverse events, deaths, 
adverse events leading to discontinuation of study medication or to withdrawal from 
study, adverse events of different severity and adverse events of different chronicity. 
Treatment-emergent adverse events will be coded using MedDRA and summarized by 
system organ class and preferred term for each treatment group. For selected adverse 
events, time to first event may be visualized using Kaplan-Meier plots and tested between 
treatment using the log-rank test. 
Available laboratory data will be summarized by each visit including change from 
baseline. The number of normal, abnormal not clinically significant and abnormal 
clinically significant values on each parameter will be summarized for change over study 
using shift tables. All data will be listed and values outside reference ranges will be 
highlighted in the listings. 
Vital signs will be summarized by each visit including change from baseline. All data will 
be listed and values outside reference ranges will be highlighted in the listings.  
10.5.1 Missing Data 
The patients withdrawn from treatment will be followed up regarding their status 
according to the 7-point ordinal scale at Day 29 as far as possible (exceptions for patients 
with withdrawn consent or lost to follow-up) and this data will be the primary source for 
handling missing data in the study. Status on the 7-point scale, including vital status, will 
also be collected at the Day 60 follow-up.  In survival analysis, patients with death as 
outcome will be censored at Day 29 (Day 60), unless the required event was reached prior 
to death. In analyses of oxygen need, patients in ventilator care or with death as outcome 
will be considered in oxygen need. In analyses of ventilator need, patient with death will 
be considered in ventilator need. Further details on imputation will be given in the 
Statistical Analysis Plan. 
 
10.6 Interim Analyses 
There will be no formal interim analysis in the study.  

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 53 of 73 
11 DATA MONITORING COMMITTEE  
Ensifentrine has been studied in over 1000 patients with COPD, which is a group known 
to have severely compromised lung physiology and multiple comorbidities, including in 
over 600 patients for 4 weeks duration. Because the safety profile in this population has 
been shown to be similar to placebo over the maximal study duration and expected 
exposure for this study with a 2 mg twice daily pMDI dose is similar to that expected 
from a twice daily 3 mg nebulized dose in COPD patients, a formal data safety 
monitoring board is not planned. 
This is a single site study with a small number of patients.  Given the potential severity of 
COVID-19 and limited information about the expected clinical course, a protocol team 
composed of the Sponsor’s Medical Monitor, the Investigator and 2 independent 
physicians, will review blinded pools of AE data at regular intervals (approximately every 
10 patients randomized) to evaluate whether a significant number of unexpected AEs are 
occurring (AEs that do not fit with the known course of COVID-19).  
If there are a significant number of unexpected AEs, the protocol team will be asked to 
review unblinded safety data in an ad hoc meeting. The committee can recommend dose 
reduction, or stopping the study for safety or unblinding concerns. The study will not stop 
enrollment awaiting these reviews, although the protocol team may recommend 
temporary or permanent cessation of enrollment based on their safety reviews. 
 
 
 
