Conditions: Coronavirus Infection Covid-19 SARS-CoV-2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 45
Healthy volunteers: no

Brief summary:
This pilot study is being performed to assess the efficacy and safety of inhaled ensifentrine delivered via pMDI compared with a matching placebo in conjunction with standard of care treatments on recovery in patients hospitalized due to COVID-19 infection.

Detailed description:
Expploratory endpoint, pilot study, not statistically powered

go to protocol

Arms:
arm 1: 30 subjects randomized to receive blinded, inhaled ensifentrine in addition to standard of care treatment for COVID-19 infection arm 2: 15 subjects randomized to receive blinded, inhaled placebo in addition to standard of care treatment for COVID-19 infection

Interventions: intervention 1: Ensifentrine Dose 1 intervention 2: Placebo pMDI
Intervention descriptions: intervention 1: Study drug delivered twice daily via pMDI intervention 2: Placebo delivered twice daily via pMDI

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
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 
 
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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.


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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, 


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Verona Pharma 
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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. 


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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 


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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. 
 
 


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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 


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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 


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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 
 


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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 
 


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LIST OF IN-TEXT FIGURES 
Figure 1. Study schematic. .............................................................................. 17 
 


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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. 
 


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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. 


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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.   


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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. 
 


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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 


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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 
  
  
  
  
  
  
  
  


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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. 


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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 


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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. 


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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.  


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More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of ensifentrine can be found in the Verona Pharma plc. 
Ensifentrine Clinical Investigators Brochure v. 19, 20th May 2020.  


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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). 


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• 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 


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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 


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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 


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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 


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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. 


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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. 


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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.  
 


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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 
 


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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 


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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.  
 
 
 
 
 


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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. 
 


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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: 


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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). 


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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.


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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: 


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• 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 


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• 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 
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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.). 


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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). 


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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. 


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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. 
 
 


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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 
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• 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. 


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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.  


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• 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.  
 


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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. 


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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 


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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.  


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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. 
 
 
 
 
 


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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 


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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.   
 
 


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13 APPENDICES 
 


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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 


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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 


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Appendix 2: Regulatory, Ethical, and Study Oversight Consideration 
 
Regulatory and Ethical Considerations  
• This study will be conducted in accordance with the protocol and with the following:  
- Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines.  
- Applicable 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.  
 
 


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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. 
 
 


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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 
 


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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.  


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Source Documents  
The Investigator/institution should maintain adequate and accurate source documents and 
study records that include all pertinent observations on each of the study center’s patients. 
Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete. Changes to source data should be traceable, should not obscure the original 
entry, and should be explained if necessary (e.g. via an audit trail).  
• 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.  


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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) 


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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 
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• 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 


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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. 


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• 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 


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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. 
 
 
 


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Reporting of SAEs 
SAE Reporting to the Sponsor/Sponsor’s designee via an Electronic Data Collection 
Tool 
• The primary mechanism for reporting an SAE to the Sponsor/Sponsor’s designee 
will be the electronic data collection tool.  
• If the electronic system is unavailable, then the study center will use the paper 
SAE data collection tool (see next section).  
• The study center will enter the SAE data into the electronic system as soon as it 
becomes available.  
• After the study is completed, 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. 
 
 
 


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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 


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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 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
Verona Pharma Inc 
 
Statistical Analysis Plan 
RPL554-COV-201 
 
v. 3.0 dated 17 March 2021 
 
pg. 1 
Confidential 
 
 
 
Statistical Analysis Plan 
 
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 
Investigational Product: 
Ensifentrine pMDI 
Study Phase: 
II 
Sponsor Name: 
Verona Pharma Inc 
US IND Number: 
150701 
ClinicalTrials.gov Identifier 
NCT04527471 
Version: 
3.0  
Date: 
17 March 2021 
 
 
 
 


Verona Pharma Inc 
 
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RPL554-COV-201 
 
v. 3.0 dated 17 March 2021 
 
pg. 2 
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1 
STATISTICAL ANALYSIS PLAN APPROVAL 
 
The signatures below indication review and approval of this Statistical Analysis Plan (SAP). 
 
Statistician: 
 
 
 
 
Printed Name 
Signature 
Date 
 
 
 
 
 
 
 
 
Principal 
Investigator: 
 
 
 
 
Printed Name 
Signature 
Date 
 
 
 
 
 
 
 
 
Sponsor: 
 
 
 
 
Printed Name 
Signature 
Date 
 
Document Version History: 
Version date 
Number 
Change 
20 Nov 2020 
1 
Original draft 
19 Jan 2021 
2 
Version revised based off of FDA comments 
dated10Dec2020 (Reference ID: 4715173) and 
additional reviews 
17 Mar 2021 
3 
Version revised for clarifications 
 
 
 


1 
STATISTICAL ANALYSIS PLAN APPROVAL 
 
The signatures below indication review and approval of this Statistical Analysis Plan (SAP). 
 
Statistician: 
Inmaculada B. Aban 
 
04/05/2021 
 
Printed Name 
Signature 
Date 
 
 
 
 
 
 
 
 
Principal 
Investigator: 
J. Michael Wells 
 
Apr 5, 2021 
 
Printed Name 
Signature 
Date 
 
 
 
 
 
 
 
 
Sponsor: 
 
 
 
 
Printed Name 
Signature 
Date 
 
Document Version History: 
Version date 
Number 
Change 
20 Nov 2020 
1 
Original draft 
19 Jan 2021 
2 
Version revised based off of FDA comments 
dated10Dec2020 (Reference ID: 4715173) and 
additional reviews 
17 Mar 2021 
3 
Version revised for clarifications 
 
 
 






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Statistical Analysis Plan 
RPL554-COV-201 
 
v. 3.0 dated 17 March 2021 
 
pg. 3 
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Table of Contents 
1 
STATISTICAL ANALYSIS PLAN APPROVAL .................................................................................... 2 
2 
LIST OF TABLES ................................................................................................................................. 4 
3 
LIST OF ABBREVIATIONS .................................................................................................................. 5 
4 
PREFACE ............................................................................................................................................. 6 
5 
INTRODUCTION ................................................................................................................................... 7 
5.1 
Purpose of the Analyses ................................................................................................................... 7 
6 
INVESTIGATIONAL PLAN ................................................................................................................... 8 
6.1 
Overall Study Design and Plan ......................................................................................................... 8 
6.2 
Objectives .......................................................................................................................................... 8 
6.3 
Selection of Study Population ........................................................................................................... 9 
6.4 
Treatments Administered ................................................................................................................ 10 
6.5 
Identity of Investigational Product(s) ............................................................................................... 10 
6.6 
Method of Assigning Patients to Treatment Groups (Randomization)............................................ 11 
6.7 
Prior and Concomitant Therapy ...................................................................................................... 11 
6.8 
Treatment Compliance .................................................................................................................... 12 
7 
DEFINITIONS...................................................................................................................................... 13 
7.1 
General ............................................................................................................................................ 13 
7.2 
Endpoints ........................................................................................................................................ 14 
8 
GENERAL STATISTICAL CONSIDERATIONS ................................................................................ 18 
8.1 
Sample Size .................................................................................................................................... 18 
8.2 
General Principles ........................................................................................................................... 18 
8.3 
Analysis Populations ....................................................................................................................... 18 
8.4 
Subgroups ....................................................................................................................................... 18 
8.5 
Missing Data.................................................................................................................................... 19 
8.6 
Interim Analyses .............................................................................................................................. 20 
8.7 
Safety Analysis ................................................................................................................................ 20 
9 
ANALYSIS .......................................................................................................................................... 21 
9.1 
Descriptive Information ................................................................................................................... 21 
9.2 
Study Medication Compliance ......................................................................................................... 22 
9.3 
Primary Endpoint Analysis .............................................................................................................. 22 
9.4 
Secondary Endpoint Analysis ......................................................................................................... 23 
9.5 
Safety Analysis ................................................................................................................................ 26 
9.6 
Other or Exploratory Analyses ........................................................................................................ 27 
9.7 
Figures ............................................................................................................................................ 27 
10 
LISTINGS ........................................................................................................................................ 28 
11 
REPORTING CONVENTIONS ....................................................................................................... 30 
12 
TECHNICAL DETAILS ................................................................................................................... 30 
13 
REFERENCES ................................................................................................................................ 31 
 
 
 


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2 
LIST OF TABLES 
Table 1. Clinical study RPL554-COV-201 treatment arms. ........................................................................ 10 
Table 2. Clinical study RPL554-COV-201 study medication composition. ................................................. 10 
Table 3. Clinical study RPL554-COV-201 prohibited concomitant medications. ........................................ 12 
Table 4. Clinical study RPL554-COV-201 general definitions. ................................................................... 13 
Table 5. Clinical study RPL554-COV-201 endpoint definitions. ................................................................. 14 
Table 6. Clinical study RPL554-COV-201 analysis tables - Disposition. .................................................... 21 
Table 7. Clinical study RPL554-COV-201 analysis tables - Demographics. .............................................. 21 
Table 8. Clinical study RPL554-COV-201 analysis tables - Baseline Clinical Characteristics. .................. 22 
Table 9. Clinical study RPL554-COV-201 analysis tables - Study Medication Compliance. ...................... 22 
Table 10. Clinical study RPL554-COV-201 analysis tables - Primary Analysis. ......................................... 23 
Table 11. Clinical study RPL554-COV-201 analysis tables - Secondary Analyses.................................... 25 
Table 12. Clinical study RPL554-COV-201 analysis tables - Safety Analyses. .......................................... 26 
Table 13. Clinical study RPL554-COV-201 Figures. .................................................................................. 27 
Table 14. Clinical study RPL554-COV-201 Listings. .................................................................................. 28 
 
 
 


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v. 3.0 dated 17 March 2021 
 
pg. 5 
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3 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
CI 
Confidence Interval 
CoV / COV 
Coronavirus 
CRF / eCRF 
Case Report Form / Electronic Case Report Form 
CSR 
Clinical Study Report 
ECMO 
Extracorporeal Membrane Oxygenation 
FDA 
Food and Drug Administration 
ICH 
International Conference on Harmonization 
ITT 
Intention to Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
N 
Number of patients/subjects 
PCR 
Polymerase Chain Reaction 
PI 
Principal Investigator 
pMDI 
Pressurized metered dose inhaler 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS 
Severe Acute Respiratory Syndrome 
SD 
Standard Deviation 
SOC 
Standard of Care 
US 
United States 
WHO 
World Health Organization 
 
 
 


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v. 3.0 dated 17 March 2021 
 
pg. 6 
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4 
PREFACE 
The SAP for “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” describes and expands 
upon the statistical information presented in the protocol. 
This document describes all planned analyses and provides reasons and justifications for these 
analyses. It also includes sample tables, listings, and figures planned for the final analyses. 
Any deviation from this SAP will be described and justified in protocol amendments and/or in the 
clinical study report (CSR), as appropriate.  
The reader of this SAP is encouraged to also review the study protocol for details on conduct of 
the study and the operational aspects of clinical assessments. 
 
