Clinical trial NCT04091360
Conditions: COPD
Keywords: COPD Adults Phase II RPL554 Ensifentrine
Sponsor: Verona Pharma plc
Start date: 2019-04-29; Completion date: 2021-01-21
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to investigate 5 doses of RPL554 and placebo, administered by pressurized metered dose inhaler (pMDI), in patients with moderate to severe chronic obstructive pulmonary disease (COPD).

Detailed description:
The study will consist of two parts. Part A is a parallel group, placebo-controlled single dose study to ascertain the Pharmacokinetics (PK) profile, safety and bronchodilator effect of a single dose of RPL554 administered via pMDI. Five of the 6 treatment arms will be double-blind and one will be single-blind (due to the different number of capsules administered). Part B is a 7-day placebo-controlled, complete block cross-over, repeat dose study to assess the bronchodilator effect of repeat doses of RPL554 delivered via pMDI.

Arms: arm 1: Part A: Patients receive 1 dose of either RPL554 100mcg via metered dose inhaler.

Part B: not applicable arm 2: Part A: Patients receive 1 dose of RPL554 300mcg via metered dose inhaler. Part B: Patients receive repeat doses of RPL554 300mcg via metered dose inhaler in crossover fashion. arm 3: Part A: Patients receive 1 dose of RPL554 1000mcg via metered dose inhaler. Part B: Patients receive repeat doses of RPL554 3000mcg via metered dose inhaler in crossover fashion. arm 4: Part A: Patients receive 1 dose of either RPL554 3000mcg via metered dose inhaler.

Part B: Patients receive repeat doses of RPL554 3000mcg via metered dose inhaler in crossover fashion. arm 5: Part A: Patients receive 1 dose of either RPL554 6000mcg via metered dose inhaler.

Part B: not applicable arm 6: Part A: Patients receive 1 dose of RPL554 placebo via metered dose inhaler. Part B: Patients receive repeat doses of RPL554 placebo via metered dose inhaler in crossover fashion.
Interventions: intervention 1: Part A: RPL554 intervention 2: Placebos intervention 3: Part B: RPL554
Intervention descriptions: intervention 1: Single dose RPL554 via metered dose inhaler. intervention 2: Part A: Single dose placebo via metered dose inhaler. Part B: Repeat doses of placebo via metered dose inhaler in crossover fashion. One dose administered twice daily over 7 days. intervention 3: Part B: Repeat doses via metered dose inhaler in crossover fashion. One dose administered twice daily over 7 days.

Protocol documents:
Prot_002.pdf: 
THIS STUDY WILL BE CONDUCTED IN ACCORDANCE WITH THE 
INTERNATIONAL COUNCIL ON HARMONISATION GUIDELINES FOR GOOD 
CLINICAL PRACTICE (DIRECTIVE CPMP/ICH/135/95), THE DECLARATION OF 
HELSINKI (1964) AS AMENDED AND APPLICABLE REGULATORY 
REQUIREMENTS
CONFIDENTIAL
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CLINICAL STUDY PROTOCOL
A PHASE II, RANDOMISED STUDY TO ASSESS THE 
PHARMACOKINETICS, SAFETY AND
PHARMACODYNAMICS OF SINGLE AND REPEAT DOSES 
OF RPL554 ADMINISTERED BY PRESSURISED METERED 
DOSE INHALER IN PATIENTS WITH COPD
STUDY NO. RPL554-MD-201
Version:
3.0
Date:
24 December 2019 
Phase: 
II
Investigational 
Medicinal Product: 
RPL554
EudrACT number: 
2018-004896-11 
Verona Pharma plc


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SPONSOR SIGNATURE PAGE
THIS DOCUMENT HAS BEEN APPROVED BY VERONA PHARMA PLC:
Name and Title
Signature
Date
Kathleen Rickard, MD
Chief Medical Officer


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INVESTIGATOR SIGNATURE PAGE
I, the undersigned, am responsible for the conduct of the study at my study centre and agree to 
the following:
I understand that this protocol is a confidential document for the use of the Investigator’s team 
and other persons involved in the study only, and for the information of the Independent Ethics 
Committee (IEC). The information contained herein must not be communicated to a third party 
without prior written approval from the Sponsor.  
I understand and will conduct the study according to the protocol, any approved protocol 
amendments, ICH GCP and all applicable regulatory authority requirements and national laws. 
To ensure compliance with the guidelines, the study will be monitored by a representative of 
the Sponsor and may be audited by an independent body. I agree, by written consent to the 
protocol, to fully co-operate with compliance checks by allowing access to all documentation 
by authorised individuals. 
I have read and understand fully the Investigator Brochure and I am familiar with the study 
medication and its use according to this protocol. 
Name and Title
Signature
Date
CONFIDENTIALITY STATEMENT
The contents of this document are the property of Verona Pharma plc and should be regarded 
as confidential. 
It is intended to provide information on the investigational medicinal product for the use of 
clinical Investigators, their research associates, members of IECs as well as others directly 
concerned in the conduct of clinical studies. 
It may not be copied, reproduced or cited as a reference without the permission of Verona 
Pharma plc from whom additional copies can be obtained if needed.  
No unpublished information contained herein may be disclosed without the prior written 
approval of Verona Pharma plc. 


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CONTACT LIST
Sponsor 
Verona Pharma plc 
3 More London Riverside 
London, SE1 2RE 
UK
+44 (0)203 283 4200
Contract Research
IQVIA
Organisation
4820 Emperor Boulevard 
Durham, NC 27703 
USA
A full list of all vendors will be provided to all participating study centres and maintained in 
the study file.


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DETAIL OF AMENDMENTS SINCE THE PREVIOUS VERSION
Synopsis
The Planned Study Period has been extended to June 2020. 
Section 4.1, Inclusion Criteria
In Inclusion Criterion 4, the range for heart rate obtained from ECG has been changed from 
50-90 to 45-109 beats per minute.
Section 4.2, Exclusion Criteria 
Wording for Exclusion Criterion 14 has been changed as follows: 
From: Documented cardiovascular disease, including any history (<1 year) of arrhythmias, 
angina, recent or suspected myocardial infarction, congestive heart failure, unstable or 
uncontrolled hypertension, or diagnosis of hypertension within 3 months prior to Screening. 
To: Historical or current evidence of clinically significant cardiovascular disease.  Significant 
is defined as any disease that in the opinion of the investigator could put the safety of the patient 
at risk, or could affect the efficacy or safety analyses if the condition were to exacerbate during 
the study.  In particular, the following are excluded: 
x
Myocardial infarction within 1 year prior to Screening
x
Unstable angina within 6 months prior to Screening
x
Unstable or life-threatening arrythmia requiring intervention within 3 months prior to
Screening
x
Diagnosis of NYHA class III or IV heart disease
Section 6.4.1.2, Study Medication Administration
During Day 1 of each treatment period in Part B, the time window for administering the second 
(evening) dose has been increased from ±10 minutes to ±30 minutes. 


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SYNOPSIS
Title of Study: 
A Phase II, Randomised Study to Assess the Pharmacokinetics, Safety and
Pharmacodynamics of Single and Repeat Doses of RPL554 Administered by 
Pressurised Metered Dose Inhaler in Patients with COPD
Protocol Number:
RPL554-MD-201
EudrACT Number: 
2018-004896-11
Phase: 
II
Sponsor:
Verona Pharma plc
Study Centre(s): 
Two or three study centres in the UK
Planned Study Period:
April 2019 to June 2020
Objectives:
Part A:
Primary Objective
To investigate the pharmacokinetic (PK) profile of single doses of RPL554, 
administered by pressurised metered dose inhaler (pMDI), in patients with moderate 
to severe chronic obstructive pulmonary disease (COPD). 
Secondary Objectives
x
To investigate the safety and tolerability of single doses of RPL554
administered by pMDI, including effects on peak pulse and heart rate
x
To investigate the bronchodilator effect of single doses of RPL554
administered by pMDI, in terms of peak forced expiratory volume in 1 second
(FEV1), average FEV1 area under the curve (AUC)0-4h and average FEV1 AUC0-
12h
Part B:
Primary Objective
To investigate the bronchodilator effect of repeat doses of RPL554 administered by 
pMDI, assessed in terms of peak FEV1.
Secondary Objectives
x
To investigate the safety and tolerability of repeat doses of RPL554,
administered by pMDI
x
To investigate the bronchodilator effect of RPL554 administered by pMDI, in
terms of average FEV1 AUC0-12h, average FEV1 AUC0-4h, and trough FEV1
x
To determine the onset of action of RPL554 administered by pMDI
x
To evaluate the PK profile of RPL554 administered by pMDI
x
To evaluate the amount of rescue medication use during treatment periods
Exploratory Objectives
x
To assess the dose response of RPL554 on peak and average FEV1 AUC0-12h
after morning dose on Day 7, and morning trough FEV1 prior to the last dose
on Day 7
x
To examine the effect of RPL554 administered by pMDI on a Likert dyspnoea
scale
Study Design and 
Methodology:
This study will consist of two parts: 
Part A is a parallel group, placebo controlled single dose study to ascertain the PK 
profile, safety and bronchodilator effect of RPL554 administered via a pMDI. There 
will be six treatment arms; five will be double blind and one will be single-blind (due 
to the different number of puffs administered). 
Part B is a placebo controlled, complete block crossover, repeat dose study to assess 
the bronchodilator effect of repeat doses of RPL554 dosed twice daily via a pMDI 
over 7 days. The treatments will be double blind.