 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 54 of 73 
12 REFERENCE LIST 
1 
Abbott-Banner KH, Page CP. Dual PDE3/4 and PDE4 inhibitors: novel treatments 
for COPD and other inflammatory airway diseases. Basic Clin Pharmacol Toxicol. 
2014 May; 114 (5): 365-76.  doi: 10.1111/bcpt.12209.   
2 
Bjermer L, Abbott-Banner K, Newman K. Efficacy and safety of a first-in-class 
inhaled PDE3/4 inhibitor (ensifentrine) vs salbutamol in asthma. Pulm Pharmacol 
Ther. 2019 Oct; 58: 101814. doi: 10.1016/j.pupt.2019.101814.   
3 
Boswell-Smith V, Spina D, Oxford AW, Comer MB, Seeds EA, Page CP. The 
pharmacology of two novel long-acting phosphodiesterase 3/4 inhibitors, RPL554 
[9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-
3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-
dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-
a]isoquinolin-4-one]. J Pharmacol Exp Ther. 2006 Aug; 318 (2): 840-8.  DOI: 
10.1124/jpet.105.099192.   
4 
Edwards MR, Facchinetti F, Civelli M, et al. Anti-inflammatory effects of the 
novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus-inducible 
cytokines. Pharmacol Res Perspect. 2016 Jan 15;4(1): e00202. doi: 
10.1002/prp2.202.  
5 
Franciosi LG, Diamant Z, Banner KH, Zuiker R, Morelli N, Kamerling IM, de 
Kam ML, Burggraaf J, Cohen AF, Cazzola M, Calzetta L, Singh D, Spina D, 
Walker MJ, Page CP. Efficacy and safety of RPL554, a dual PDE3 and PDE4 
inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive 
pulmonary disease: findings from four clinical trials. Lancet Respir Med. 2013 
Nov; 1 (9): 714-27.  doi: 10.1016/S2213-2600(13)70187-5.   
6 
Gianello V, Salvi V, Parola C, et al. The PDE4 inhibitor CHF6001 modulates pro-
inflammatory cytokines, chemokines and Th1- and Th17-polarizing cytokines in 
human dendritic cells. Biochem Pharmacol. 2019 May; 163:371-380. 
7 
Gong J, Dong H, Qing Xia S, et al. Correlation Analysis Between Disease 
Severity and Inflammation-related Parameters in Patients with COVID-19 
Pneumonia. Med Rxiv 2020.02.25.20025643; doi: 
https://doi.org/10.1101/2020.02.25.20025643. 
8 
Mata M, Martinez I, Melero JA, et al. Roflumilast Inhibits Respiratory Syncytial 
Virus Infection in Human Differentiated Bronchial Epithelial Cells. PLoS One. 
2013; 8(7): e69670. doi: 10.1371/journal.pone.0069670. 
9 
Matera MG, Page C, Cazzola M. PDE inhibitors currently in early clinical trials 
for the treatment of asthma. Expert Opin Investig Drugs. 2014 Sep; 23 (9): 1267-
75. doi: 10.1517/13543784.2014.921157.  
10 Pedersen S. Inhalers and nebulizers: Which to choose and why? Respiratory 
Medicine, 1996; 90: 69-77. 
11 Savelikhina I, Ostrovskyy M, Ostrovska K, et al. Proinflammatory cytokine IL-6 
detection in severe COPD patients: Focus on roflumilast. European Respiratory 
Journal 2018 52: OA3267; DOI: 10.1183/13993003.congress-2018.OA3267. 
12 Singh D, Abbott-Banner K, Bengtsson T, Newman K. The short-term 
bronchodilator effects of the dual phosphodiesterase 3 and 4 inhibitor RPL554 in 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 55 of 73 
COPD. Eur Respir J. 2018 Nov 1; 52 (5). pii: 1801074.  doi: 
10.1183/13993003.01074-2018.   
13 Singh D, Martinez FJ, Watz H, Bengtsson T, Maurer BT. A dose-ranging study of 
the inhaled dual phosphodiesterase 3 and 4 inhibitor ensifentrine in COPD. Respir 
Res. 2020 Feb 10;21(1):47. doi: 10.1186/s12931-020-1307-4. 
14 Turner MI, Matthes E, Billet A, et al. The dual phosphodiesterase 3 and 4 
inhibitor RPL554 stimulates CFTR and ciliary beating in primary cultures of 
bronchial epithelia. Am J Physiol Lung Cell Mol Physiol. 2016 Jan 1;310(1): L59-
70. doi: 10.1152/ajplung.00324.2015. 
15 Verona Pharma plc. Ensifentrine Clinical Investigators Brochure v. 19.0. 20th May 
2020. 
16 WHO ordinal scale: Coronavirus disease (COVID-2019) R&D. Geneva: World 
Health Organization (http://www.who.int/blueprint/priority-diseases/key-
action/novel-coronavirus/en/). 
17 WHO-ISARIC (World Health Organization–International Severe Acute 
Respiratory and Emerging Infections Consortium) case record form 
(https://isaric.tghn.org). Licensed under a Creative Commons Attribution-Share A 
like 4.0 International License by ISARIC on behalf of Oxford University. 
18 Zuo H, Cattani-Cavalieri I, Musheshe N, Nikolaev VO, Schmidt M. 
Phosphodiesterases as therapeutic targets for respiratory diseases. Pharmacol 
Ther. 2019 May; 197: 225-242. doi: 10.1016/j.pharmthera.2019.02.002.   
 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 56 of 73 
13 APPENDICES 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 57 of 73 
Appendix 1: Abbreviations 
 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BAL 
Bronchoalveolar Lavage 
BID 
Twice Daily 
CBC 
Complete Blood Count 
CFTR 
Cystic Fibrosis Transmembrane Conductance Regulator 
Cmax 
Maximum Serum Concentration 
COPD 
Chronic Obstructive Pulmonary Disease 
DPI 
Dry Powder Inhaler 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygenation 
GCP 
Good Clinical Practice 
HBE 
Human Bronchial Epithelial 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IRB/IEC 
Institutional Review Board/Ethics Committee 
LFT 
Liver Function Tests 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention to Treat 
mL 
Milliliter 
nM 
Nanomolar 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamics 
PDE4 
Phosphodiesterase 4 
PK 
Pharmacokinetics 
pMDI 
Pressurized Metered Dose Inhaler 
RNA 
Ribonucleic Acid 
RSV 
Respiratory Syncytial Virus 
SAE 
Serious Adverse Event 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 58 of 73 
SoA 
Schedule of Activities 
SoC 
Standard of Care 
SpO2 
Oxygen Saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
UAB 
University of Alabama at Birmingham 
ULN 
Upper Limit of Normal 
USA 
United States of America 
WBC 
White Blood Cell  
WHO 
World Health Organization 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 59 of 73 
Appendix 2: Regulatory, Ethical, and Study Oversight Consideration 
 