 
 
 


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v. 3.0 dated 17 March 2021 
 
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5 
INTRODUCTION 
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. 
In terms of clinical outcomes, Verona Pharma (the sponsor) 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 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 (measured with the 7-point ordinal scale), 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. 
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. 
 
5.1 
Purpose of the Analyses 
This SAP encompasses the final analysis of primary and secondary outcome measures. These 
analyses will be included in the CSR. 
This is a pilot study which will expand our knowledge and understanding about how ensifentrine 
can be used to facilitate recovery or prevent deterioration in hospitalized, COVID-19 patients. 
 
 
 


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v. 3.0 dated 17 March 2021 
 
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6 
INVESTIGATIONAL PLAN 
6.1 
Overall Study Design and Plan 
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 patients 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 within 4 days of hospital admission 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 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 (Day 29) and 
55-65 days (Day 60) following receipt of 1st dose of study medication for assessment of clinical 
status via the 7-point ordinal scale, need for re-hospitalization and vital status. 
 
6.2 
Objectives 
The primary objective is to evaluate the effect of ensifentrine on the proportion of patients with 
recovery from COVID-19 over 29 days. 
Secondary objectives include the evaluation of: 
• 
The effect of ensifentrine on COVID-19 related time to recovery, clinical status and risk 
of deterioration, 
• 
The effect of ensifentrine on hospitalization, non-invasive and invasive ventilation and 
oxygen use. 
The safety objective is to evaluate the safety and tolerability of ensifentrine in patients with 
COVID-19. 
 
 


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6.3 
Selection of Study Population 
Male and non-pregnant female adults ≥18 to 80 years of age or older with COVID-19 and who 
meet all eligibility criteria will be enrolled at one site. 
6.3.1 Inclusion Criteria 
• 
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. 
• 
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. 
• 
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 
(Protocol Appendix 5). 
• 
Clinical status consistent with 3, 4 or 5 on the 7-point ordinal scale AND the patient 
requires to be hospitalized for at least 72 hours following randomization:  
o 
3. Hospitalized, not requiring supplemental oxygen, but requiring ongoing 
medical care;  
o 
4. Hospitalized, requiring any supplemental oxygen; or  
o 
5. Hospitalized, requiring non-invasive ventilation or use of high flow oxygen 
devices. 
• 
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 (or as per hospital testing protocols) AND displays at least one of the 
following:  
o 
Respiratory rate > 24 breaths per minute,  
o 
new cough,  
o 
new atypical chest pain,  
o 
new dyspnea,  
o 
oxygen saturation < 97% at rest,  
o 
or chest x-ray with new changes consistent with COVID- related airspace 
disease. 
• 
Capable of complying with all study restrictions and procedures including ability to use 
the pMDI correctly. 
6.3.2 Exclusion Criteria 
• 
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. 
• 
Evidence of multiorgan failure. 
• 
Requiring mechanical ventilation at screening. 


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• 
Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 X upper limit 
of normal (ULN) at screening. 
• 
Creatinine clearance < 30 mL/min at screening. 
• 
Pregnancy or lactation at screening. 
• 
Allergy or other contraindication or one of ensifentrine. 
• 
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. 
• 
Use of prohibited medications. 
• 
Any other reason that the Investigator considers makes the patient unsuitable to 
participate. 
 
6.4 
Treatments Administered 
Once eligibility is confirmed, patients will be randomized in a 2:1 ratio to one of two treatment 
arms listed in Table 1. 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 1. Clinical study RPL554-COV-201 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 
 
6.5 
Identity of Investigational Product(s) 
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. 
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 
(Table 2). Each actuation of pMDI containing ensifentrine will deliver 0.5 mg, such that 4 puffs 
will equal a 2 mg dose. 
 
Table 2. Clinical study RPL554-COV-201 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 
 


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6.6 
Method of Assigning Patients to Treatment Groups (Randomization) 
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 an independent 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. 
6.6.1 Selection of Dose in the Study 
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. 
6.6.2 Selection and Timing of Dose for Each Patient 
Each patient is randomly assigned 2:1 to a treatment group as described in Section 4.2.3. Study 
medication dosing starts on Day 1 after randomization and continues twice daily, approximately 
every 12 hours, until discharge or Day 29, whichever is first.  
6.6.3 Blinding 
The UAB IDS Pharmacy’s unblinded pharmacist will label the study medication and perform 
accountability measures. 
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 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. 
 
6.7 
Prior and Concomitant Therapy 
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 3. 
• 
UAB’s standard treatment for COVID-19 infection will be recorded in the eCRF from 
screening to discharge. 


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Table 3. Clinical study RPL554-COV-201 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 
 
6.8 
Treatment Compliance 
All days the study medication was received and the doses/day will be recorded on the 
appropriate eCRF. If study medication dose was missed, decreased or halted, the information 
will be recorded to track compliance. 
 
 
 
 


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7 
DEFINITIONS 
7.1 
General 
General clinical study definitions are listed in Table 4. 
Table 4. Clinical study RPL554-COV-201 general definitions. 
Term 
Definition for Study 
Baseline 
The most recent pre-dose assessment prior to first dose of study medication. 
Clinical status 
assessment 
(Protocol Section 8.1.1) Daily clinical status will be assessed using the 7-point 
ordinal scale 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_180
22020.pdf according to the following criteria: 
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 
* eligible for study entry 
COVID disease 
severity 
(Protocol Section 8.1.2) At baseline/randomization, the categorization of 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).  
• 
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, 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, 


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Term 
Definition for Study 
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. 
Day 
Calendar day 
Day 1 
The day a patient received their first dose of study medication. 
• 
If a patient received their 1st dose of study medication the day following 
randomization, the study day number will be adjusted so that Day 1 = 1st 
dose of study medication. 
Discharge 
The patient is discharged and leaves the hospital alive.  
This does not include if a patient is moved to another unit. 
• 
The time to discharge = the elapsed time (in days) from Day 1 to the 
earliest day at which the patient is Discharged from hospital (= Day 
where the 7-point ordinal scale score is equal to 1 or 2). 
Improvement in 
clinical status 
A decrease from baseline of at least one point in the 7-point ordinal score (eg, 5 
to 4). 
Worsening 
clinical status 
An increase from baseline of at least one point in the 7-point ordinal scale score 
(eg, 5 to 6). 
 
7.2 
Endpoints 
Clinical study endpoints and associated definitions are listed in Table 5. Additional definitions 
are included in Section 8. Analysis tables are included in Section 9.3, Section 9.4 and Section 
9.5.  
Table 5. Clinical study RPL554-COV-201 endpoint definitions. 
Endpoints 
Definitions 
Primary  
Refer to Section 
9,  
Table 10 
The proportion of patients 
who are in recovery state at 
Day 29. 
  
Clinical status assessed using the 7-point 
ordinal scale score.  
 
The proportion of patients in each treatment arm 
that meet the definition of recovery. 
 
Recovery = one of the following two categories 
from the 7-point ordinal scale: 
1. not hospitalized, no limitations of activities; 
2. not hospitalized, limitation of activities, home 
oxygen requirement, or both.  
Secondary 
Refer to Section 
9,  
 
Table 11 
Time to a recovery state (Day 
1-Day 29; measured in days) 
Clinical status assessed using the 7-point 
ordinal scale score.  
 
Time to recovery = elapsed time (in days) from 
Day 1 to the first day on which patients satisfy 
either 1 or 2 category listed in the primary 
endpoint. 
Proportion of patients who 
are in a recovery state at 
Days 7, 14 and 60. 
Clinical status assessed using the 7-point 
ordinal scale score.  
 
The proportion of patients in each treatment arm 
that meet the definition of recovery. 
 
Recovery = one of the following two categories 
from the 7-point ordinal scale: 


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Endpoints 
Definitions 
1. not hospitalized, no limitations of activities; 
2. not hospitalized, limitation of activities, home 
oxygen requirement, or both. 
Proportion of patients with 
improvement of one category 
using the 7-point ordinal scale 
(Day 1 - Days 7, 14 and 29). 
Clinical status assessed using the 7-point 
ordinal scale score.  
 
The proportion of patients in each treatment arm 
that meet the definition of a one category 
improvement in clinical status. 
 
Improvement in clinical status = a decrease 
from baseline of one point in the 7-point ordinal 
score (eg, 5 to 4). 
Proportion of patients with 
improvement of two 
categories using the 7-point 
ordinal scale (Day 1 - Days 7, 
14 and 29). 
Clinical status assessed using the 7-point 
ordinal scale score.   
 
The proportion of patients in each treatment arm 
that meet the definition of a two category 
improvement in clinical status. 
 
Improvement in clinical status = a decrease 
from baseline of two points in the 7-point ordinal 
score (eg, 5 to 3). 
All-cause mortality at Days 29 
and 60. 
Clinical status assessed using the 7-point 
ordinal scale score.   
 
Death = 7-point ordinal scale score is equal to 7 
or using a vital records search returns a death 
record, the date on the record will be the date of 
death. 
Proportion of patients alive 
and not in respiratory failure 
(invasive mechanical 
ventilation or extracorporeal 
membrane oxygenation 
(ECMO)) at Days 7, 14 and 
29. 
Clinical status assessed using the 7-point 
ordinal scale score.  
 
The proportion of patients in each treatment arm 
that meet the definition of alive and not is 
respiratory failure. 
 
Alive and not in respiratory failure (invasive 
mechanical ventilation or ECMO) = 7-point 
ordinal scale score is equal to 1, 2, 3, 4 or 5. 
Proportion of patients 
needing re-hospitalization 
(post-dose Day 1 – Day 60). 
Assessed following discharge: the eCRF 
question regarding re-hospitalization will be 
used at Day 29 and Day 60 follow-up contact.  
 
The proportion of patients in each treatment arm 
that meet the definition of re-hospitalization 
following discharge. 
 