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Patients will be screened for eligibility, including a reversibility test (spirometry both 
pre- and post-four puffs of salbutamol) between 7 and 14 days before the first dose 
of study medication.
Part A:
After passing Screening and meeting all inclusion and no exclusion criteria, 
approximately 36 patients will participate in a parallel group, single dose treatment. 
They will be randomised equally to one of six treatment arms with approximately six 
patients per arm. A single dose of RPL554 or placebo will be administered followed 
by 12 hours of study assessments, including PK, safety and serial spirometry. Patients 
will return the following day for assessments at 24 hours post-dose. The data from 
Part A will be locked, unblinded and analysed prior to commencing Part B. Safety, 
PK and efficacy/pharmacodynamic data will be assessed for each treatment arm to
determine which dose levels from Treatment Arms 1 through 4 will be evaluated in 
Part B. 
Part B:
Patients from Part A will then be randomly assigned to one of up to five treatment 
sequences in a crossover design, consisting of up to five 1-week treatment periods 
separated by a 7 to 10 day washout period. Each treatment sequence will include up 
to four dose levels of RPL554 administered by pMDI (selected from Part A) and a
double blind placebo pMDI treatment. Each treatment period consists of 6 days of 
twice daily dosing, followed by a morning dose administered only on Day 7. Patients 
will undergo study assessments over 12 hours on Days 1 and 7 in each treatment 
period. Patients will return for an End of Study Visit approximately 7 days after the 
completion of the final Treatment Period (or sooner in the case of early termination). 
The pre-dose FEV1 on Day 1 of Treatment Periods 2 and forward must be within 
±20% of the pre-dose FEV1 on Day 1 of Treatment Period 1, in order to ensure 
consistent baseline FEV1 for each study treatment.  
Patients will be dispensed rescue medication to be used as needed during the 
Screening, treatment and washout periods. 
Study Procedures:
The following will be performed at each treatment visit:
x
Measurements of lung function (FEV1 and forced vital capacity [FVC]) by
spirometry

Screening

Part A: Pre-dose and up to 12 hours post-dose

Part B: Pre-dose up to 12 hours post-dose on Days 1 and 7

End of Study Visit
x
12-lead electrocardiogram (ECG)

Screening

Part A: Pre-dose and up to 8 hours post dose

Part B: Pre-dose on Days 1 and 7
x
Vital signs

Screening

Part A: Pre-dose and up to 24 hours post-dose

Part B: Pre-dose and up to 12 hours post-dose on Days 1 and 7

End of Study Visit
x
PK

Part A: Pre-dose and up to 24 hours post-dose

Part B: Pre-dose and up to 12 hours post-dose on Days 1 and 7
x
Laboratory safety tests

Screening, pre-dose on Days 1 and 7 of each treatment period in Part B,
and End of Study Visit
Adverse events will be recorded throughout the study.


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Number of Patients Planned:
Approximately 36 randomised patients
Main Criteria for Eligibility:
Inclusion Criteria
Male and female patients with moderate to severe COPD, with a post-bronchodilator 
FEV1 of 40 to 80% of predicted and FEV1)9&UDWLRRI. They must have a 
baseline increase in FEV1 of >150 mL following four puffs of salbutamol. They must 
have at least a 10 pack-year smoking history, and may be either a current or former
smoker. 
Exclusion Criteria 
Patients must be clinically stable without recent COPD exacerbations or 
hospitalisations. They must not have uncontrolled disease or chronic heart failure.
Study Treatments:
In Part A (parallel group), study medication will be administered as a single dose as 
follows: 
Treatment Arm 1: RPL554 100 Pg double blind
Treatment Arm 2: RPL554 300 Pg double blind
Treatment Arm 3: RPL554 1000 Pg double blind
Treatment Arm 4: RPL554 3000 Pg double blind
Treatment Arm 5: RPL554 6000 Pg single-blind
Treatment Arm 6: Placebo double blind
In Part B (double blind crossover), study medication will be administered as repeat
doses (twice daily) over either four or five treatment periods within a putative range 
of 100 Pg up to 3000 Pg, plus placebo, depending on the results from Part A.
Duration of Treatment:
Part A: 7 to 14 day Screening period, followed by single dose treatment and then an
analysis period (exact timing to be determined). 
Part B: Four or five treatment periods, each consisting of 7 days treatment, separated 
by 7 to 10 day washout periods. 
Statistical Methods:
Treatments will be compared using appropriate analysis of covariance models for 
Parts A and B, respectively. Multiplicative models will be used for FEV1 and additive 
models for blood pressure, pulse rate and ECG heart rate. RPL554 by pMDI
treatments will be compared to placebo using a closed test procedure starting with 
the highest dose of RPL554.
Sample Size Determination:
The sample size is determined for Part B. Assuming a residual coefficient of variation
of 6% for peak FEV1, 30 patients will give an 80% power to detect a pairwise 
difference in peak FEV1 of 4.6%. Assuming a mean baseline FEV1 of 1.5 L, this will 
correspond to a difference of about 70 mL. To account for withdrawals, 
approximately 36 patients will be randomised to Part A. 


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TABLE OF CONTENTS AND LIST OF TABLES AND FIGURES
Table of Contents
SPONSOR SIGNATURE PAGE .............................................................................................. 2 
INVESTIGATOR SIGNATURE PAGE................................................................................... 3 
CONFIDENTIALITY STATEMENT....................................................................................... 3 
CONTACT LIST ....................................................................................................................... 4 
DETAIL OF AMENDMENTS SINCE THE PREVIOUS VERSION...................................... 5 
SYNOPSIS................................................................................................................................. 6 
TABLE OF CONTENTS AND LIST OF TABLES AND FIGURES...................................... 9 
Table of Contents ............................................................................................................. 9 
List of Tables and Figures .............................................................................................. 12 
LIST OF ABBREVIATIONS .................................................................................................. 13 
1 
INTRODUCTION .......................................................................................................... 14 
1.1 
Disease and Study Medication Review ................................................................. 14 
1.2 
Summary of Risks and Benefits ............................................................................ 15 
2 
OBJECTIVES................................................................................................................. 16 
2.1 
Part A .................................................................................................................... 16 
2.1.1 
Primary Objective ................................................................................... 16 
2.1.2 
Secondary Objectives ............................................................................. 16 
2.2 
Part B .................................................................................................................... 16 
2.2.1 
Primary Objective ................................................................................... 16 
2.2.2 
Secondary Objectives ............................................................................. 16 
2.2.3 
Exploratory Objectives ........................................................................... 16 
3 
INVESTIGATIONAL PLAN ........................................................................................ 17 
3.1 
Overall Study Design and Plan Description ......................................................... 17 
3.2 
Discussion of Study Design, Including the Choice of Control Groups ................ 17 
3.3 
Planned Duration of the Study .............................................................................. 18 
3.4 
Definition of the End of the Study ........................................................................ 18 
4 
SELECTION OF STUDY POPULATION .................................................................... 19 
4.1 
Inclusion Criteria................................................................................................... 19 
4.2 
Exclusion Criteria ................................................................................................. 20 
4.3 
Removal of Patients from Therapy or Assessment ............................................... 21 
4.3.1 
Study Treatment Discontinuation ........................................................... 21 
4.3.2 
Patient Withdrawal ................................................................................. 21 
4.3.3 
Study Discontinuation ............................................................................. 22 
4.3.4 
Replacement Policy ................................................................................ 22 
5 
STUDY TREATMENTS ............................................................................................... 23 
5.1 
Study Treatments Administered............................................................................ 23 
5.1.1 
Treatments Administered in Part A ........................................................ 23 
5.1.2 
Treatments Administered in Part B ........................................................ 23 