Regulatory and Ethical Considerations  
• This study will be conducted in accordance with the protocol and with the following:  
- Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines.  
- Applicable ICH Good Clinical Practice (GCP) Guidelines. 
- Applicable laws and regulations.  
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC and Regulatory 
Healthy Authority and reviewed and approved 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 patients.  
• The Investigator will be responsible for the following:  
- Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC.  
- Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures.  
- Providing oversight of the conduct of the study at the study center and adherence 
to requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, EU Clinical Trials Directive 2001/20/EC (if applicable), and all other 
applicable local regulations.  
• After reading the protocol, the Principal Investigator will sign the protocol signature 
page and send a copy of the signed page to the Sponsor or designee (Appendix 6). 
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 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.  
 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 60 of 73 
Financial Disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
 
Insurance  
Financial arrangements are detailed in the Investigator Agreement between the Sponsor 
and Investigator. 
The Sponsor will arrange clinical study insurance to compensate patients for any potential 
injury or death caused by the study.  
 
Informed Consent Process  
• The Investigator or his/her representative will explain the nature of the study to the 
patient and/or the patient’s legally authorized representative and answer all questions 
regarding the study.  
• Patients must be informed that their participation is voluntary. Patients will be 
required to sign a statement of informed consent that meets the requirements of 21 
CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study center.  
• The medical record must include a statement that written informed consent was 
obtained before the patient was entered in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign 
the ICF.  
• A copy of the original ICF(s) must be provided to the patient or the patient’s legally 
authorized representative.  
• ICF New Information: New information since the time of the original consent can be 
presented to patients in format(s) or method(s) including, but not limited to those 
listed below unless excluded by local requirements: 
- Revised consent document 
- Addendum to consent 
- Memo or other communication to subjects 
- Orally by phone or in person 
Documentation of the method the new information was presented to the patient along 
with the name of the site staff member and date the new information was presented to the 
patient must be documented in the patient’s source document. 
 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 61 of 73 
Data Protection 
• Patients will be assigned a unique identifier by the Sponsor. Any patient records or 
datasets that are transferred to the Sponsor will contain the identifier only; patient 
names or any information which would make the patient identifiable will not be 
transferred.  
• The patient must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the patient.  
• The patient must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
• 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.  
• The Sponsor/Sponsor’s designee will not provide individual genotype results to 
patients, any insurance company, any employer, their family members, general 
physician, or any other third party, unless required to do so by law.  
 