Re-hospitalization = following their treatment 
with study medication and subsequent 
discharge from hospital, they were re-admitted 
to a hospital for COVID related issue(s). 


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Endpoints 
Definitions 
Total time of hospitalization 
between Day 1 - Day 29 
(measured in days). 
Clinical status assessed using the 7-point 
ordinal scale score.  
 
Hospitalized = # days where the 7-point ordinal 
scale score is equal to 3, 4, 5 or 6. 
• 
Or 7-point ordinal scale score is equal 
to 7 if patient dies while hospitalized 
between Day 1-29. 
Change from baseline in 7-
point ordinal scale (Days 7, 
14 and 29). 
Clinical status assessed using the 7-point 
ordinal scale score.   
 
The mean change from baseline of the 7-point 
ordinal scale in each treatment arm as 
assessed by the statistical analysis. 
Total time on supplemental 
oxygen (Day 1 - Day 29; 
measured in days). 
Clinical status assessed using the 7-point 
ordinal scale score.  
 
Hospitalized patient supplemental oxygen = # 
days where the 7-point ordinal scale score is 
equal to 4, 5, or 6. 
• 
Or 7-point ordinal scale score is equal 
to 7 if patient dies while hospitalized 
between Day 1-29. 
 
Not hospitalized patient supplemental oxygen = 
# days where the 7-point ordinal scale score is 
equal to 2 (if required to have home oxygen). 
Total time of non-invasive 
ventilation or high flow 
oxygen use (post-dose Day 1 
- Day 29; measured in days). 
Clinical status assessed using the 7-point 
ordinal scale score.   
 
Non-invasive ventilation or high flow oxygen use 
= # days where the 7-point ordinal scale score 
is equal to 5 or 6. 
• 
Or 7-point ordinal scale score is equal 
to 7 if patient dies while hospitalized 
between Day 1-29. 
Proportion of patients alive 
and with oxygen use at Days 
7, 14 and 29 
Clinical status assessed using the 7-point 
ordinal scale score.   
 
The proportion of patients in each treatment arm 
that meet the definition of requiring oxygen use. 
 
Hospitalized patient supplemental oxygen = the 
7-point ordinal scale score is equal to 4, 5, or 6. 
• 
Or 7-point ordinal scale score is equal 
to 7 if patient dies while hospitalized 
between Day 1-29. 
 
Not hospitalized patient supplemental oxygen = 
the 7-point ordinal scale score is equal to 2 (if 
required to have home oxygen). 
Proportion of patients alive at 
Days 7, 14 and 29 with non-
Clinical status assessed using the 7-point 
ordinal scale score.   
 


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Endpoints 
Definitions 
invasive ventilation or high 
flow oxygen use  
The proportion of patients in each treatment arm 
that meet the definition of requiring non-invasive 
ventilation/high-flow oxygen use. 
 
Non-invasive ventilation or high flow oxygen use 
= the 7-point ordinal scale score is equal to 5 or 
6. 
• 
Or 7-point ordinal scale score is equal 
to 7 if patient dies while hospitalized 
between Day 1-29. 
Proportion of patients alive 
and receiving invasive 
mechanical ventilation or 
extracorporeal membrane 
oxygenation (ECMO) at Days 
7, 14 and 29). 
Clinical status assessed using the 7-point 
ordinal scale score.  
 
The proportion of patients in each treatment arm 
that meet the definition of requiring invasive 
mechanical ventilation. 
 
The 7-point ordinal scale score is equal to 6. 
• 
Or 7-point ordinal scale score is equal 
to 7 if patient dies while hospitalized 
between Day 1-29. 
Safety 
Refer to Section 
9, Table 12 
Incidence of Adverse Events 
(AEs). 
Number of AEs and number of patients with 
AEs for all TEAEs and for subcategories of AEs 
(SAEs, severe AEs, fatal AEs etc). 
 
Incidence = proportion of patients in each 
treatment arm that experience an adverse 
event. 
Adverse Events (AEs) 
between Day 1 – 29 or 
discharge and Day 60. 
Time to combined AE (death, SAE, Severe AE 
or ET/W from study medication) = elapsed time 
(in days) from Day 1 to the earliest date of any 
of the events through hospitalization, Day 29 
and Day 60. 
Vital signs during 
hospitalization between Day 1 
– Day 29 or discharge. 
• 
Respiration rate (breaths per minute 
• 
Heart rate (beats per minute) 
• 
Oxygen saturation (SpO2) 
• 
Supplemental oxygen use (yes/no) 
• 
Body temperature (Celcius) 
• 
Blood pressure (mmHg) 
• 
Level of consciousness graded on the 
AVPU scale (Alert, Verbal = voice response 
present, Pain = pain response present, 
Unresponsive). 
Other parameters may include (but are not 
required per protocol): Dehydration status, 
Fraction of inhaled oxygen (FiO2), Sternal 
capillary refill time 
Laboratory values during 
hospitalization between Day 1 
– Day 29 or discharge. 
 
 
 


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8 
GENERAL STATISTICAL CONSIDERATIONS 
8.1 
Sample Size 
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. 
 
8.2 
General Principles 
This is a double-blind, placebo controlled randomized pilot study which may inform on treatment 
effect for future studies. 
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. 
 
8.3 
Analysis Populations 
Summaries and analysis of safety data will be presented for the Safety Analysis Population. 
Summaries and analysis of efficacy data will be presented for the intent-to-treat (ITT) 
population. 
• 
Intent to treat (ITT): Will consist of all randomized patients. Efficacy will be evaluated as 
randomized. 
• 
Per protocol population (PP): Will consist of all patients in ITT without any major protocol 
deviations (determined prior to database lock) deemed to have an effect on efficacy 
analyses. 
• 
Safety set (SS): Will consist of all randomized and treated patients (at least one dose). 
Safety will be evaluated by actual treatment. 
 
8.4 
Subgroups 
In an exploratory manner, we will perform subgroup analyses for outcomes (i.e. the primary and 
key secondary analyses) where possible (minimum size required) to evaluate the treatment 
effect across the potential subgroups listed below: 
• 
COVID disease severity: Mild, Moderate, Severe or Critical disease (severe and critical 
may be combined). 
• 
Randomization day (prior to 1st dose of study medication) clinical status assessed using 
the 7-point ordinal scale: 3, 4 or 5. 
• 
Gender: Female, Male. 
• 
Race: White; Black/African American; Asian; Other. 


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• 
Baseline presence of comorbidities: None, One, Two or more. 
• 
Age group: <40, 40-64, 65 and older (may use two age groups instead of three). 
• 
Smoking history: Never, Current, Past. 
 
8.5 
Missing Data 
All attempts will be made to collect all data per protocol. 
• 
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. 
Any data point that appears to be erroneous or inexplicable based on clinical judgment will be 
investigated as a possible outlier. 
• 
If data points are identified as outliers, sensitivity analyses may be performed to examine 
the impact of including or excluding the outliers. Any substantive differences in these 
analyses will be reported. 
For survival analyses, patients with death as outcome will be censored at Day 29 (Day 60), 
unless the required event was reached prior to death.  Patients who are lost to follow-up or 
terminate the study prior to Day 29 (Day 60) for other reason than death and prior to 
observing/experiencing the event will be censored at the time of their last observed assessment.  
The only time to event analyses is the time to recovery. 
For secondary endpoint analyses, the following imputation rules will be used for patients who 
are lost to follow-up, terminate early from the study, or do not have further outcome data 
available after discharge for any reason than death: 
• 
Patients with no data collected at the actual time point of interest for other reason than 
death, the last assessment of their status prior to this time point will be used as a 
representative for that time point. Especially, if the patient’s clinical status scale is 1 or 2 
at the last observed assessment, then the patient will be considered to be recovered 
through Day 29. 
• 
For endpoints assessing total time (oxygen or non-invasive ventilator care), the status 
for patients with no data collected for other reason than death, will be assumed 
unchanged from last assessment of the score up to last day in the definition of the 
endpoint (Day 29). Thus, no extra days will be added for patients without oxygen or 
patients without non-invasive ventilator care at last assessment.  
• 
Patients that die in the study will be handled as worst case in all the analyses, that is 
they are considered to be on oxygen need, non-invasive and invasive mechanical 
ventilator need for all time points following the death.  
• 
In analyses of oxygen need, patients in ventilator care (non-invasive or invasive 
mechanical) will be considered in oxygen need for the corresponding time period and 
patients with death as outcome will be considered in oxygen need for the remainder of 
the time period of evaluation.  
• 
In analyses of non-invasive ventilator need, patients that require invasive mechanical 
ventilation will be considered also as having a non-invasive ventilator need.  Patients 
with death as an outcome will be considered as having non-invasive ventilator need from 


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time of death for the remainder of the time period of evaluation. 
• 
In analyses of invasive mechanical ventilator need, patients with death as an outcome 
will be considered in invasive mechanical ventilator need for the remainder of the time 
period of evaluation 
• 
The change from baseline in the 7-point ordinal scale will use the baseline score and the 
score at the endpoint using imputation for missing data as stated above, that is the last 
assessment of their status prior to this time point will be used. 
• 
If the patient is discharged and no further hospitalization data are available, then the 
patient will be assumed to not have been readmitted. Thus, no additional imputed days 
on hospitalization will be added to the number of days recorded on available 
assessments for these patients. 
 
8.6 
Interim Analyses 
No interim analyses will be performed. 
 
8.7 
Safety Analysis 
Time to first combined event. 
Any patients that are lost to follow-up or terminated early prior to experiencing any of the events 
will be censored at the day of their last observed assessment. 
Patients who complete follow-up but do not experience any of the events will be censored at the 
day of their Day 29 visit. 
 
 
 
 


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9 
ANALYSIS 
9.1 
Descriptive Information 
Table 6 lists the summaries for patient disposition, analysis populations and protocol deviations. 
 
Table 6. Clinical study RPL554-COV-201 analysis tables - Disposition. 
Table # 
Table Name 
Table Contents 
14.1.1 
Patient Disposition. 
The disposition of patients by treatment group and 
include study milestones 
• 
total number screened, randomized, completed 
7, 14, 29 days of treatment, completed Day 29 
and Day 60 follow-ups and withdrawn patients 
in total and by withdrawal reason. 
14.1.2 
Screen Failures. 
A summary of the reasons that patients were screened 
but not enrolled. 
14.1.3 
Major Protocol Deviations. 
Major protocol deviations summarized by the reason 
for the deviation, the deviation category, treatment 
group, COVID disease severity and (separately) site for 
all patients.  
14.1.4 
Analysis Sets 
The composition of analysis populations, including 
reasons for patient exclusion by treatment group. 
 