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5.2 
Identity, Preparation and Labelling of Study Treatments ..................................... 23 
5.3 
Selection of Doses and Dosing Schedule .............................................................. 24 
5.3.1 
Selection of Doses in the Study .............................................................. 24 
5.3.2 
Timing of Dose for Each Patient ............................................................ 24 
5.4 
Storage .................................................................................................................. 24 
5.5 
Accountability ....................................................................................................... 24 
5.6 
Method of Assigning Patients to Treatment Groups ............................................. 25 
5.7 
Blinding ................................................................................................................. 25 
5.8 
Prior and Concomitant Therapies and Medications .............................................. 25 
5.8.1 
Prior and Concomitant COPD Medications ............................................ 25 
5.8.2 
Other (non-COPD) Prior and Concomitant Medications ....................... 27 
5.9 
Rescue Medications .............................................................................................. 27 
5.10 Treatment Compliance .......................................................................................... 27 
6 
STUDY PROCEDURES AT EACH VISIT .................................................................. 28 
6.1 
Pre-visit Restrictions.............................................................................................3 
6.2 
Screening...............................................................................................................3 
6.3 
Part A: Single Dose Treatment .............................................................................3 
6.3.1 
Pre-dose Assessments.............................................................................3 
6.3.2 
Study Medication Administration ........................................................... 33 
6.3.3 
Post-dose Assessments ...........................................................................3 
6.4 
Part B: Repeat Dose Treatment.............................................................................3 
6.4.1 
Day 1 of Each Treatment Period.............................................................3 
6.4.1.1 
Pre-dose Assessments ............................................................3 
6.4.1.2 
Study Medication Administration ..........................................3 
6.4.1.3 
Post-dose Assessments...........................................................3 
6.4.2 
Day 7 of Each Treatment Period.............................................................3 
6.4.2.1 
Pre-dose Assessments ............................................................3 
6.4.2.2 
Study Medication Administration ..........................................3 
6.4.2.3 
Post-dose Assessments...........................................................3 
6.5 
End of Study Visit .................................................................................................3 
7 
STUDY METHODOLOGY...........................................................................................3 
7.1 
Demographics, Baseline Characteristics and Eligibility Assessments .................3 
7.1.1 
Demographic Variables ..........................................................................3 
7.1.2 
Medical and Disease History..................................................................3 
7.1.3 
Reversibility Test....................................................................................3 
7.1.4 
Screening Laboratory Assessments, Chest X-ray...................................3 
7.1.5 
Prior and Concomitant Medications and Therapies ................................3 
7.1.6 
Eligibility Check.....................................................................................3 
7.2 
Efficacy/Pharmacodynamic Assessments.............................................................3 
7.2.1 
Pulmonary Function Tests ......................................................................3 
7.2.2 
Dyspnoea Scale.......................................................................................3 


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7.2.3 
Rescue Medication..................................................................................3 
7.3 
Pharmacokinetic Assessments .............................................................................. 39 
7.4 
Safety Assessments............................................................................................... 
7.4.1 
Adverse Events ....................................................................................... 
7.4.1.1 
Adverse Event Definitions ..................................................... 
7.4.1.2 
Recording and Assessing Adverse Events .............................4 
7.4.1.2.1 Severity..................................................................4 
7.4.1.2.2 Chronicity ..............................................................4 
7.4.1.2.3 Causality ................................................................4 
7.4.1.2.4 Action and Outcome ..............................................4 
7.4.1.3 
Reporting Procedure for SAEs...............................................4 
7.4.2 
Pregnancy................................................................................................4 
7.4.3 
Laboratory Assessments .........................................................................4 
7.4.3.1 
Haematology ..........................................................................4 
7.4.3.2 
Blood Chemistry ....................................................................4 
7.4.3.3 
Urinalysis ...............................................................................4 
7.4.4 
Vital Signs...............................................................................................4 
7.4.5 
Physical Examination .............................................................................4 
7.4.6 
12-Lead ECG .......................................................................................... 43 
8 
QUALITY ASSURANCE AND QUALITY CONTROL .............................................4 
8.1 
Audit and Inspection .............................................................................................4 
8.2 
Monitoring and Source Document Verification....................................................4 
8.3 
Data Management and Coding..............................................................................4 
9 
STATISTICAL METHODS ..........................................................................................4 
9.1 
Statistical and Analytical Plans.............................................................................4 
9.2 
Populations to be Analysed...................................................................................4 
9.3 
Study Endpoints ....................................................................................................4 
9.3.1 
Part A......................................................................................................4 
9.3.1.1 
Primary Endpoint ...................................................................4 
9.3.1.2 
Secondary Endpoints .............................................................. 48 
9.3.2 
Part B ......................................................................................................4 
9.3.2.1 
Primary Endpoint ...................................................................4 
9.3.2.2 
Secondary Endpoints ..............................................................4 
9.3.2.3 
Exploratory Endpoint .............................................................4 
9.4 
Statistical Methods................................................................................................ 
9.4.1 
Patient Disposition.................................................................................. 
9.4.2 
Protocol Deviations................................................................................. 
9.4.3 
Demographics and Other Baseline Characteristics................................. 
9.4.4 
Extent of Exposure and Treatment Compliance..................................... 
9.4.5 
Efficacy/Pharmacodynamics .................................................................. 
9.4.6 
Pharmacokinetics....................................................................................5 


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9.4.7 
Safety ......................................................................................................5 
9.4.8 
Handling of Withdrawals or Missing Data.............................................5 
9.4.9 
Interim Analyses.....................................................................................5 
9.5 
Determination of Sample Size ..............................................................................5 
10 
ETHICAL CONSIDERATIONS ...................................................................................5 
10.1 Guidelines .............................................................................................................5 
10.2 Ethics and Regulatory Approval ...........................................................................5 
10.3 Informed Consent Process ....................................................................................5 
10.4 Patient Confidentiality ..........................................................................................5 
10.5 Record Maintenance/Retention.............................................................................5 
11 
FINANCE AND INSURANCE .....................................................................................5 
12 
PUBLICATION POLICY..............................................................................................5 
13 
REFERENCES...............................................................................................................5 
14 
APPENDICES................................................................................................................ 
14.1 Birth Control Methods For Women of Childbearing Potential Which May Be 
Considered As Highly Effective ........................................................................... 
14.2 Interpreting Adverse Event Causality...................................................................6 
List of Tables and Figures
Figure 1 
Study Flow Chart .................................................................................................. 17 
Table 1 
Treatment Arms, Inhaler and Puff Combinations in Part A ................................. 23 
Table 2 
Composition of RPL554 pMDI............................................................................. 24 
Table 3 
Restrictions for COPD Medications Prior to Screening ....................................... 26 
Table 4 
Schedule of Assessments for Screening and Part A ............................................. 29 
Table 5 
Schedule of Assessments for Part B, Days 1 and 7 of each Treatment Period 
and End of Study Visit .......................................................................................... 30 


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LIST OF ABBREVIATIONS
ATS
American Thoracic Society 
AUC
Area under the curve
BMI
Body mass index
Cmax
Maximum concentration
COPD
Chronic obstructive pulmonary disease
CV
Coefficient of variation
ECG
Electrocardiogram
eCRF
Electronic case report form
DPI
Dry powder inhaler
EDTA
Ethylenediaminetetraacetic acid
ERS
European Respiratory Society
FEV1
Forced expiratory volume in 1 second
FSH
Follicle-stimulating hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HFA
Hydrofluoroalkane
HRT
Hormone replacement therapy
ICH
International Council on Harmonisation
ICS
Inhaled corticosteroid
ID
Identification
IEC
Independent Ethics Committee
IUPAC
International Union of Pure and Applied Chemistry
LABA
Long acting ȕ2-agonists
LAMA
Long acting muscarinic antagonists
MedDRA
Medical Dictionary for Regulatory Activities
NHANES
National Health and Nutrition Examination Survey
PDE
Phosphodiesterase
PK
Pharmacokinetics
pMDI
Pressurised metered dose inhaler
QTcF
QT interval corrected for heart rate using Fridericia’s formula
SAE
Serious adverse event
SAS
Statistical analysis software
SOC
System organ class
SUSAR
Suspected, unexpected serious adverse reaction
tmax
Time to maximum concentration


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1
INTRODUCTION
1.1
Disease and Study Medication Review
Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow 
obstruction that is not fully reversible. Chronic inflammation of the respiratory tract, acute 
exacerbations primarily caused by viral and/or bacterial infections, airway remodelling, and 
excessive mucus production are believed to contribute to the airflow obstruction and lung 
parenchymal destruction. COPD is predicted to be the third leading cause of death and fourth 
most common cause of disability worldwide by 2030, and chronic tobacco smoke exposure is 
believed to be a key etiological factor (Stuckler, 2008).  
Current standard of care treatments include inhaled short- and long-acting bronchodilators, 
inhaled corticosteroids and, more recently, the phosphodiesterase (PDE) 4 inhibitor 
roflumilast. These therapies have little or no effect on disease progression or mortality, 
although there is evidence to suggest that they can reduce exacerbation rates and improve 
quality of life (Rabe et al, 2005; Calverley et al, 2007; Rennard et al, 2006, Singh et al, 2015). 
Approximately 30% to 40% of moderate to severe COPD patients on triple inhaled therapy 
(inhaled corticosteroid [ICS]/long acting muscarinic antagonists [LAMA]/long acting 
ȕ2-agonists [LABA]) remain uncontrolled and continue to experience airway obstruction, 
COPD symptoms and exacerbations (Vestbo et al, 2017). Thus, there is an urgent unmet 
medical need for drugs with novel mechanisms of action that can be used by these patients in 
addition to current therapies.  
RPL554, a small molecule isoquinolone derivative, is a dual inhibitor of two isoforms (type 3 
and 4) of the PDE family of enzymes. PDE3 and PDE4 are known to have a role in modulating 
the inflammatory airway response in respiratory diseases, including COPD, allergic asthma 
and allergic rhinitis. In general, PDE3 inhibitors act as bronchodilators (through interaction 
with smooth muscle cells), whilst PDE4 inhibitors have anti-inflammatory properties. There is 
also evidence to suggest that combined inhibition of PDE3 and PDE4 can have additive or 
synergistic anti-inflammatory and bronchodilator effects (Abbott-Banner & Page, 2014). 
Pharmacological evidence from pre-clinical experiments with dual PDE3/4 inhibitors suggests 
that RPL554 may have potential therapeutic activity in COPD, cystic fibrosis and possibly 
asthma.  
PDE4 inhibitors, administered orally, have exhibited anti-inflammatory actions; however, they 
have been associated with unfavourable gastrointestinal side effects such as nausea, emesis, 
diarrhoea, abdominal pain, loss of appetite and weight loss (Harbinson et al, 1997; van 
Schalkwyk et al, 2005; Compton et al, 2001; Rabe et al, 2005; Rennard et al, 2006; 
Calverley et al, 2007; Gamble et al, 2003; Grootendorst et al, 2007). Dual PDE3/PDE4 
inhibitor,
administered 
by 
inhalation,
have 
exhibited 
both 
bronchodilator 
and 
anti-inflammatory actions, with a more favourable side effect profile (Ukena et al, 1995). It is 
plausible that increased efficacy with reduced side effects may be achievable with 
administration of a dual PDE3/4 inhibitor by the inhaled route compared to orally administered 
PDE3 or PDE4 inhibitors. It has also been demonstrated in tracheal ring preparations that 
RPL554 causes a synergistic bronchodilator effect when added to anti-muscarinic agents, as 
well as additive properties with ȕ2-agonists (Calzetta et al, 2013; Calzetta et al, 2015). 
Therefore, RPL554 has the potential to benefit patients not satisfactorily treated with existing 
medicines. 
The safety, bronchodilator, bronchoprotective and anti-inflammatory activities of RPL554 
have been evaluated in 12 completed clinical studies involving over 730 subjects. Initially, five 
studies were done in healthy subjects, patients with mild to moderate persistent asthma and 