Administrative Structure  
Table 16. Study administrative structure. 
Function 
Responsible Organization 
Study Operations Management  
Verona Pharma 
Medical Monitoring 
Verona Pharma 
Safety Reporting 
IQVIA 
Study Master File 
Verona Pharma 
Randomization Code 
UAB 
Data Management 
UAB 
Clinical Supply Management 
Verona Pharma 
Quality Assurance Auditing 
Verona Pharma 
Biostatistics 
UAB 
Medical Writing 
Verona Pharma 
Laboratory Assessments 
UAB 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 62 of 73 
Table 17. Medical monitor. 
Primary Medical Monitor: 
Kathleen Rickard, MD 
Chief Medical Officer, Verona Pharma 
8045 Arco Corporate Drive, Suite 130 
Raleigh, NC 27617 
T- +1 646 740-7081 
E- kathleen.rickard@veronapharma.com 
24-hour Urgent Medical Contact 
Kathleen Rickard, MD 
 
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 trial, which is defined as the date of final data collection for the primary outcome 
measure.  
 
Data Quality Assurance  
• All patient data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the Sponsor or designee electronically (e.g. laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct 
and will need to confirm that the blinding procedures have or have not been 
maintained for each patient by physically or electronically signing the eCRF.  
• The Investigator must maintain accurate documentation (source data) that 
supports the information entered in 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 
patients are being protected; and that the study is being conducted in accordance 
with the currently approved protocol and any other study agreements, ICH GCP, 
and all applicable regulatory requirements.  
• 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.  

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 63 of 73 
Source Documents  
The Investigator/institution should maintain adequate and accurate source documents and 
study records that include all pertinent observations on each of the study center’s patients. 
Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete. Changes to source data should be traceable, should not obscure the original 
entry, and should be explained if necessary (e.g. via an audit trail).  
• Source documents provide evidence for the existence of the patient and 
substantiate the integrity of the data collected. Source documents are filed at the 
Investigator’s study center.  
• 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 patients by the Investigator.  
• Discontinuation of further study medication development.  
 
Publication Policy  
The data generated by this study are confidential information of the Sponsor.  

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 64 of 73 
Appendix 3: Laboratory Tests 
Specified laboratory tests conducted as part of COVID-19 standard of care will be 
recorded in the electronic case record as these are conducted. The laboratory reports must 
be filed with the source documents. 
The following safety laboratory tests are required for eligibility verification and upon 
discharge at the discretion of the treating physician and, if completed, may be completed 
within 24 hours of the patient’s discharge from the hospital if not already conducted as 
part of standard of care: 
• Alanine Aminotransferase (ALT)/Serum glutamic-pyruvic transaminase (SGPT) 
(U/L) 
• Aspartate Transaminase (AST)/Serum glutamic-oxaloacetic transaminase (SGOT) 
(U/L) 
• Creatinine (μmol/L) 
• Serum pregnancy testing (as applicable) 
 
Standard of care laboratory tests may include: 
• Activated partial thromboplastin ratio (APTR) 
• Activated partial thromboplastin time (APTT) (seconds) 
• ALT/SGPT (U/L) 
• AST/SGOT (U/L) 
• Basic metabolic panel (BMP) 
• C-reactive protein (CRP) (mg/L) 
• Creatine kinase (U/L) 
• Creatinine (μmol/L) 
• D-dimer (mg/L) 
• Ferritin (ng/mL) 
• Glucose (mmol/L)  
• Hematocrit (%) 
• Hemoglobin (g/L) 
• Interleukin 6 (IL-6) (pg/mL) 
• International normalized ratio (INR)Troponin I (ng/mL) 
• Lactate (mmol/L) 
• Lactate dehydrogenase (LDH) (U/L) 
• Lymphocyte count (109/L) 
• Neutrophil count (109/L) 
• Platelets (x109/L) 
• Potassium (mmol/L) 
• Procalcitonin (ng/mL) 
• Prothrombin time (PT) test (seconds) 
• Sodium (mmol/L) 
• Total bilirubin (μmol/L) 
• Urea (BUN) (mmol/L) 
• White blood cell (WBC) count (x109/L) 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 65 of 73 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up and Reporting 
 
Definition of AE 
• An AE is any untoward medical occurrence in a patient 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. 
• Any medical condition that is present at the time that the subject is screened will 
be considered as baseline and not reported as an AE. However, if the severity of 
any pre-existing medical condition increases, it should be recorded as an AE. 
 