 
Tables summarizing patient demographics are displayed in Table 7. Demographics include 
age/DOB, sex, height, weight, BMI (calculated), ethnicity, and race; smoking history, date of 
randomization and date of inhaler training. 
 
Table 7. Clinical study RPL554-COV-201 analysis tables - Demographics. 
Table # 
Table Name 
Table Contents 
14.1.5 
Baseline Demographic Characteristics. 
Overall, by treatment group, by COVID disease 
severity and by baseline clinical status 
assessment using the 7-point ordinal scale for 
ITT, PP and SS (if different). 
 
 
Summaries of baseline clinical characteristics are displayed in Table 8. Baseline clinical 
characteristics include brief physical exam findings, vital signs, clinical status assessment using 
the 7-point ordinal scale score, COVID-19 symptom onset, admission date, COVID disease 
severity, existing co-morbidities, surgical history, prior medications, concomitant medications, 
and COVID-19 standard medications and treatments. 
 
 


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Table 8. Clinical study RPL554-COV-201 analysis tables - Baseline Clinical Characteristics. 
Table # 
Table Name 
Table Contents 
14.1.6 
Baseline clinical characteristics 
(Eg. 7-point ordinal scale score, vital sign 
values, COVID disease severity, co-morbid 
conditions - obesity, hypertension, diabetes 1, 
asthma, and COPD). 
Overall, by treatment group and COVID 
disease severity for ITT, PP and SS (if 
different). 
14.1.7 
Proportion patients with 7-point ordinal scale 
score or 3, 4 and 5, ITT. 
Overall and by treatment group. 
14.1.8 
Proportion patients with COVID disease 
severity of mild, moderate, severe and critical, 
ITT. 
Overall and by treatment group. 
14.1.9 
Disease onset (days with COVID symptoms, 
hospital admission date, COVID disease 
severity and oxygen need at randomization), 
ITT. 
Overall and by treatment group. 
14.1.10 
Number and proportion taking concomitant 
dexamethasone or remdesivir, ITT. 
Overall, by treatment group and COVID 
disease severity. 
14.1.11 
COVID-19 treatment and other respiratory 
medications introduced after randomization, 
ITT. 
Overall, by treatment group and COVID 
disease severity. 
 
9.2 
Study Medication Compliance  
Summaries of study non-medication compliance are listed in Table 9. 
 
Table 9. Clinical study RPL554-COV-201 analysis tables - Study Medication Compliance. 
Table # 
Table Name 
Table Contents 
14.2.1 
Study Medication Compliance  
(number of patients who had study medication 
halted/slowed and the number of patients with 
missed doses) 
The number of patients with 
discontinued or missed doses (except 
due to discharge) by treatment group 
for ITT and PP. 
14.2.2 
Patient study medication discontinuation by 
study day. 
By treatment group for ITT and PP. 
 
9.3 
Primary Endpoint Analysis 
The proportion of patients with recovery at Day 29 will be compared between treatment groups 
using a logistic regression model adjusting for treatment and COVID disease severity. The 
difference between treatment arms will be expressed as a difference in proportions as 
measured by the Cochran Mantel-Haenzel (stratum)-weighted estimator based on the fitted 
logistic regression model. The delta method will be used to calculate the standard error for the 
difference and the associated confidence interval [Ge, 2011]. In addition, the raw proportions 
per treatment group will be given. If 0 events in any of the groups only raw proportions will be 
given. 
• 
Sub-group analysis will only be performed for sub-groups with a minimum size.  
 
Summaries of the results of the primary analysis are displayed in Table 10. 
 
 


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Table 10. Clinical study RPL554-COV-201 analysis tables - Primary Analysis. 
Table # 
Table Name 
Table Contents 
14.2.3 
Proportion of Patients with Recovery at 29 
Days, ITT 
Overall and by Treatment Group 
• 
By Age Group 
• 
By Gender 
• 
By COVID Disease Severity 
• 
By Smoking History 
• 
By # co-morbidities 
14.2.4 
Proportion of Patients with Recovery at 29 
Days, PP 
Overall and by Treatment Group 
 
 
9.4 
Secondary Endpoint Analysis 
Patients that die in the study will be handled as worst case in all analyses. 
To have an evaluation using all patients we will count an event as the type of need or worse (eg, 
patients with oxygen need; non-invasive ventilator need; ventilator need; or with death at time of 
evaluation will be counted as having data supporting oxygen need), and included in both 
denominator and numerator (refer to Section 8.5). 
9.4.1 Time to a recovery state (Day 1 - Day 29; measured in days) 
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 the median time to recovery 
estimated if appropriate. Stratification in the model with respect to COVID disease severity will 
be done if the randomization outcome has sufficient numbers in each group with respect to 
these characteristics. 
9.4.2 Proportion of patients endpoint analyses 
Secondary endpoints assessing proportion of patients fulfilling an event will be compared 
between treatments using a logistic regression model adjusting for treatment and COVID 
disease severity state. The difference between treatment arms will be expressed as a difference 
in proportions as measured by the Cochran Mantel-Haenzel (stratum)-weighted estimator based 
on the fitted logistic regression model. The delta method will be used to calculate the standard 
error for the difference and the associated confidence interval. For endpoints with a low number 
of events, the baseline disease state will be dropped from the model. In addition, the raw 
proportions per treatment group will be given. If 0 events in any of the groups only raw 
proportions will be given. 
• 
Proportion of patients who are in a recovery state (Days 7, 14 and 60). 
• 
Proportion of patients with improvement 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). 
• 
Proportion of patients in use of oxygen (Days 7, 14 and 29). 
• 
Proportion of patients alive and not in respiratory failure (invasive mechanical ventilation 
or ECMO (Days 7, 14 and 29). 


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• 
Proportion of patients receiving non-invasive ventilation (Days 7, 14 and 29). 
• 
All-cause mortality. 
9.4.2.1 Sub-sets based on post-randomization outcome 
Descriptive summaries of the proportion of patients as well as the duration of the worsening 
following initiation of study medication will be provided for these endpoints: 
• 
Proportion of patients needing re-hospitalization (post-dose Day 1 – Day 60). 
o Applies to the sub-set of patients that were randomized, treated with study 
medication and discharged from the hospital alive then re-admitted to the 
hospital for COVID-19 related treatment. 
• 
Proportion of patients and duration of new oxygen use (post-dose Day 1 - Day 29; 
measured in days). 
o Applies to the sub-set of patients that were randomized and treated with study 
medication but then had a new need for supplemental oxygen (score worsened 
to 4, 5 or 6). 
o Or those which improved during hospitalization (to 3) and then their clinical status 
worsened again (to 4, 5 or 6). 
• 
Proportion of patients and duration of new non-invasive ventilation or high flow oxygen 
use (post-dose Day 1 - Day 29; measured in days). 
o Applies to the sub-set of alive patients that were randomized and treated with 
study medication but then had a new need for non-invasive ventilation or high-
flow oxygen use (score worsened to 5 or 6). 
o Or those which improved during hospitalization (to 3 or 4) and then their clinical 
status worsened again (to 5 or 6) 
The total number of days with recorded use will be the sum of all reported days, regardless of 
whether the days occur consecutively or in disjoint intervals.  
9.4.3 Change from baseline in 7-point ordinal scale (Days 7, 14 and 29). 
Change from baseline in 7-point ordinal scale will be compared between treatments using 
ANCOVA models with treatment and COVID disease severity state as factors and baseline as a 
covariate. Estimated treatment difference with 95% confidence intervals and associated 2-sided 
p-value will be given. Sub-group analysis will only be performed for sub-groups with a minimum 
size.  
9.4.4 Total time on supplemental oxygen (Day 1 - Day 29; measured in days). 
The total number of days with recorded use will be the sum of all reported days, regardless of 
whether the days occur consecutively or in disjoint intervals. Results will be summarized by 
descriptive statistics including medians and quartiles by treatment arm and compared between 
treatment groups using Wilcoxon rank sum test. Patients that do not reach the specified score 
on any day will be counted as 0 days. 
9.4.5 Total time on non-invasive ventilator use (Day 1 - Day 29; measured in days). 
The total number of days with recorded use will be the sum of all reported days, regardless of 
whether the days occur consecutively or in disjoint intervals. Results will be summarized by 
descriptive statistics including medians and quartiles by treatment arm and compared between 
treatment groups using Wilcoxon rank sum test. Patients that do not reach the specified score 


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on any day will be counted as 0 days. 
9.4.6 Duration of hospitalization (Day 1 - Day 29; measured in days) 
The total number of days with recorded use will be the sum of all reported days, regardless of 
whether the days occur consecutively or in disjoint intervals. Results will be summarized by 
descriptive statistics including medians and quartiles by treatment arm and compared between 
treatment groups using Wilcoxon rank sum test.  
Summaries of the results of the secondary analyses are displayed in Table 11. 
Table 11. Clinical study RPL554-COV-201 analysis tables - Secondary Analyses. 
Table # 
Table Name 
Table Contents 
14.2.5 
Time to recovery, Day 1 - Day 29 
Overall and by Treatment group 
14.2.6 
Proportion of patients in recovery at Day 60, ITT 
Overall and by Treatment group 
Day 1 – Day 7 
Day 1 – Day 14 
14.2.7 
Proportion of patients with improvement of one 
category using the 7-point ordinal scale from Day 
1, ITT  
Overall and by Treatment group 
Day 1 – Day 7 
Day 1 – Day 14 
Day 1 – Day 29 
14.2.8 
Proportion of patients with improvement of two 
categories using the 7-point ordinal scale from 
Day 1, ITT 
Overall and by Treatment group 
Day 1 – Day 7 
Day 1 – Day 14 
Day 1 – Day 29 
14.2.9 
All-cause mortality, ITT  
Overall and by Treatment group 
At Day 29 
At Day 60 
14.2.10 
Proportion of patients alive and not in respiratory 
failure (invasive mechanical ventilation or 
extracorporeal membrane oxygenation (ECMO) 
at Day 29, ITT 
Overall and by Treatment group 
Day 1 – Day 7 
Day 1 – Day 14 
 