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those with allergic rhinitis and COPD, using a nebulised solution in citrate/phosphate buffered 
saline at pH 3.2 (Franciosi et al, 2013; summarised in the Investigator’s Brochure).  
RPL554 was subsequently re-formulated in a pH neutral suspension formulation for 
nebulisation. This formulation has been tested in seven completed clinical studies. It was found 
to have exceptional bronchodilator activity in healthy volunteers and patients with asthma and 
COPD, and to significantly improve symptoms and health status in patients with COPD. 
RPL554 was well tolerated in all seven studies, with adverse event rates that were similar to 
the subjects treated with placebo. All clinical studies are described in the Investigator’s 
Brochure.  
A new formulation has been developed to allow for delivery of RPL554 using a convenient,
hand-held pressurised metered dose inhaler (pMDI). Although the current study will be the 
first clinical assessment of the pMDI formulation of RPL554 in humans, the RPL554 active 
pharmaceutical ingredient used in the pMDI formulation is the identical physical form and 
morphology as that used in the nebuliser suspension product in previous studies. Furthermore, 
a non-clinical assessment of local and systemic toxic potential of a dry powder inhaler (DPI)
formulation of RPL554 (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 RPL554 suspended in hydrofluoroalkane (HFA)-134a propellant
only. Results from this initial bridging toxicology study with an RPL554 lactose dry powder 
blend showed no new findings when this vehicle formulation is used, and this body of data 
supports clinical evaluation of both the DPI and pMDI formulations over the same period. A
clinical study evaluating the DPI formulation has recently been initiated in the United States.
The purpose of this study is to assess the efficacy, safety and pharmacokinetics (PK) of RPL554 
administered via pMDI, in order to support further development of RPL554 in a pMDI format.
1.2
Summary of Risks and Benefits
Data from non-clinical studies had suggested a potential for hypotension and tachycardia at 
high doses. However, in the clinical studies to date, RPL554 has been well tolerated in healthy 
subjects as well as patients with moderate to severe COPD, asthma and allergic rhinitis. The 
most common adverse events that have been reported at least twice in subjects who have 
received single or multiple doses of the nebulised suspension of RPL554 were generally mild 
and in descending order of frequency were headache, cough, dizziness, and palpitations. 
Adverse events for single and multiple dose studies are summarised in the Investigator’s 
Brochure.  
RPL554 has been demonstrated to have favourable non-clinical toxicology and PK profiles 
when delivered via the inhaled route as both a nebulised suspension and as a DPI.
While there have been few adverse events related to the cardiovascular or gastrointestinal 
systems, small and transient increases in heart rate at doses of 6 and 12 mg have been reported. 
Holter assessments have indicated no arrhythmogenic potential in the completed studies.  
In single dose studies, there appears to be an increase in the rate of headache that is most 
pronounced at doses over 6 mg. Results from multiple dose data in patients with COPD 
suggests a transient increase in dizziness, the majority of which occurred during spirometry
manoeuvres or dosing; otherwise, the rate of adverse events was similar between RPL554 and 
placebo treated patients. 


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2
OBJECTIVES 
2.1
Part A 
2.1.1
Primary Objective
To investigate the PK profile of single doses of RPL554, administered by pMDI, in patients 
with moderate to severe COPD. 
2.1.2
Secondary Objectives
x
To investigate the safety and tolerability of single doses of RPL554 administered by
pMDI, including effects on peak pulse and heart rate
x
To investigate the bronchodilator effect of single doses of RPL554 administered by
pMDI, in terms of peak forced expiratory volume in 1 second (FEV1), average FEV1
area under the curve (AUC)0-4h and average FEV1 AUC0-12h
2.2
Part B
2.2.1
Primary Objective
To investigate the bronchodilator effect of repeat doses of RPL554 administered by pMDI,
assessed in terms of peak FEV1.
2.2.2
Secondary Objectives
x
To investigate the safety and tolerability of repeat doses of RPL554, administered by
pMDI
x
To investigate the bronchodilator effect of RPL554 administered by pMDI, in terms of
average FEV1 AUC0-4h, average FEV1 AUC0-12h and trough FEV1
x
To determine the onset of action of RPL554 administered by pMDI
x
To evaluate the PK profile of RPL554 administered by pMDI
x
To evaluate the amount of rescue medication use during treatment periods
2.2.3
Exploratory Objectives 
x
To assess the dose response of RPL554 on peak FEV1 and average FEV1 AUC0-12h after
morning dose on Day 7, and morning trough FEV1 prior to the last dose on Day 7
x
To examine the effect of RPL554 administered by pMDI on a Likert dyspnoea scale


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3
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan Description
This is a Phase II, randomised, placebo controlled, two part study. Part A is a parallel group, 
single dose assessment of RPL554 administered by pMDI, with all but one of the treatment 
arms double blind (see Section 3.2). Part B is a double blind, complete block crossover, repeat 
dose assessment of RPL554 administered by pMDI. The study design is shown in Figure 1. 
Figure 1 
Study Flow Chart
7- 14 days
   Timing TBD
7-10 days
7-10 days
7-10 days
7- 10 days
4-10 days
Abbreviations: TBD=to be determined; TP=Treatment Period
In Part A, patients will be screened for eligibility, including a reversibility test with salbutamol.
Between 7 and 14 days later, a total of approximately 36 patients will be given a single dose of 
RPL554 or placebo and will be assessed over 12 hours in the clinic. Patients will receive three
inhalers and will be administered either six or 12 puffs via pMDI (depending on treatment arm
assignment; see Section 5). Patients will return to the clinic the following day for a 24-hour 
post-dose assessment of PK and lung function. At the conclusion of Part A, the database will 
be locked and the data unblinded and analysed prior to commencing Part B (see Section 9.4.9 
for details on the unblinding of Part A). Specific treatments are shown in Table 1.
In Part B, the patients from Part A will be randomly assigned in crossover fashion to one of 
10 treatment sequences, each consisting of up to five 1-week treatment periods separated by a 
7 to 10 day washout period. Each treatment period consists of 6 days of twice daily doses of 
RPL554, and a single morning dose on Day 7. In each treatment period, patients will undergo 
assessments over 12 hours on Days 1 and 7. Specific treatments are shown in Table 2. 
Patients will return for an End of Study Visit approximately 7 days after the completion of the 
final Treatment Period (or sooner in the case of early termination). 
3.2
Discussion of Study Design, Including the Choice of Control Groups 
Part A is designed as a single dose, parallel group study to evaluate the safety and terminal PK 
profile of a range of doses of RPL554 in a new pMDI formulation compared to placebo. The 
safety and bronchodilatory response following a single dose will also be assessed. 
In Part A, five dose levels ranging from 100 Pg up to 6000 Pg have been selected to evaluate 
the safety, PK and efficacy/pharmacodynamic characteristics of this formulation over a dose
range covering a 60-fold increase in doses. Approximately 36 COPD patients aged 40 to 
80 years (inclusive) will be randomised. Patients in Part A will be randomly assigned to receive 
either RPL554 or placebo via pMDI. Following an analysis of the safety, PK and 
efficacy/pharmacodynamics, up to four doses will be selected for Part B. Study medication
administered via pMDI will be double blind, except for the 6000 Pg treatment arm in Part A 
which will be single blind due to the number of puffs required, in order to minimise any 
potential bias in the overall assessment of treatment effect and safety. 
END OF 
STUDY 
VISIT
SCREEN
PART A
Single 
Dose 
PART B
TP 1
Repeat 
Dose 
PART B
TP 2
Repeat 
Dose 
PART B
TP 3
Repeat 
Dose 
PART B
TP 4
Repeat 
Dose 
Interim 
Analysis 
PART B
TP 5
Repeat 
Dose 