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.  
• 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 or those associated 
with underlying disease including expected progression, signs, or symptoms of the 
disease/disorder being studied.  
• 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 
• The disease/disorder being studied. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.  
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).  

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 66 of 73 
• 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. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening  
The term ‘life-threatening’ in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization  
In general, hospitalization signifies that the patient has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.  
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d) Results in persistent disability/incapacity  
• The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  
• This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations: 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.  
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 67 of 73 
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 patient’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 patient identifiers, with the exception of the 
subject/patient number, will be redacted on the copies of the medical records 
before submission to records to the Sponsor/Sponsor’s designee.  
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: 
For AEs not included in the protocol defined grading system, the following guidelines 
will be used to describe severity. 
Mild: An event that is easily tolerated by the patient, causing minimal discomfort and not 
interfering with everyday activities.  
• Grade 1: Events that are usually transient and may require only minimal or no 
treatment or therapeutic intervention and generally do not interfere with the 
subject’s usual activities of daily living. 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.  
• Grade 2: Events that are usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
subject. 
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. 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 68 of 73 
• Grade 3: Events interrupt usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. Severe events are 
usually incapacitating. 
• Grade 4: Events that are potentially life threatening. 
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 unrelated, 
unlikely to be related, possibly related, probably related, or unknown (unable to 
judge).  
o “Probably related” conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship 
cannot be ruled out.  
o “Possibly related” suggests that the association of the AE with the study 
medication is unknown; however, the AE is not reasonably supported by 
other conditions.  
o “Unlikely to be related” suggests that only a remote connection exists 
between the study medication and the AE. Other conditions, including 
chronic illness, progression or expression of the disease state or reaction to 
concomitant therapy, appear to explain the reported AE.  
o “Unrelated” is used if there is not a reasonable possibility that the study 
medication caused the AE.  
o All efforts should be made to classify the AE according to the above 
categories. The category “unknown” (unable to judge) may be used only if 
the causality is not assessable (e.g., because of insufficient evidence, 
conflicting evidence, conflicting data, or poor documentation). 
• 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 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 69 of 73 
assessment of causality for every event before the initial transmission of the SAE 
data to the Sponsor/Sponsor’s designee.  
• The Investigator may change his/her opinion of causality in light of 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) 
- Recovered or resolving (patient is recovering) 
- Not recovered or not resolved (adverse event remains without signs of 
improvement) 
- Recovered or resolved with sequelae (adverse event has resulted in 
permanent disability or incapacity) 
- Fatal 
- Unknown (only applicable if patient has been lost to follow-up) 
• 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 patient dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor/Sponsor’s designee with a copy 
of any postmortem findings including histopathology.  
• 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. 
 
 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 70 of 73 
Reporting of SAEs 
SAE Reporting to the Sponsor/Sponsor’s designee via an Electronic Data Collection 
Tool 
• The primary mechanism for reporting an SAE to the Sponsor/Sponsor’s designee 
will be the electronic data collection tool.  
• If the electronic system is unavailable, then the study center will use the paper 
SAE data collection tool (see next section).  
• The study center will enter the SAE data into the electronic system as soon as it 
becomes available.  
• After the study is completed, the electronic data collection tool will be taken off-
line to prevent the entry of new data or changes to existing data. 
• If a study center receives a report of a new SAE from a patient or receives updated 
data on a previously reported SAE after the electronic data collection tool has 
been taken off-line, then the study center can report this information on a paper 
SAE form (see next section) or to the medical monitor/SAE coordinator by 
telephone.  
• Contacts for SAE reporting can be found in Appendix 2 on the Medical Monitor 
Contact Information page. 
 