14.2.11 
Summary of the proportion of patients re-
hospitalized following initiation of study 
medication and subsequent discharge (over 60 
days), ITT 
Overall and by Treatment group 
14.2.12 
Duration of hospitalization from Day 1 (Day 1 - 
Day 29; measured in days), ITT 
Overall and by Treatment group 
14.2.13 
Change from baseline in 7-point ordinal scale at 
Days 7, 14 and 29, ITT  
Overall and by Treatment group 
Baseline – Day 7 
Baseline – Day 14 
Baseline – Day 29 
14.2.14 
Total time on supplemental oxygen (Day 1 - Day 
29; measured in days), ITT  
Overall and by Treatment group 
14.2.15 
Total time of non-invasive ventilation or high flow 
oxygen use (post-dose Day 1 - Day 29; 
measured in days). 
Overall and by Treatment group 
14.2.16 
Summary of the proportion of patients with 
oxygen use at Days 7, 14 and 29, ITT  
Overall and by Treatment group 
14.2.17 
Summary of the proportion of patients with non-
invasive ventilation or high flow oxygen use at 
Days 7, 14 and 29), ITT 
Overall and by Treatment group 
14.2.18 
Proportion of patients receiving invasive 
mechanical ventilation or extracorporeal 
membrane oxygenation (ECMO, 7-point ordinal 
scale criteria #6) at Days 7, 14 and 29, ITT  
Overall and by Treatment group 
Day 1 – Day 7 
Day 1 – Day 14 
Day 1 – Day 29 


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9.5 
Safety Analysis 
Safety endpoints include SAEs and AEs (Protocol 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.  
The time to the composite AE endpoint (death, SAE, severe AE or ET/W of treatment during 
first 29 days) will be compared between treatment groups using the log-rank test and difference 
between treatment arms will be expressed as a difference in proportions as measured by the 
Cochran Mantel-Haenzel (stratum)-weighted estimator based on the fitted logistic regression 
model 
• 
If ‘0’ events, proportions will be presented. 
Summaries of the results of the safety analysis are displayed in Table 12. 
 
Table 12. Clinical study RPL554-COV-201 analysis tables - Safety Analyses. 
Table # 
Table Name 
14.3.1 
Time to first composite AE (Safety Analysis Set) 
14.3.2 
Number/Proportion Treatment emergent adverse events summary (Safety Analysis 
Set) 
14.3.3 
Number/Proportion TEAEs by system organ class and preferred term (Safety 
Analysis Set) 
14.3.4 
Number/Proportion TEAEs leading to discontinuation of study treatment by system 
organ class and preferred term (Safety Analysis Set) 
14.3.5 
Number/Proportion TEAEs causally related to the study treatment by system organ 
class and preferred term (Safety Analysis Set) 
14.3.6 
Number/Proportion TEAEs by maximum severity by system organ class and 
preferred term (Safety Analysis Set) 
14.3.7 
Number/Proportion Serious TEAEs by system organ class and preferred term (Safety 
Analysis Set) 
14.3.8 
Number/Proportion Serious TEAEs causally related to the study treatment by system 
organ class and preferred term (Safety Analysis Set) 
14.3.9 
Number/Proportion Serious TEAEs by maximum severity by system organ class and 
preferred term (Safety Analysis Set) 
14.3.10 
Number/Proportion Serious TEAEs leading to discontinuation of study treatment by 
system organ class and preferred term (Safety Analysis Set) 
14.3.11 
Number/Proportion TEAEs with an outcome of death by system organ class and 
preferred term (Safety Analysis Set) 
 
 
9.5.1 Deaths, Serious Adverse Events and other Significant Adverse Events 
Narratives will be provided for deaths and serious adverse events. 


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9.5.2 Pregnancies 
For any patients in the Safety population who become pregnant during the study, every attempt 
will be made to follow these patients to completion of pregnancy to document the outcome, 
including information regarding any complications with pregnancy and/or delivery.  
 
9.6 
Other or Exploratory Analyses 
Proportion of patients in recovery, Day 1 – 7 and Day 1 – 14. 
Proportion of patients alive and not in respiratory failure (invasive mechanical ventilation or 
extracorporeal membrane oxygenation (ECMO): Day 1- 7 and Day 1 – 14. 
Description of the distribution of the 7-point ordinal scale outcomes using plots (e.g., stacked 
bar plots representing the proportion of patients in each category, by treatment arm, over time). 
Descriptive summary of the number of days between hospital admission, positive PCR test (or 
as per hospital testing protocol) and randomization. 
Proportion of total patients requiring any oxygen at randomization. 
• 
For those that required oxygen, the mean/standard deviation or median/IQR for the 
oxygen amount (in FiO2). 
Oxygen use while hospitalized and undergoing study treatment. 
• 
Measurement of the oxygen requirement: compare the oxygen requirement (mean and 
median) for each arm using daily supplemental oxygen flow (L/min).  
 
9.7 
Figures 
The study specific figures are displayed in Table 13. 
 
Table 13. Clinical study RPL554-COV-201 Figures. 
Figure # 
Figure Name 
1 
Patient disposition (adapted from the Consort Statement). 
2 
Kaplan–Meier plot of time to Recovery, ITT. 
3 
Histogram of ordinal scores at Day 7, 14, 29 by treatment group and baseline ordinal 
scale, ITT. 
4 
Proportion of patients in oxygen need by day in study. 
 
 
 
 


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Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
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10 LISTINGS 
Data is presented on a by-patient basis in this section. The study specific listings are displayed 
in Table 14. The following categories apply to the listings:  
• 
16.2.1 Patient Dispositions, Patient Eligibility 
o Listing of disposition: It should be clear which patients discontinued the study 
early, their study treatment, when they discontinued and the reason;  
o Listing of visit dates 
o Listing of eligibility: e.g. confirmation patients met the inclusion/exclusion criteria 
• 
16.2.2 Protocol Deviations  
o Listing of all patients with protocol deviations, with the deviation specified. 
• 
16.2.3 Study Populations 
o Listing of patients and whether they are included in each population;  
o Listing of patients excluded from key population(s) e.g. the efficacy population 
• 
16.2.4 Demographic and Baseline Characteristic Data  
o Listing of demographics;  
o Listing of other baseline data (e.g. COVID disease severity; brief physical 
examination findings; medical history; hospital admission information) 
o Listing of prior and concomitant medications 
• 
16.2.5 Compliance with study medication  
• 
16.2.6 Individual Efficacy Data - Listing of efficacy data 
• 
16.2.7 Adverse Event Listings - Listing of all adverse event information 
• 
16.2.8 Laboratory Safety Tests - Listings of all laboratory data.  
• 
16.2.9 Vital Signs, Physical Findings and Other Observations  
 
Table 14. Clinical study RPL554-COV-201 Listings. 
Listing Name 
Listing Contents 
Completed/Discontinued 
Patients  
A patient listing of analysis population eligibilities. 
Protocol Deviations 
All patient-specific protocol deviations and non-patient specific 
protocol deviations. 
Patients Excluded from 
Analysis Sets 
A listing of patients overall. 
Analysis Population 
Inclusions/Exclusions 
A listing of patients by Treatment Group. 
Patients who Early 
Terminated or Discontinued 
Treatment 
A listing of patients by Treatment Group who discontinued dosing or 
terminated study follow-up and the reason. 
Patient-Specific Protocol 
Deviations  
A listing of patients by Treatment Group. 
Non-Patient-Specific 
Protocol Deviations 
A listing of deviations. 


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Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
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Listing Name 
Listing Contents 
Baseline Demographic 
Characteristics 
Individual listings for all demographic information by Treatment 
Group. 
Baseline Disease 
Characteristics 
Individual listings for all baseline COVID information by Treatment 
Group. 
Baseline Medical History 
Individual listing for all co-morbid conditions and surgical history by 
Treatment Group. 
Baseline Brief Physical 
Exam Findings  
Individual listing by Treatment Group.  
Study Medication 
Compliance for each study 
day 
Individual listings for all patients who received at least at least one 
dose of study medication, including the number of days taken and 
number of doses received; and for all patients who discontinued 
dosing, missed doses, or halted or slowed doses 
7-point ordinal scale score at 
baseline and for each study 
day 
Individual listing by Treatment Group. 
Vital signs at baseline and 
for each study day 
Individual listing by Treatment Group. 
Prior and Concomitant 
Medications at baseline and 
for each study day 
Individual listings of medications that were started prior to dosing and 
continuing at the time of dosing by Treatment Group (those listed in 
the concomitant medication list as: Other (and comments), Medical 
History or Adverse Event). 
Medications for the 
Treatment of COVID-19 
(Standard of Care) at 
baseline and for each study 
day 
Individual listing by Treatment Group (those listed in the concomitant 
medication list as: Treatment of COVID-19).  
Medication classes:  
1. Angiotensin converting enzyme inhibitors (ACE inhibitors),  
2. Angiotensin II receptor blockers (ARBs),  
3. Antibiotics,  
4. Antifungal agent,  
5. Antiviral agent,  
6. Corticosteroid,  
7. Immunosuppressant agents (not oral steroids),  
8. Intravenous fluids,  
9. Non‐steroidal anti‐inflammatory (NSAIDs),  
10. Oral/orogastric fluids, 
11. Other targeted COVID‐19 medications (comments) 
Treatment or Therapy for 
COVID-19 (Standard of 
Care) at baseline and for 
each study day 
Individual listings for all standard of care COVID-related 
treatments/therapies (excluding medications) received while 
hospitalized and the duration. 
Standard of Care Laboratory 
Test Results at baseline and 
for each study day 
Individual listings for all standard of care laboratory results while 
hospitalized. 
New respiratory illness or 
other illness during 
hospitalization 
Individual listing by Treatment Group 
Listing of Non-Serious 
Adverse Events  
Individual listing by Treatment Group. 
Safety Laboratory Results at 
screening and discharge 
Individual listing by Treatment Group. 
Listing of Death and Other 
Serious Adverse Events  
Individual listing by Treatment Group. 
Pregnancy Reports 
Individual listing by Treatment Group. 
 
 


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Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
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11 REPORTING CONVENTIONS 
P-values will be reported to 3 decimal places; p-values less than 0.0005 will be reported as 
“<0.001” and p-values greater than 0.9995 will be reported as “>0.999”. 
The mean, standard deviation, and other statistics will be reported to1 decimal place greater 
than the original data. The minimum and maximum will use the same number of decimal places 
as the original data. 
Proportions will be presented as 2 decimal places; values greater than zero but <0.005 will be 
presented as “<0.01”.  
Estimated parameters, not on the same scale as raw observations (e.g. regression coefficients) 
will be reported to 3 significant figures. 
 