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Part B is designed as a crossover study to assess the steady state efficacy/pharmacodynamic 
effect of up to four dose levels of RPL554 administered by pMDI after a week of twice daily 
dosing, and to compare that effect with placebo pMDI. Steady state PK and safety will also be 
assessed. One week of treatment was selected to evaluate efficacy/pharmacodynamics, PK and 
safety at steady state, as clinical data to date has shown that steady state PK is achieved after 
approximately 3 days of twice-daily dosing with the nebulised formulation.
In Part B, all patients from Part A will undergo up to five treatment periods in a randomised,
crossover design; therefore, each patient will act as his or her own control. This design makes 
it possible to obtain unbiased inferences about differences between treatments, based on 
intra-patient differences. 
The washout period between the treatment periods has been selected based upon the available 
PK of RPL554 in healthy subjects, and patients with asthma or COPD. Five half-lives is 
considered as the time for elimination of RPL554 from the body. In this study, a washout period 
of 7 to 10 days from the last dose of study medication has been deemed adequate to ensure 
there is no overlap between the PK profiles of treatments with RPL554 in consecutive treatment 
periods.  
The pre-dose FEV1 on Day 1 of Treatment Periods 2 and forward each must be within ±20% 
of the pre-dose FEV1 on Day 1 of Treatment Period 1 in order to ensure consistent baseline 
FEV1 for each study treatment. If the FEV1 varies by more than 20%, the start of the treatment 
period will be rescheduled.
3.3
Planned Duration of the Study
The approximate planned duration for each patient (not counting the interim analysis period)
will be between 75 and 100 days: 7 to 14 days Screening, 24 hours for Part A, up to five 
treatment periods of 7 days each in Part B separated by 7 to 10 days, and an End of Study Visit 
4 to 10 days after Day 7 of the last treatment period. Repeat, rescheduled and unscheduled 
visits are permitted at the discretion of the Investigator. 
3.4
Definition of the End of the Study
The end of the study is defined as the date of the End of Study Visit of the last patient to 
complete the study.  


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4
SELECTION OF STUDY POPULATION
The population to be recruited into this study are stable patients with moderate to severe COPD 
without significant heart disease. Specific criteria are as follows:
4.1
Inclusion Criteria
1.
Sign an informed consent document indicating they understand the purpose of and
procedures required for the study and are willing to participate in the study.
2.
Male or female aged between 40 and 80 years inclusive, at the time of informed consent.
3.
Must agree to meet the following from the first dose up to 1 month after the last dose of
study medication:
If male:
x
Not donate sperm
x
Either: be sexually abstinent in accordance with a patient’s usual and preferred
lifestyle (but agree to abide by the contraception requirements below should their
circumstances change)
Or: use a condom with all sexual partners. If the partner is of childbearing potential
the condom must be used with spermicide and a second reliable form of
contraception must also be used (e.g. diaphragm/cap with spermicide, established
hormonal contraception, intra-uterine device)
If female: be of non-childbearing potential or use a highly effective form of contraception 
as defined in Section 14.1.
4.
Have a 12-lead electrocardiogram (ECG) recording at Screening and pre-dose in Part A
showing the following:
x
Heart rate at least 45 beats per minute and less than 110 beats per minute (Sinus
EUDG\FDUGLD  ESP DQG WDFK\FDUGLD  ESP VKRXOG EH FRQILUPHG E\ 
additional readings at least 5 minutes apart)
x
47LQWHUYDOFRUUHFWHGIRUKHDUWUDWHXVLQJ)ULGHULFLD¶VIRUPXOD47F)PVHF
IRUPDOHVDQGPVHFIRUIHPDOHV
x
456LQWHUYDOPVHF
x
No clinically significant abnormality including morphology (e.g. left bundle
branch block, atrioventricular nodal dysfunction, ST segment abnormalities
consistent with ischemia)
5.
Capable of complying with all study restrictions and procedures including ability to use
the pMDI correctly.
6.
Body mass index (BMI) between 18 and 35 kg/m2 (inclusive) with a minimum weight of
45 kg.
7.
COPD diagnosis: Patients with a diagnosis of COPD as defined by the American
Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines (Celli and
MacNee, 2004) with symptoms compatible with COPD for at least 1 year prior to
Screening.
8.
Ability to perform acceptable and reproducible spirometry.
9.
Post-bronchodilator (four puffs of salbutamol) spirometry at Screening demonstrating
the following:
x
FEV1/forced vital capacity (FVC) UDWLRRI
x
FEV1 4DQG80% of predicted normal


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x
P/LQFUHDVHIURPSUH-bronchodilator FEV1
10.
Clinically stable COPD in the 4 weeks prior to Screening and during the period between
Screening and Part A. In particular, the average pre-dose FEV1 in Part A must be within
±20% of the value obtained at the Screening Visit.
11.
A chest X-ray (posterior-anterior) at Screening, or in the 12 months prior to Screening
showing no clinically significant abnormalities unrelated to COPD.
12.
Meet the concomitant medication restrictions (within the time intervals defined in
Section 5.8.1) and be expected to do so for the rest of the study.
13.
&XUUHQWDQGIRUPHUVPRNHUVZLWKVPRNLQJKLVWRU\RISDFN-years.
14.
Capable of withdrawing from long acting bronchodilators for the duration of the study,
and short acting bronchodilators for 6 hours prior to spirometry testing.
4.2
Exclusion Criteria 
1.
A history of life-threatening COPD including Intensive Care Unit admission and/or
requiring intubation.
2.
COPD exacerbation requiring oral or parenteral steroids, or lower respiratory tract
infection requiring antibiotics, within 3 months of Screening or prior to Part A.
3.
A history of one or more hospitalisations for COPD or pneumonia within 6 months of
Screening or prior to Part A.
4.
Intolerance or hypersensitivity to salbutamol
or RPL554 or any of its
excipients/components.
5.
Other respiratory disorders: Patients with a current diagnosis of asthma, active
tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, interstitial lung
diseases, sleep apnoea, known alpha-1 antitrypsin deficiency, core pulmonale, clinically
significant pulmonary hypertension or other active pulmonary diseases.
6.
Previous lung resection or lung reduction surgery.
7.
Use of immunosuppressive therapy, including oral corticosteroids.
8.
Pulmonary rehabilitation, unless such treatment has been stable from 4 weeks prior to
Screening and remains stable during the study.
9.
History of, or reason to believe a patient has, drug or alcohol abuse within the past
5 years.
10.
Women who are pregnant or breastfeeding
11.
Received an experimental drug within 30 days or five half-lives, whichever is longer.
12.
Patients with uncontrolled disease including, but not limited to, endocrine, active
hyperthyroidism, neurological, hepatic, gastrointestinal, renal, haematological,
urological, immunological, psychiatric, or ophthalmic diseases that the Investigator
believes are clinically significant.
13.
Historical or current evidence of clinically significant cardiovascular disease.  Significant
is defined as any disease that in the opinion of the investigator could put the safety of the
patient at risk, or could affect the efficacy or safety analyses if the condition were to
exacerbate during the study.  In particular, the following are excluded:
x
Myocardial infarction within 1 year prior to Screening
x
Unstable angina within 6 months prior to Screening
x
Unstable or life-threatening arrythmia requiring intervention within 3 months prior to
Screening


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x
Diagnosis of NYHA class III or IV heart disease
14.
Use of non-VHOHFWLYHRUDOȕ-blockers.
15.
Major surgery (requiring general anaesthesia) within 6 weeks prior to Screening, lack of
full recovery from surgery at Screening, or planned surgery through the end of the study.
16.
A disclosed history or one known to the Investigator, of significant non-compliance in
previous investigational studies or with prescribed medications.
17.
Required use of oxygen therapy, even on an occasional basis.
18.
History of malignancy of any organ system within 5 years, with the exception of localised
skin cancers (basal or squamous cell).
19.
Clinically significant abnormal values for viral serology or laboratory safety tests
(haematology, biochemistry or urinalysis) at Screening, as determined by the Investigator
(see Section 7.1.4 and Section 7.4.3). In particular, alanine aminotransferase or aspartate
aminotransferase cannot be more than twice the upper limit of normal.
20.
Any other reason that the Investigator considers makes the patient unsuitable to
participate.
4.3
Removal of Patients from Therapy or Assessment
4.3.1
Study Treatment Discontinuation
Study treatment must be discontinued for the following reasons:
x
Unacceptable toxicity related to study treatment
x
Intolerable or persistent adverse events of any severity
x
General or specific changes in the patient's condition rendering the patient unacceptable
for further treatment in the judgment of the Investigator
x
Clinically significant progression of disease
x
Pregnancy in a female patient
4.3.2
Patient Withdrawal
Investigators have the authority to withdraw a patient at any time for medical or 
non-compliance reasons. Should the Investigator decide it is necessary to withdraw any patient 
for specific reasons, this should be recorded in writing and transmitted to the patient in 
question. Such reasons for withdrawal are expected to be medical or related to lack of 
co-operation by the patient. 
The patient has the right to withdraw at any time and for any reason, without explanation and 
without jeopardising any subsequent treatment by the clinician, if applicable. However, anyone 
withdrawing should be encouraged to offer an explanation for their withdrawal, particularly if 
it relates or is perceived to relate in any way to the study medication, or to the conduct of the 
study. Patients can also be withdrawn in case of protocol violations and non-compliance.
If a patient withdraws following randomisation, every attempt should be made to contact the 
patient to determine the reason for withdrawal and to complete the recording of any available 
efficacy/pharmacodynamic data and all adverse event data. The reasons for withdrawal and 
results of all relevant tests will be recorded in the electronic case report form (eCRF). These 
patients should have an End of Study Visit unless it is considered by the Investigator that they 
require greater medical supervision and/or investigations and in which case an unscheduled 
visit prior to and in addition to the scheduled follow up visit may be performed.  