SAE Reporting to Sponsor/ Sponsor’s Designee via Paper CRF if eCRF is not 
available 
• If the eCRF is not available, facsimile transmission of the SAE paper CRF may be 
used to transmit this information to the medical monitor or the SAE coordinator.  
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service.  
• 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 in Table 17. 
 
 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 71 of 73 
Appendix 5: Contraceptive Guidance and Collection of Pregnancy Information for 
Patients  
 
Contraception Guidance  
Male Patients  
• Male patients with female partners of childbearing potential are eligible to 
participate if they agree to ONE of the following from the first dose up to 30 days 
after the last dose of study medication:  
- Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long-term and persistent basis) and agree to remain 
abstinent. 
- Agree to use a male condom plus partner use of a contraceptive method 
with a failure rate of < 1% per year when having penile-vaginal intercourse 
with a woman of childbearing potential who is not currently pregnant. 
• In addition, male patients must refrain from donating sperm for the duration of the 
study and for 30 days after the last dose of study medication. 
• Male patients with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each 
episode of penile penetration during the study and for 30 days after the last dose 
of study medication.  
Female patients 
Female patients of childbearing potential are eligible to participate if they are not 
breastfeeding and agree to either abstinence or use at least one primary form of highly 
effective contraception not including hormonal contraception from the time of screening 
through Day 60. 
Pregnancy Testing: 
• WOCBP should only be included after a negative highly sensitive pregnancy test. 
• Additional pregnancy testing should be performed at times specified in the SoA 
(Section 1.3). 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.  
Pregnancy testing will be performed and assayed in the central laboratory. 
 
Collection of Pregnancy Information  
Male subjects with partners who become pregnant 
The Investigator will attempt to collect pregnancy information on any male patient’s 
female partner who becomes pregnant while the male subject is in the study. This applies 
only to male patients who receive ensifentrine. 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 72 of 73 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
Female Patients who become pregnant 
• The Investigator will collect pregnancy information on any female patient who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the Sponsor within 24 hours of learning of a 
patient’s pregnancy. 
• The patient will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the patient and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.  
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported 
as such.  
• Any post-study pregnancy related SAE considered reasonably related to the study 
medication by the Investigator will be reported to the Sponsor as described in Section 
8.6.5. While the Investigator is not obligated to actively seek this information in 
former patients, he or she may learn of an SAE through spontaneous reporting.  
• Any female patient who becomes pregnant while participating in the study will 
discontinue study medication and be withdrawn from the study. 
 

CONFIDENTIAL 
 
Protocol RPL554-COV-201– Version 4.0 
 
 
Amendment 3.0; 13 October 2020 
 
Verona Pharma 
CONFIDENTIAL 
Page 73 of 73 
Appendix 6: Signature of Investigator 
PROTOCOL TITLE:  A SINGLE-CENTER PILOT RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF ENSIFENTRINE IN THE 
RECOVERY OF HOSPITALIZED PATIENTS WITH COVID-
19. 
PROTOCOL NO:    RPL554-COV-201 
VERSION:                   4.0 
Version Date:               13 October 2020 
This protocol is a confidential communication of Verona Pharma. I confirm that I have 
read this protocol, I understand it, and I will work according to this protocol. I will also 
work consistently with the ethical principles that have their origin in the Declaration of 
Helsinki and that are consistent with Good Clinical Practices and the applicable laws and 
regulations. Acceptance of this document constitutes my agreement that no unpublished 
information contained herein will be published or disclosed without prior written 
approval from the Sponsor.  
Instructions to the Investigator:  Please SIGN and DATE this signature page. PRINT 
your name title and the name of the study center in which the study will be conducted. 
Return the signed copy to the Sponsor. 
  
I have read this protocol in its entirety and agree to conduct the study accordingly:  
 
 
Signature of Investigator 
Date 
 
 
 
Printed Name 
 
Investigator Title 
 
Name/Address of Center