 
12 TECHNICAL DETAILS 
Additional summaries/data points may be included in the final version of a table, figure, or 
listing.  
Additional tables, figures, and listings may be generated to supplement the planned output. 
 
 
 
 


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Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
pg. 31 
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13 REFERENCES 
1 
Singh D, Abbott-Banner K, Bengtsson T, Newman K. The short-term bronchodilator effects 
of the dual phosphodiesterase 3 and 4 inhibitor RPL554 in COPD. Eur Respir J. 2018 Nov 
1; 52 (5). pii: 1801074.  doi: 10.1183/13993003.01074-2018.   
2 
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. 
3 
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.   
4 
Ge M, Durham LK, Meyer RD, Xie W, Thomas N. Covariate-adjusted Difference in 
Proportions from Clinical Trials Using Logistic Regression and Weighted Risk Differences. 
Drug Information Journal, Vol. 45, pp. 481–493, 2011 
 
 


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14 EXAMPLE SHELLS 
 
 
 


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Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
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Table 14.1.1 Patient Disposition 
 
Patient Disposition 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Completed Day 7 
 
 
 
 
Completed Day 14 
 
 
 
 
Completed Day 29 
 
 
 
 
Completed post-Discharge Follow-up (outpatient) 
 
Completed D29 post Follow-up (outpatient) 
 
 
 
 
Completed D60 post Follow-up (outpatient) 
 
 
 
 
Withdrawal 
 
 
 
 
Reason of withdrawal  
 
 
 
         Adverse Event 
 
 
 
         Death 
 
 
 
         Lost to follow up 
 
 
 
         Pregnancy 
 
 
 
         Protocol Violation 
 
 
 
         Physician Decision 
 
 
 
         Study Termination by Sponsor 
 
 
 
         Withdrawal by Patient 
 
 
 
         Other 
Change of Consent by Patient - Reconsent (withdrawl from 
study medication, continued in follow-up) 
          
 
 
 
 
 
Total number screened: 122 (77 failed screen) 
Discharge=The patient is discharged and leaves the hospital alive. 
Eligible patients were randomized within 4 days of hospital admission. 
Randomized patients received study medication until hospital discharge or up to 29 days of 
treatment, whichever was first.  
Completed Day 7=patient randomized and hospitalized taking study medication for ≥7 days. 
Completed Day 14= patient randomized and hospitalized taking study medication for ≥14 days. 
Completed Day 29= patient randomized and hospitalized taking study medication for 29 days. 
Discharge f/u= 4-10 days after hospital discharge. 
Day 29 f/u = 26-32 days following receipt of 1st dose of study medication for telephone review of the 
7-point ordinal scale, need for re-hospitalization and vital status 
Day 60 f/u = 55-65 days following receipt of 1st dose of study medication for telephone review of the 
7-point ordinal scale, need for re-hospitalization and vital status 
 
 
 
 
 
 
 
 


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Table 14.1.2: Screen Failures   
 
Reasons Patients were Screened but not Enrolled 
N (%) 
Investigator decision - patient unsuitable to participate 
 
Creatinine clearance < 30 mL/min at screening 
 
Participation in any other clinical trial 
 
Evidence of multiorgan failure 
 
 
 
Total 
 
 
 
 
 
 


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Table 14.1.3: Major Protocol Deviations 
 
 
 


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Table 14.1.4: Analysis Sets 
 
 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Number Randomized 
 
Number iTT  
 
Number Per Protocol 
 
Number Safety Set 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 14.1.5: Baseline Demographic Characteristics 
 
Baseline Demographic Characteristics 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Age 
Mean, Years (SD) 
 
 
 
 
Median  
 
 
 
 
(min, max) 
 
 
 
 
Gender 
Female 
 
 
 
 
Male 
 
 
 
 
Height 
Height (cm) (SD) 
 
 
 
 
Weight 
Weight (kg) (SD) 
 
 
 
 
BMI 
BMI (kg/m2) (SD) 
 
 
 
 
Ethnicity 
Hispanic or Latino 
 
 
 
 
Not Hispanic or Latino 
 
 
 
 
Not Reported 
 
 
 
 
Race 
American Indian or Alaska 
 
 
 
 
Asian 
 
 
 
 
Black or African American 
 
 
 
 
Native Hawaiian/Other Pacific Islanders 
 
 
 
 
Other 
 
 
 
 
White 
 
 
 
 
Smoking  
History 
Never a smoker 
 
 
 
Present tobacco smoker 
 
 
 
 
Pretentious tobacco smoker 
 
 
 
 
 
 
* %: uses Column total as the denominator.  
a All randomized participants reported 2-Moderate of COVID disease severity at baseline 
 
 
 
 
 
 


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v. 3.0 dated 17 March 2021 
 
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Table 14.1.5a: Baseline Demographic Characteristics by Baseline Clinical Status: Scale = 3a 
 
Baseline Demographics 
(Baseline Clinical Status = 3) 
Enrolled 
(N=1) 
Ensifentrine 
(N=1) 
Placebo 
(N=0) 
Age 
Years of Age (SD) 
 
 
 
 
Gender 
Female 
 
 
 
 
Male 
 
 
 
 
Height 
Height (cm) (SD) 
 
 
 
 
Weight 
Weight (kg) (SD) 
 
 
 
 
BMI 
BMI (kg/m2) (SD) 
 
 
 
 
Ethnicity 
Hispanic or Latino 
 
 
 
 
Not Hispanic or Latino 
 
 
 
 
Not Reported 
 
 
 
 
Race 
American Indian or Alaska 
 
 
 
 
Asian 
 
 
 
 
Black or African American 
 
 
 
 
Native Hawaiian/Other Pacific Islanders 
 
 
 
 
Other 
 
 
 
 
White 
 
 
 
 
Smoking  
History 
Never a smoker 
 
 
 
Present tobacco smoker 
 
 
 
 
Previous tobacco smoker 
 
 
 
 
a7-point scale: Scale 3-Hospitalized, not requiring supplemental oxygen, but requiring ongoing 
medical care 
 


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Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
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Table 14.1.5b: Baseline Demographic Characteristics by Baseline Clinical Status: Scale = 4b 
 
Baseline Demographic Characteristics 
(Baseline Clinical Status = 4) 
Enrolled 
(N=44) 
Ensifentrine 
(N=1) 
Placebo 
(N=0) 
Age 
Years of Age (SD) 
 
 
 
 
Gender 
Female 
 
 
 
 
Male 
 
 
 
 
Height 
Height (cm) (SD) 
 
 
 
 
Weight 
Weight (kg) (SD) 
 
 
 
 
BMI 
BMI (kg/m2) (SD) 
 
 
 
 
Ethnicity 
Hispanic or Latino 
 
 
 
 
Not Hispanic or Latino 
 
 
 
 
Not Reported 
 
 
 
 
Race 
American Indian or Alaska 
 
 
 
 
Asian 
 
 
 
 
Black or African American 
 
 
 
 
Native Hawaiian/Other Pacific Islanders 
 
 
 
 
Other 
 
 
 
 
White 
 
 
 
 
Smoking  
History 
Never a smoker 
 
 
 
Present tobacco smoker 
 
 
 
 
Previous tobacco smoker 
 
 
 
 
b7-point scale: Scale 4-Hospitalized, requiring any supplemental oxygen 
 
 


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Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
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Table 14.1.6: Baseline Clinical Characteristics 
 
Baseline Clinical Characteristics 
                                                        Mean (SD) or Count % 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
 
n 
n 
n 
7-Point Ordinal 
Scale 
3-Hospitalized, no supplemental 
oxygen 
 
 
 
 
4-Hospitalized, any supplemental 
oxygen 
 
 
 
 
5-Hospitalized, requiring non-
intensive ventilation or use of high 
flow oxygen devices 
 
 
 
COVID disease 
severity 
Mild 
 
 
 
 
moderate 
 
 
 
 
Severe 
 
 
 
 
 
 
 
 
Symptom display 
for eligibility 
 
 
 
 
 
Respiratory rate: >24 bpm 
 
 
 
 
New cough 
 
 
 
 
New atypical chest pain 
 
 
 
 
New dyspnea 
 
 
 
 
O2 saturation: <97% 
 
 
 
 
Chest x-ray: new changes 
consistent with COVID related 
airspace disease 
 
 
 
 
Temperature 
ºC (SD) 
 
 
 
 
Pulse Rate/Heart 
Rate 
beats per minute 
 
 
 
 
Respiratory Rate 
beats per minute  
 
 
 
 
Blood Pressure 
(SBP) 
mmHg  
 
 
 
 
Blood Pressure 
(DBP) 
mmHg  
 
 
 
 
Arterial Blood 
Pressure  
mmHg  
 
 
 
 
Oxygen Saturation SPO2  
 
 
 
 
Supplemental 
Oxygen 
FiO2  
 
 
 
 
Co-morbid 
conditions 
None 
 
 
 
 
One 
 
 
 
 
Two or more 
 
 
 


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Baseline Clinical Characteristics 
                                                        Mean (SD) or Count % 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
 
n 
n 
n 
 
Obesity 
Yes 
 
 
 
 
No 
 
 
 
 
Hypertension 
Yes 
 
 
 
 
No 
 
 
 
 
Diabetes Type 1 
Yes 
 
 
 
 
No 
 
 
 
 
Asthma 
Yes 
 
 
 
 
No 
 
 
 
 
COPD 
Yes 
 
 
 
 
No 
 
 
 
 
 
FDA’s document: COVID-19: Developing Drugs and Biological Products for Treatment or Prevention 
Guidance for Industry (May 2020). 
• 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, 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. 
 