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If a patient had signed a consent form but withdrew from the study without receiving any study 
treatment, no further follow-up is necessary.
4.3.3
Study Discontinuation
Conditions that may warrant termination of the study include, but are not limited to: 
x
The discovery of an unexpected, serious, or unacceptable risk to patients enrolled in the
study
x
The decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or
development of RPL554
x
Serious failure of the Investigator to comply with the International Council on
Harmonisation (ICH) Guidelines on Good Clinical Practice (GCP) or local regulations
x
Submission of knowingly false information from the research facility to the Sponsor, the
Independent Ethics Committee (IEC) or any national regulatory officials
x
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.
4.3.4
Replacement Policy
It is planned to have 30 patients complete the study; it is expected that approximately 
36 patients will be randomised to meet this target. Withdrawn patients may need to be replaced,
depending on the actual discontinuation rate. 


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5
STUDY TREATMENTS
5.1
Study Treatments Administered
5.1.1
Treatments Administered in Part A
Patients will be randomly assigned to receive a single dose of one of six possible treatments,
as shown in Table 1. For Treatment Arms 1 through 4 and 6, each patient will be instructed to 
take two puffs (inhalations) from each of Inhalers 1 through 3, for a total of six inhalations. For 
Treatment Arm 5, each patient will be instructed to take four puffs from each of Inhalers 1 
through 3, for a total of 12 inhalations.
Table 1 
Treatment Arms, Inhaler and Puff Combinations in Part A
Arm
No. of 
Patients
No. of Puffs 
per Inhaler
Total Dose
Inhaler No.1 
Inhaler No.2
Inhaler No.3
1
6
2
100 μg
50 μg 
Placebo
Placebo
2
6
2
300 μg
150 μg 
Placebo
Placebo
3
6
2
1000 μg
500 μg 
Placebo
Placebo
4
6
2
3000 μg
500 μg
500 μg
500 μg
5*
6
4
6000 ug
500 μg
500 μg
500 μg
6
6
2
Placebo
Placebo
Placebo
Placebo
* Single-blind (see Section  5.7)
5.1.2
Treatments Administered in Part B
During Part B, patients will undergo four or five repeat dose treatment periods in a crossover 
fashion, with the sequence to be randomly assigned. Each treatment period will consist of 7 
days of dosing, which will occur in the morning and evening of Days 1 through 6 and morning 
only on Day 7.   
The doses to be used in Part B will be determined from the analyses performed on data from 
Part A; however, the highest dose will not exceed 3000 ȝJThe dosage strengths, in addition 
to placebo, will be as follows: 100 μg, and/or 300 μg, and/or 1000 μg, and/or 3000 μg (either 
3 or 4 of these values), dosed twice daily.  
Each patient will be instructed to inhale two puffs from each inhaler dispensed to them
(depending on the doses chosen for Part B) twice daily, for a total of six inhalations for each 
morning or evening dose.  
5.2
Identity, Preparation and Labelling of Study Treatments
The International Union of Pure and Applied Chemistry (IUPAC) name for RPL554 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 RPL554 pMDI is manufactured 
in accordance with Good Manufacturing Practice (GMP) guidelines. 
The compositions of the pMDI formulations are shown in Table 2. 


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RPL554 pMDI is supplied as a pressurised canister with a yellow plastic actuator. Each inhaler 
will be packed and labelled in kits as three inhalers in a carton and labelled with a unique 
medication identification (ID) number. Appropriate study centre personnel will dispense the 
appropriate double blind kit medication ID number according to the randomisation schedule 
and blinded kit list. Detailed dispensing instructions are provided in the study Pharmacy 
Manual.
5.3
Selection of Doses and Dosing Schedule
5.3.1
Selection of Doses in the Study
The doses of RPL554 have been selected to cover a 60-fold dose range of the pMDI
formulation. The top dose level in Part B will not exceed 3000 Pg, dosed twice daily, due to 
the logistical infeasibility of repeated administration of 12 puffs required to deliver a 6000 Pg
dose, and the enhanced possibility for poor treatment compliance. In prior studies, up to 24 mg 
of RPL554 has been evaluated as a twice daily nebulised suspension, and was well tolerated
clinically. 
Efficacy and safety data from Part A will be evaluated to determine if a dose can be dropped 
from the dose range in Part B.  
5.3.2
Timing of Dose for Each Patient
In Part A and the first dose of each treatment period in Part B study medication is to be 
administered between 7 and 11 am. All subsequent doses in Part B are to be taken at 12-hour 
intervals (±30 minutes) relative to the Day 1 first dose. 
5.4
Storage 
RPL554 and placebo drug products 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 medications that are to be returned 
by the Investigator/staff or have expired must be stored separately from the unused study 
medications.
5.5
Accountability
The Investigator will be responsible for the 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. The study medication supplies and 
>5('$&7('@


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inventory must be available for inspection by the designated representatives of the Sponsor 
upon request. 
Upon receipt of the study medication, the Investigator or designee will inspect the contents and 
return the completed acknowledgement of receipt. Copies of all study medication inventory
records must be retained for accountability of study products and supplies. Accountability must 
be documented from the time of initial receipt at the study centre to their final removal from 
the centre.  
Written records must also be maintained to confirm the purpose and reason for any study 
medication disposal, e.g. the amount contaminated, broken, or lost, and the name/signature of 
the personnel responsible for reporting the event. 
At the end of the study, the unused study medication can be destroyed locally after 
accountability has been verified and written authorisation has been provided by the Sponsor.
5.6
Method of Assigning Patients to Treatment Groups
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 the centre
number and YYY is the patient number (001, 002, etc.). 
In Part A of the study, patients will be randomly assigned to receive a single dose of one of six 
possible treatments (see Section 5.1.1). In Part B, patients will again be randomised and 
assigned to a set of selected treatment sequences balanced with respect to both period and 
first-order carry-over effects (see Section 5.1.2). Available randomisation numbers must be 
used sequentially for the next enrolled patient, to determine the treatment dose to be dispensed 
and administered. 
5.7
Blinding
In Part A, Treatment Arms 1 through 4 and 6 will be double blind, while Treatment Arm 5 will 
be single-blind; study centre staff will be aware of treatment assignment due to the number of 
puffs required. The placebo is the same as the active medication (RPL554) except for the 
omission of the active ingredient. 
In Part B, the treatments will be double blind. 
The blind should be broken only if specific emergency treatment would be dictated by knowing 
the treatment status of the patient. If the blind needs to be broken, the Investigator should 
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. Blind break envelopes will be provided to the study centre and must be kept in a secure 
access area.
5.8
Prior and Concomitant Therapies and Medications
5.8.1
Prior and Concomitant COPD Medications
All prior therapies for COPD taken in the 3 months prior to the first study medication
administration and all concomitant COPD therapies will be recorded in the eCRF, with the 
medication, dose, route and start and stop date(s) and time(s) clearly recorded to document all 
required washout periods and compliance with the Inclusion and Exclusion Criteria. 


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Upon providing informed consent, patients will discontinue COPD medications for the time 
periods described in Table 3 Restrictions for COPD Medications Prior to Screening prior to 
both the Screening visit for Part A and Day 1 of Part B. Patients will remain off these 
medications until the completion of Part A, at which point maintenance LAMA or LABA 
therapy may be temporarily resumed. However, patients must discontinue these prohibited 
medications according to the time periods described in Table 3 prior to Day 1, Treatment Period 
1 of Part B, and remain off these medications (except for rescue use) until the end of Day 7 of 
the final treatment period.
Table 3
Restrictions for COPD Medications Prior to Screening and Part B
Medication
Time Interval Prior to Screening and Start of Part B
Oral COPD therapies – e.g. oral steroids, 
theophylline, roflumilast 
3 months 
Antibiotics
3 months
Terbutaline
1 day
Long acting bronchodilators (LABAs or LAMAs)
x
Once-daily bronchodilators
x
Twice daily bronchodilators
x
48 hours
x
24 hours
Inhaled corticosteroids 
$OORZHGLIGRVHLVVWDEOHZHHNVSULRUWR6FUHHQLQJ
and expected to remain stable throughout the study
Abbreviations: COPD=chronic obstructive pulmonary disorder; LABA=long acting ȕ2-agonist; LAMA=long 
acting muscarinic antagonist 
The following therapies are subject to restriction as indicated: 
x
Patients taking LAMAs and LABAs should be placed on short acting bronchodilators
(e.g. salbutamol, ipratropium or Combivent®) as per the discretion of the Investigator.
These can be dosed on a regularly scheduled basis or as needed (subject to additional
restrictions in the 3rd bullet below)
x
Patients taking LABA/ICS combination products should be prescribed the ICS at the
same or equivalent dose contained in the combination product to allow continuation of
steroid use regularly throughout the study while stopping the LABA component.ICS
medication should be procured via prescription for patients requiring its use
x
No scheduled regular use of salbutamol or ipratropium is allowed during the 7-day
treatment periods; but may be used as a rescue medication (see Section 5.9). Short-acting
bronchodilators must be withheld for at least 6 hours prior to spirometry (per below), and
this is to be confirmed in the eCRF at the start of each treatment period. If this withhold
is not met, the patient should be rescheduled for a repeat visit within permitted windows.
Short acting bronchodilators should be withheld as follows:
-
Screening:  6 hours prior to pre-reversibility spirometry
-
Part A:
o
Day 1: 6 hours prior to pre-dose spirometry until completion of the 12-hour
post-dose spirometry
o
Day 2: 6 hours prior to 24-hour post-dose spirometry
-
Part B, Days 1 and 7 of each treatment period:
o
6 hours prior to pre-dose spirometry until completion of the 12-hour post-
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If following the above requirements provides inadequate symptom control, patients should 
contact the Investigator. 
x
Pulmonary rehabilitation programs should not be started or completed during
participation in the study, although an ongoing maintenance program is acceptable in
accordance with Exclusion Criterion #8
x
Oxygen therapy and non-selective oral ȕ-blockers are Exclusion Criteria and are not to
be used at any time during the study
x
Oral mucolytics and ocular ȕ-blockers are allowed
5.8.2
Other (non-COPD) Prior and Concomitant Medications 
All concomitant medications must be documented in the eCRF, as well as any medications 
taken within 3 months prior to the Screening visit.  
Patients may continue other prescribed non-respiratory therapies during the study that the 
Investigator considers to neither compromise patient safety nor affect study data. Such other 
prior prescription or non-prescription medications (medication, dose, route, treatment duration 
and indication) taken within 3 months before the first study medication administration must be 
recorded in order to confirm compliance with the Inclusion and Exclusion Criteria. 
5.9
Rescue Medications
Short acting bronchodilators may be used as rescue medication. Salbutamol is to be used for 
primary rescue use. Rescue medication will be sourced by the study centre and dispensed as
follows: 1) at the time informed consent is provided, and 2) on Day 2 at the end of Part A (in 
sufficient quantity to cover the discontinuation of COPD medications prior to Part B, as well 
as full duration of Part B). See Section 5.8.1 for withholding requirements prior to spirometry 
and rescheduled visit allowances.
Rescue medication use during each study visit must be separately documented in the eCRF 
(medication, dose, route, and date and time of each administration). During Part B, rescue use 
between Days 1 and 7 of each treatment period will be determined primarily by information 
provided by patients on paper diaries, which will be transcribed into the eCRF.  The day(s) on 
which rescue was used and the number of puffs taken on each day of use will be recorded.  In 
the event of missing or incomplete diaries (which will be noted as a protocol deviation), rescue 
use will be determined analytically, based on changes in the weight of the canister which will 
be recorded in the eCRF.
5.10
Treatment Compliance
In Part A, the single dose of study medication will be administered at the study centre by study 
personnel.  
In Part B, patients will also be dosed at the study centre on the morning and evening of Day 1 
and on the morning of Day 7. Patients will self-administer study medication for the other dosing 
times (i.e. on Days 2 through 6). The pMDIs dispensed and returned will be recorded, and will 
be weighed at the beginning and end of each visit. 
The precise date and time of dose administrations performed in clinic at study visits, and in the 
evening prior to study visits, shall be documented in the eCRF. Additionally, on Day 7 patients 
will be queried on how many doses (if any) since Day 1 were missed; this information shall 
also be documented in the eCRF. 


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6
STUDY PROCEDURES AT EACH VISIT
The study will consist of the following:
x
Screening will take place in the period between 7 and 14 days prior to the first study
medication administration in Part A. Screening procedures may be performed as a single
visit or more than one visit
x
Part A will consist of a single dose of study medication, with assessments over the
ensuing 12 hours and again at 24 hours on the following day
x
Part B will commence at a time to be determined, following database lock and analysis
of Part A and will consist of up to five 7-day treatment periods of repeat doses of study
medication, each separated by a washout period of 7 to 10 days
x
An End of Study Visit will occur between 4 and 10 days after the completion of the final
treatment period
Patients who screen fail may be considered for re-screening upon consultation with the Medical 
Monitor. 
Repeat, rescheduled, and unscheduled visits and procedures are permitted at the discretion of 
the Investigator.
The schedules of assessments are shown in Table 4 for Part A and Table 5 for Part B.
Assessments are listed by visit in Section 6.2 to Section 6.5 and are described in Section 7.
Post-dose assessments generally should be performed in the following order (as applicable):
1) 12-lead ECG, 2) vital signs, 3) PK blood sample, 4) spirometry (prioritised on the
timepoint).


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Table 4
Schedule of Assessments for Screening and Part A
Screen
(Day -14 
to -7)
Day 1
Day 2
Time Relative to End of Dosing
Pre-dose
0
5m
15m
30m
1h
1.5h
2h
4h
8h
11h
12h
24h
Informed consent
X1
Rescue medication dispensing
X1
X
Demographics including height & weight
X
Viral serology test
X
FSH test (if required)
X2
Medical/surgical and disease history 
X
Eligibility criteria
X
X
Physical examination
Full
X
X 
Brief
Vital signs 
X
X
X
X
X
X
X
X
Prior/concomitant medications/therapies
X
X
Pregnancy testing (as applicable)3
X
X
Laboratory safety tests4
X
Urinalysis 
X
12-lead ECG
X
X
X
X
X
X
Chest X-ray (as required)
X
Reversibility testing
X
Spirometry
X
X5
X
X
X
X
X
X
X
X
X
X
Rescue canister weight
X
X
Inhalation training
X
Randomisation
X
Study medication administered
X
Pharmacokinetic sample
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
Abbreviations: ECG=electrocardiogram; FEV1=forced expiratory volume in 1 second; FSH=follicle stimulating hormone; h=hours; m=minutes
1.
May need to be performed prior to screening, to accommodate washout of prohibited medications
2.
To confirm post-menopausal status
3.
For women of childbearing potential only. Serum and urine pregnancy test at Screening, urine pregnancy test only Pre-dose.
4.
Haematology and blood chemistry
5.
Pre-dose spirometry shall be conducted at -1 hour (±5 minutes) and immediately (within 5 minutes) pre-dose. The average FEV1 value must be within ±20% of the pre-salbutamol value obtained
at Screening


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Table 5
Schedule of Assessments for Part B, Days 1 and 7 of each Treatment Period and End of Study Visit 
Abbreviations: ECG=electrocardiogram; FEV1=forced expiratory volume in 1 second; h=hours; m=minutes; pMDI=pressurised metered dose inhaler; TP=Treatment Period 
1.
Patients will be contacted by phone the night before their Day 7 visits to remind them of the requirements stipulated in Section 6.4.1.3
2.
For women of childbearing potential only
3.
Haematology and blood chemistry
4.
Pre-dose spirometry shall be conducted at -1 hour (±5 minutes) and immediately (within 5 minutes) pre-dose. The pre-dose FEV1 on Day 1 of Treatment Periods 2 and forward must be within ±20% of the
pre-dose FEV1 on Day 1 of Treatment Period 1, in order to ensure consistent baseline FEV1 for each study treatment
5.
Treatment Period 1 only
Day 1
Day 71
4-10
days
after
TP 4
Pre-
dose 
0 
5 m
15m
30m
1h
1.5h
2h
4h
8h
12h
Pre- 
dose 
0 
30m
1h
1.5h
2h
4h
8h
11h
12h
Physical examination
Full
X
Brief
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
pMDI weight
X
X
X
X
Rescue canister weight
X
X
Recording of prior evening dose time
X
Urine pregnancy test2
X
X
Urinalysis
X
X
Laboratory safety tests3
X
X
X
12-lead ECG
X
X
Spirometry
X4
X
X
X
X
X
X
X
X
X
X4
X
X
X
X
X
X
X
X
X
Dyspnoea scale
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inhalation training
X
Randomisation
X5
Study medication administered in-clinic
X
X
X
Pharmacokinetic sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study medication, rescue medication and
paper diary dispensed6
X
Study medication and paper diary
collected
X
Study medication compliance
X
Adverse events
X
X
X
Prior/concomitant medications
X
X
X
6.
Patients will be instructed to take study medication in the morning and evening on Days 2 through 6. Study medication should be withheld on the morning of Day 7 prior to the visit, to allow for
administration in the clinic. Additional rescue medication may also be dispensed if needed