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v. 3.0 dated 17 March 2021 
 
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Table 14.1.9: Disease onset, ITT  
 
    
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
 
 
 
 
 
 
N 
N 
n 
 
Days with COVID Symptoms 
before randomization 
Mean (SD) 
 
 
 
 
Median (Min. – Max.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
N 
n 
 
Oxygen at Randomization 
Yes 
 
 
 
 
No 
 
 
 
 
 
 


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Statistical Analysis Plan 
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Table 14.1.10: Number and Proportion Taking Dexamethasone or Remdesivir, ITT 
 
Overall, and by Treatment Group from initiation of study medication 
 
 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Taking Dexamethasone and Remdesivir 
Yes 
 
 
 
 
No& 
 
 
 
Taking Dexamethasone only 
Yes 
 
 
 
 
No 
 
 
 
 
Taking Remdesivir only 
Yes 
 
 
 
 
No 
 
 
 
 
 
 
 
&No Dexamethasone and No Remdesivir 
 
a All randomized participants reported 2-Moderate of COVID disease severity at baseline 
 
 
 


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Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
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Table 14.1.11: COVID-19 Treatment and other Concomitant Respiratory Medications, ITT 
 
                         Medications Introduced from initiation of study medication 
 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Taking COVID-19 Treatment 
Yes 
 
 
 
 
No 
 
 
 
 
Antibiotics 
Yes 
 
 
 
 
No 
 
 
 
 
Antiviral Agent 
Yes 
 
 
 
 
No 
 
 
 
 
Corticosteroid 
Yes 
 
 
 
 
No 
 
 
 
 
Intravenous Fluids 
Yes 
 
 
 
 
No 
 
 
 
 
Non-steroidal Anti-inflammatory 
Yes 
 
 
 
 
No 
 
 
 
 
other 
Yes 
 
 
 
 
No 
 
 
 
 
 
 
 


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Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
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Table 14.2.1: Study Medication Compliance from initiation of study medication 
 
 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
 
Missed dose of study medication after 
administration of 1st  
 
Yes 
No* 
 
 
 
 
*No means 100% compliance 
Listing will have information for doses missed 
 
 
 


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Statistical Analysis Plan 
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Table 14.2.2: Patient last day receiving study medication from initiation of study medication, 
by study day 
 
 
Study 
Day 
Enrolled 
(N=45) 
Ensifentrin
e 
(N=30) 
Placebo 
(N=15) 
Patient final day receiving study 
medication  
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
                                                                          10 
 
 
 
                                                                          11 
 
 
 
 
 
Study day of when the patient was administered their last dose of study medication (post-1st dose on 
Day 1). 
 
 


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v. 3.0 dated 17 March 2021 
 
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Table 14.2.3: Proportion of Patients with Recovery* from initiation of study medication at 29 
Days, ITT 
 
 
 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Proportion Recovered 
(scored 1 or 2) at Day 29 
Overall 
 
 
N 
N 
Analysis results 
 
 
 
 
 
 
 
 
 
Proportion recovered by: 
 
 
 
 
Age Group 
< 65 years old 
 
N 
N 
 
 
 
(XX%) 
 
 
> 65 years 
 
N 
N 
 
 
 
 
 
Gender 
Male 
 
N 
N 
 
 
 
 
 
 
Female 
 
N 
N 
 
 
 
 
 
Disease Severity 
Moderate 
 
N 
N 
 
 
 
 
 
Smoking History 
Present  
 
N 
N 
 
 
 
 
 
 
Previous 
 
N 
N 
 
 
 
 
 
 
Never  
 
N 
N 
 
 
 
 
 
# of Co- morbidities 
None 
 
N 
N 
 
 
 
 
 
 
One 
 
N 
N 
 
 
 
 
 
 
Two or more 
 
N 
N 
 
 
 
 
 
n = number of patients with recorded value 
* Recovery = one of the following two categories from the 7-point ordinal scale: 
1. not hospitalized, no limitations of activities; 
2. not hospitalized, limitation of activities, home oxygen requirement, or both. 
 
 


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Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
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Table 14.2.4: Proportion of Patients with Recovery* from initiation of study medication at 29 
Days, PP 
 
 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Overall 
 
 
 
 
 
Patient with Recovery 
Yes 
 
 
 
 
No 
 
 
 
 
* Recovery = one of the following two categories from the 7-point ordinal scale: 
1. not hospitalized, no limitations of activities; 
2. not hospitalized, limitation of activities, home oxygen requirement, or both. 
 
 


pg. 49 
Confidential 
 
Table 14.2.5: Time to recovery*, from initiation of study medication - Day 29 (or discharge, 
whichever was first) 
 
 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
p-value 
(log-
rank) 
 
 
Days to recovery  
n 
 
 
 
 
Mean (SD) 
 
 
 
 
Median (Min. – Max.)  
 
 
 
 
 
n = number of patients with recorded value 
* Recovery = one of the following two categories from the 7-point ordinal scale: 
1. not hospitalized, no limitations of activities; 
2. not hospitalized, limitation of activities, home oxygen requirement, or both. 
 
 


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Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
 
pg. 50 
Confidential 
 
Table 14.2.6: Proportion of patients in recovery*  from initiation of study medication, ITT 
 
 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Recovery through Day 60 
n 
 
 
 
 
Yes 
 
 
 
 
No 
 
 
 
 
Recovery Day 1 - Day 7 
n 
 
 
 
 
Yes 
 
 
 
 
No 
 
 
 
 
Recovery Day 1 - Day 14 
n 
 
 
 
 
Yes 
 
 
 
 
No 
 
 
 
 
n = number of patients with recorded value 
* Recovery = one of the following two categories from the 7-point ordinal scale: 
1. not hospitalized, no limitations of activities; 
2. not hospitalized, limitation of activities, home oxygen requirement, or both. 
 
 
 


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v. 3.0 dated 17 March 2021 
 
 
pg. 51 
Confidential 
 
Table 14.2.7: Proportion of patients with improvement of one category using the 7-point 
ordinal scale from initiation of study medication, ITT 
 
 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
One Category Improvement, Day 1 - Day 7 
n 
 
 
 
 
Yes 
 
 
 
 
No 
 
 
 
 
One Category Improvement, Day 1 - Day 14 
n 
 
 
 
 
Yes 
 
 
 
 
No 
 
 
 
 
One Category Improvement, Day 1 - Day 29 
n 
 
 
 
 
Yes 
 
 
 
 
No 
 
 
 
 
Improvement = A decrease from baseline of at least one point in the 7-point ordinal score  
(or discharge, whichever was first) 
 
 


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Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
 
pg. 52 
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Table 14.2.8: Proportion of patients with improvement of two categories using the 7-point 
ordinal scale from initiation of study medication, ITT 
 
 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Two Categories Improvement, Day 1 - Day 7 
n 
 
 
 
 
Yes 
 
 
 
 
No 
 
 
 
 
Two Categories Improvement, Day 1 - Day 14 n 
 
 
 
 
Yes 
 
 
 
 
No 
 
 
 
 
Two Categories Improvement, Day 1 - Day 29 n 
 
 
 
 
Yes 
 
 
 
 
No 
 
 
 
 
Improvement = An increase from baseline of at least one point in the 7-point ordinal scale score  
(or discharge, whichever was first) 
 
 


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v. 3.0 dated 17 March 2021 
 
 
pg. 53 
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Table 14.2.9: All-cause mortality, ITT 
 
 
 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
 
 
 
 
Reason of death at Day 29 
 
0 (0%) 
 
 
 
 
 
Reason of death at Day 60 
 
0 (0%) 
 
 
 
 


Verona Pharma Inc 
 
Statistical Analysis Plan 
RPL554-COV-201 
 
v. 3.0 dated 17 March 2021 
 
 
pg. 54 
Confidential 
 
Table 14.2.10: Proportion of patients Alive and not in Respiratory Failure* from initiation of 
study medication, ITT 
 
Proportion of Patients Alive and not in 
Respiratory Failure (Scales less than 6) 
 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Day 1 - Day 7 
n 
 
 
 
 
Yes 
 
 
 
 
No 
 
 
 
 
Day 1 - Day 14 
n 
 
 
 
 
Yes 
 
 
 
 
No 
 
 
 
 
Day 1 - Day 29 
n 
 
 
 
 
Yes 
 
 
 
 
No 
 
 
 
 
(or discharge, whichever was first) 
*7-point ordinal scale score = 1, 2, 3, 4 or 5. 
n = number of patients with recorded value 
 
 


Verona Pharma Inc 
 
Statistical Analysis Plan 
RPL554-COV-201 
 
v. 3.0 dated 17 March 2021 
 
 
pg. 55 
Confidential 
 
Table 14.2.11: Summary of Proportion of patients re-hospitalized following initiation of study 
medication and subsequent discharge (over 60 days), ITT 
 
Proportion of Patients Re-hospitalized 
 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Day 1 - Day 60 
n 
 
 
 
 
Yes 
 
 
 
 
No 
 
 
 
 
 
n = number of patients with recorded value 
 
 
 


Verona Pharma Inc 
 
Statistical Analysis Plan 
RPL554-COV-201 
 
v. 3.0 dated 17 March 2021 
 
 
pg. 56 
Confidential 
 
Table 14.2.12: Duration of hospitalization from initiation of study medication (Day 1 - Day 29 
(or discharge, whichever was first); measured in days), ITT 
 
Days of hospitalization  
from Day 1 
Enrolled 
(N=45 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
p-value* 
 Median (Q1 - Q3) 
 
 
 
 
    *Wilcoxon rank sum test 
Hospitalized = # days where the 7-point ordinal scale score = 3, 4, 5 or 6.  
Discharge = The patient is discharged and leaves the hospital alive. 
 
 
 


Verona Pharma Inc 
 
Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
 
pg. 57 
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Table 14.2.13: Change from Baseline in 7-point Ordinal Scale at Days 7, 14, and 29, ITT 
 
Change from Baseline in  
7-point Ordinal Scale 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Day 7 
n 
 
 
 
 
Mean (SD) 
 
 
 
Day 14 
n 
 
 
 
 
Mean (SD) 
 
 
 
Day 29 
n 
 
 
 
 
Mean (SD) 
 
 
 
 
Computed from Day 1 scale minus Day 7, Day 14, and Day 29 scale accordingly (or discharge) 
(or discharge, whichever was first) 
 
 
 
 
 


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Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
 
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Table 14.2.14: Total time on Supplemental Oxygen (Day 1 - Day 29; measured in days), ITT 
 
Days of Supplemental Oxygen 
(Scale=4) 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Day 1 - 29 
Median (Q1 - Q3) 
 
 
 
 
Hospitalized patient: 7-point ordinal scale score = 4, 5, or 6. Or 7-point ordinal scale score is equal to 
7 if patient dies while hospitalized between Day 1-29. 
Not hospitalized patient supplemental oxygen = # days where the 7-point ordinal scale score is equal 
to 2 (if required to have home oxygen). 
 
 
 
 
 


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Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
 
pg. 59 
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Table 14.2.15: Total time of non-invasive ventilation or high flow oxygen use (post-dose Day 1 
- Day 29 (or discharge, whichever was first); measured in days) 
 
Days of non-invasive ventilation or  
High Flow Oxygen Use (Scale=5) 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Day 1 - 29 
Median (Q1 - 
Q3) 
 
 
 
 
Non-invasive ventilation or high flow oxygen use = # days where the 7-point ordinal scale score is 
equal to 5 or 6. Or 7-point ordinal scale score is equal to 7 if patient dies while hospitalized between 
Day 1-29. 
 
 


Verona Pharma Inc 
 
Statistical Analysis Plan 
RPL554-COV-201 
 
v. 3.0 dated 17 March 2021 
 
 
pg. 60 
Confidential 
 
Table 14.2.16: Summary of the Proportion of Patients Alive and with Oxygen Use at Days 7, 14 
and 29 (or discharge, whichever was first), ITT  
 
Proportion of Patients with 
Oxygen Use (Scales in 4, 5, and 6) 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Day 7 
Yes 
 
 
 
 
No 
 
 
 
 
Day 14 
Yes 
 
 
 
 
No 
 
 
 
 
Day 29 
Yes 
 
 
 
 
No 
 
 
 
 
Hospitalized patient supplemental oxygen = the 7-point ordinal scale score is equal to 4, 5, or 6. 
Not hospitalized patient supplemental oxygen = the 7-point ordinal scale score is equal to 2 (if 
required to have home oxygen). 
 
 
 
 


Verona Pharma Inc 
 
Statistical Analysis Plan 
RPL554-COV-201 
 
v. 3.0 dated 17 March 2021 
 
 
pg. 61 
Confidential 
 
Table 14.2.17: Summary of the Proportion of Patients Alive and with non-invasive Ventilation 
or High Flow Oxygen Use at Days 7, 14 and 29 (or discharge, whichever was first), ITT 
 
Proportion of Patients with Non-invasive 
Ventilation or High Flow Oxygen Use 
(Scale=5) 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Day 7 
Yes 
 
 
 
 
No 
 
 
 
 
Day 14 
Yes 
 
 
 
 
No 
 
 
 
 
Day 29 
Yes 
 
 
 
 
No 
 
 
 
 
Non-invasive ventilation or high flow oxygen use = the 7-point ordinal scale score is equal to 5 or 
6. 
 
 
 
 


Verona Pharma Inc 
 
Statistical Analysis Plan 
RPL554-COV-201 
 
v. 3.0 dated 17 March 2021 
 
 
pg. 62 
Confidential 
 
Table 14.2.18: Proportion of Patients Alive and Receiving Invasive Mechanical Ventilation or 
Extracorporeal Membrane Oxygenation (ECMO, 7-point ordinal scale criteria #6) at Days 7, 14 
and 29 (or discharge, whichever was first), ITT 
 
Proportion of Patients with ECMO  
(Scale=6) 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Day 7 
Yes 
 
 
 
 
No 
 
 
 
 
Day 14 
Yes 
 
 
 
 
No 
 
 
 
 
Day 29 
Yes 
 
 
 
 
No 
 
 
 
 
IMV = The 7-point ordinal scale score is equal to 6. 
 
 
 
 
 
 
 
 
 
 


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Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
 
pg. 63 
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Table 14.3.1: Time to first composite AE 
 
 
Enrolled 
(N=45) 
Ensifentrine 
(N=30) 
Placebo 
(N=15) 
Proportion of AE 
Yes 
 
 
 
 
No 
 
 
 
 
Time to first composite AEa Days from consent (SD) 
 
 
 
 
Median (min. - Max.) 
 
 
 
 
a Consider those who experienced Adverse events 
 
 
 


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Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
 
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Table 14.3.2: Number/Proportion Treatment emergent adverse events 
 
 
 
TEAE Category 
Statistic 
Total Ensifentrine 
(N=30) 
Placebo 
 
(N=15) 
Any TEAE 
N (%) 
 
 
 
Any TEAE leading to study medication 
discontinuation 
 
 
 
 
Any TEAE related to study medication 
 
 
 
 
Any serious TEAE 
 
 
 
 
Any serious TEAE leading to study medication 
discontinuation 
 
 
 
 
Any serious TEAE leading to death 
 
 
 
 
Any TEAE classified by maximum severity 
 
 
 
 
Mild 
 
 
 
 
Moderate 
 
 
 
 
Severe 
 
 
 
 
Any serious TEAE classified by maximum severity 
 
 
 
 
Moderate 
 
 
 
 
Severe 
 
 
 
 
Abbreviations: AE, adverse event; N, number of patients in treatment group; n, number of patients in 
analysis; TEAE, treatment-emergent adverse event; %, percentage of patients calculated relative to 
the total number of patients in the treatment group.  
 
TEAEs were defined as all AEs that started after the first dose of study treatment or started after the 
first dose of study treatment or started prior to first dose of study treatment and worsened, based on 
the Investigator’s assessment of severity on or after the first dose of study treatment. TEAEs with a 
missing severity were classified as severe 
 
 


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Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
 
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Table 14.3.3: Number/Proportion TEAEs by System Organ Class and Preferred Term 
 
 
 
 
Statistic Total Ensifentrine 
(N=30) 
Placebo  
(N=15) 
System Organ Class 
Preferred Term 
 
 
 
 
Patients with at least one TEAE 
N (%) 
 
 
 
 
 
 
 
 
Metabolism and nutrition disorders 
N (%) 
 
 
 
Dehydration, hyperglycemia 
N (%) 
 
 
 
 
 
 
 
 
Gastrointestinal disorders 
 
 
 
 
Diarrhoea 
 
 
 
 
 
 
 
 
 
Investigations 
N (%) 
 
 
 
Alanine aminotransferase increased, Aspartate 
aminotransferase increased 
N (%) 
 
 
 
 
 
 
 
 
Vascular disorders 
N (%) 
 
 
 
Hypertension 
N (%) 
 
 
 
Shock 
N (%) 
 
 
 
 
n = number of patients 
 
 
Table 14.3.4: Number/Proportion TEAEs Leading to Discontinuation of Study by System 
Organ Class and Preferred Term 
 
 
Table 14.3.5: Number/Proportion TEAEs Causally Related to the Study Treatment by System 
Organ Class and Preferred Term 
 
 
 
 
 
 


Verona Pharma Inc 
 
Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
 
pg. 66 
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Table 14.3.6: Number/Proportion TEAEs by Maximum Severity by System Organ Class and 
Preferred Term 
 
 
 
Severity 
Statistic Total Ensifentrine 
(N=30) 
Placebo  
(N=15) 
System Organ Class 
Preferred Term 
 
 
 
 
 
Patients with at least one TEAE 
Severe 
N (%) 
 
 
 
 
Moderate 
N (%) 
 
 
 
 
Mild 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOC 
Severe 
 
 
 
 
 
Moderate 
 
 
 
 
 
Mild 
 
 
 
 
Preferred Term 
Severe 
 
 
 
 
 
Moderate 
 
 
 
 
 
Mild 
 
 
 
 
 
 
Table 14.3.7: Number/Proportion Serious TEAEs by System Organ Class and Preferred       
Term  
 
 
Table 14.3.8: Number/Proportion Serious TEAEs Causally Related to the Study Treatment by 
System Organ Class and Preferred Term 
 
 
Table 14.3.9: Number/Proportion Serious TEAEs by Maximum Severity by System Organ 
Class and Preferred Term 
 
 
Table 14.3.10: Number/Proportion Serious TEAEs Leading to Discontinuation of Study by 
System Organ Class and Preferred Term 
 
Table 14.3.11: Number/Proportion Serious TEAEs with an Outcome of Death by System Organ 
Class and Preferred Term 
 
 
 
 
 
 


Verona Pharma Inc 
 
Statistical Analysis Plan 
RPL554-COV-201 
 
v. 3.0 dated 17 March 2021 
 
 
pg. 67 
Confidential 
 
Exploratory Analyses  
 
ECMO: invasive mechanical ventilation or extracorporeal membrane oxygenation 
 
Description of the distribution of the 7-point ordinal scale outcomes using plots (e.g., 
stacked bar plots representing the proportion of patients in each category, by treatment 
arm, over time). 
 
Descriptive summary of the number of days between hospital admission, positive PCR 
test (or as per hospital testing protocol) and randomization. 
 
Proportion of total patients requiring any oxygen at randomization. 
• For those that required oxygen, the mean/standard deviation or median/IQR for 
the oxygen amount (in FiO2). 
• Oxygen use while hospitalized and undergoing study treatment. 
 
Measurement of the oxygen requirement: compare the oxygen requirement (mean and 
median) for each arm using daily supplemental oxygen flow (L/min).  
 
 
 


Verona Pharma Inc 
 
Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
 
pg. 68 
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Figures 
Figure 1:  Patient Disposition 
 
 
 
 
 
Assessed for eligibility (n=   )
Excluded (n=  )
¨ Not meeting inclusion criteria (n= )
¨ Participation in other trial (n= )
¨ Investigator decision (n=  )
Analysed  (n=  )
¨ Excluded from analysis (give reasons) (n=  )
Lost to follow-up (give reasons) (n=  )
Discontinued intervention (give reasons) (n=  )
Allocated to intervention (n=30)
¨ Received allocated intervention (n=  )
¨ Did not receive allocated intervention (give 
reasons) (n=  )
Lost to follow-up (give reasons) (n=  )
Discontinued intervention (give reasons) (n=  )
Allocated to intervention (n=15)
¨ Received allocated intervention (n=  )
¨ Did not receive allocated intervention (give 
reasons) (n=  )
Analysed  (n=  )
¨ Excluded from analysis (give reasons) (n=  )
Allocation
Analysis
Follow-Up
Randomized (n=  )
Enrollment


Verona Pharma Inc 
 
Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
 
pg. 69 
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Figure 2:  Kaplan–Meier plot of time to Recovery 
 
 
 


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v. 3.0 dated 17 March 2021 
 
 
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Figure 3:  Histogram of ordinal scores at Day 7, 14, 29 by treatment group and 
baseline ordinal scale 
 
 
 


Verona Pharma Inc 
 
Statistical Analysis Plan 
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v. 3.0 dated 17 March 2021 
 
 
pg. 71 
Confidential 
 
Figure 4:  Proportion of Patients in Oxygen Need by Day in Study 
 
 
 
 
 


Verona Pharma Inc 
 
Statistical Analysis Plan 
RPL554-COV-201 
 
v. 3.0 dated 17 March 2021 
 
 
pg. 72 
Confidential