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6.1
Pre-visit Restrictions
The following restrictions should be adhered to (for all study visits except where noted): 
x
Patients should refrain, when possible, from xanthine (chocolate, caffeine containing
drinks and food), for at least 24 hours before and during visits. Decaffeinated beverages
are permitted
x
Patients should refrain from alcohol for 24 hours before and during visits (including visits
for safety laboratory tests) and until all procedures for that study visit are completed
x
Patients must fast (water permitted) from 2 hours pre-dose until 1 hour post-dose (does
not apply to Screening)
x
Patients should refrain from smoking at least 1 hour pre-dose, and at least 1 hour before
any measurement of lung function
x
Patients should refrain from strenuous exercise for 72 hours prior to visits and should
undertake no unaccustomed strenuous exercise from Screening until the End of Study
Visit
6.2
Screening
Written informed consent will be obtained by the Investigator as specified in Section 10.3 prior 
to any study related procedures being performed. This typically will need to be performed prior 
to the Screening visit to allow for discontinuation of any prohibited medications (see 
Section 5.8.1). Screening procedures may be performed over more than 1 day.  
Patients will be screened to determine eligibility against the Inclusion and Exclusion Criteria 
between 7 and 14 days before the first dose of study medication. Patients must observe the 
medication restrictions described in Section 5.8.1, and other restrictions described in 
Section 6.1. To account for diurnal variability in pulmonary function, the Screening visit is to 
take place in the morning.
The following assessments will be performed, generally in the order indicated (to the extent 
feasible): 
x
Obtain informed consent (if not done prior to Screening)
x
Recording of demographic information, including height and weight
x
Recording of medical/surgical and disease history
x
Recording of prior medications and therapies; confirming that medications were withheld
as required
x
Vital signs
x
Full physical examination (see Section 7.4.5)
x
12-lead ECG
x
Reversibility test:
-
Pre-reversibility spirometry
-
Four puffs of salbutamol
-
Post-reversibility spirometry (20 to 30 minutes after salbutamol)
x
Blood samples for laboratory screening and safety tests:
-
Viral serology


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-
Follicle stimulating hormone (FSH; if required to confirm post-menopausal status)
-
Serum pregnancy (for women of childbearing potential only)
-
Haematology and blood chemistry
x
Urinalysis
x
Urine pregnancy (for women of childbearing potential only) – results should be obtained
prior to the chest X-ray
x
Chest X-ray (unless historical X-ray performed in last 12 months is available)
x
Questioning for adverse events
If the patient meets all of the Inclusion and none of the Exclusion Criteria:
x
Dispense rescue medication
x
Instruct patient to return in 7 to 14 days for Part A treatment
6.3
Part A: Single Dose Treatment
Patients must withhold all medications described in Section 5.8.1 prior to the treatment in 
accordance with the washout times provided. If not, the visit must be rescheduled so as to occur
within the permitted windows. All restrictions defined in Section 6.1 should also be adhered 
to.  
6.3.1
Pre-dose Assessments
The following assessments will be performed prior to dosing:
x
Assess concomitant medications; confirm that medications were withheld as required,
and that all eligibility criteria continue to be met
x
Question for adverse events
x
Weigh rescue medication canister
x
Urine pregnancy test (women of childbearing potential only)
x
12-lead ECG
x
Vital signs
x
Brief physical examination (see Section 7.4.5)
x
Spirometry; 1 hour (±5 minutes) and immediately (within 5 minutes) pre-dose. Note: The
average of the two pre-dose FEV1 values must be within ±20% of the pre-salbutamol
value at Screening; otherwise, the patient will be screen failed in accordance with
Inclusion Criterion #10
x
PK sampling
x
Inhalation training
x
Assign randomisation number from next in sequence available at the study centre
6.3.2
Study Medication Administration
Patients will be dosed once with either blinded RPL554 or placebo according to the 
randomisation scheme.  Those assigned to receive the 6000 μg treatment will be instructed to 
take 4 puffs per inhaler; all others will be instructed to take 2 puffs per inhaler. Note:


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Instructions will be given in such a way as to preserve the single blind; i.e., patients should not 
be informed that the number of puffs differs among treatment groups.
6.3.3
Post-dose Assessments 
The following assessments will be performed, at the times indicated relative to the end of
dosing: 
x
12-lead ECGs at 1, 2, 4 and 8 hours (all ±10 minutes)
x
Vital signs at 1, 2, 4, 8, 12 and 24 hours (all ±10 minutes)
x
PK sampling at 15 (±5) and 30 (±10) minutes and 1, 1.5, 2, 4, 8, 12 and 24 hours (the
latter assessments all ±15 minutes)
x
Spirometry at 5 (±2), 15 (±5) and 30 (±10) minutes and 1, 1.5, 2, 4, 8, 11 and 12 hours
(the latter assessments all ±15 minutes)
x
Weigh rescue medication canister, if used during visit
x
Dispense new rescue medication after the 24 hour assessment
x
Question for adverse events
Patients will be discharged from the study centre after the 12-hour assessments and instructed 
to return the next morning; alternatively, they may remain resident at the study centre overnight 
at Investigator discretion. Patients will be informed that they will be contacted at some point 
after discharge to schedule the first visit for Part B and to assess for any adverse events and 
concomitant medication use.
Early terminated patients should have an End of Study Visit, whether or not they participate in 
Part B.
6.4
Part B: Repeat Dose Treatment
Prior to each visit in Part B, patients must withhold all medications described in Section 5.8.1
in accordance with the washout times provided. If not, the visit must be rescheduled so as to 
occur within the permitted windows. All restrictions defined in Section 6.1 should also be 
adhered to. Study centre staff will call the patient the day prior to the start of Part B to remind 
patients of the following: to adhere to the medication restrictions above and, prior to the Day 7 
visit only, 1) to take study medication that evening at the scheduled time and 2) not to take 
study medication the following morning prior to arriving at the clinic.
6.4.1
Day 1 of Each Treatment Period
6.4.1.1
Pre-dose Assessments
The following assessments will be performed prior to dosing:
x
Assess concomitant medications and confirm that medications were withheld as required
x
Counsel/remind patient of daily dosing schedule as needed
x
Question for adverse events
x
Dyspnoea scale
x
PK sampling
x
Blood samples for laboratory safety tests (haematology and blood chemistry)
x
Urine pregnancy test (women of childbearing potential only)


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x
Urinalysis
x
12-lead ECG
x
Vital signs
x
Brief physical examination (see Section 7.4.5)
x
Spirometry; 1 hour (±5 minutes) and immediately (within 5 minutes) pre-dose. Note:
The pre-dose FEV1 on Day 1 of Treatment Periods 2 and forward must be within ±20%
of the pre-dose FEV1 on Day 1 of Treatment Period 1, in order to ensure consistent
baseline FEV1 for each study treatment. If this requirement is not met, the visit is to be
rescheduled within protocol-defined windows
x
Inhalation training
x
Dispense inhaler and study medication
x
Dispense additional rescue medication (if required)
x
Weigh pMDI (pMDI is to be weighed after priming; see Pharmacy Manual)
x
At Treatment Period 1 only, assign randomisation number from next in sequence
available at the study centre
6.4.1.2
Study Medication Administration
Patients will be dosed once with either RPL554 or placebo according to the randomisation
scheme. The first two doses of study medication on Day 1 will be administered in the clinic.
The second dose will be administered 12 hours (±30 minutes) after the first dose. 
6.4.1.3
Post-dose Assessments 
The following assessments will be performed, at the times indicated relative to dosing:
x
Vital signs at 1, 2, 4, 8 and 12 hours (all ±10 minutes)
x
Dyspnoea scale at 30 (±10) minutes and 1, 1.5, 2, 4, 8 and 12 hours (the latter assessments
all ±15 minutes)
x
PK sampling at 15 (±10) and 30 (±10) minutes and 1, 1.5, 2, 4, 8 and 12 hours (the latter
assessments all ±15 minutes)
x
Spirometry at 5 (±2), 15 (±5) and 30 (±10) minutes and 1, 1.5, 2, 4, 8 and 12 hours (the
latter assessments all ±15 minutes)
x
Question for adverse events
x
After evening dose is administered, weigh pMDI and rescue medication canister
x
Give study medication, rescue medication and paper diary to patient to take home
Patients will be discharged from the study centre after the 12-hour assessments and instructed 
to return 6 days later for Day 7. Patients will be contacted by phone the night before the Day 7 
visit to remind them to: 1) take their study medication in the evening of Day 6 and record the 
time, 2) withhold study medication prior to the visit the next day, 3) return their medication 
during the visit and 4) follow other medication and activity restrictions as described in 
Sections 5.8.1 and Section 6.1.


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6.4.2
Day 7 of Each Treatment Period
6.4.2.1
Pre-dose Assessments
The following assessments will be performed prior to dosing:
x
Collect study medication and paper diary
x
Weigh pMDI and rescue medication canister
x
Assess study medication compliance (see Section 5.10); record time of prior evening
dose of study medication and query patient on whether any doses were missed since Day
1
x
Assess concomitant medications; confirm that medications were withheld as required
x
Question for adverse events
x
Dyspnoea scale
x
PK sampling
x
Blood samples for laboratory safety tests (haematology and blood chemistry)
x
12-lead ECG
x
Vital signs
x
Brief physical examination (see Section 7.4.5)
x
Spirometry; 1 hour (±5 minutes) and immediately (within 5 minutes) pre-dose
6.4.2.2
Study Medication Administration
Patients will be dosed once with either RPL554 or placebo according to the randomisation
scheme.  
6.4.2.3
Post-dose Assessments 
The following assessments will be performed, at the times indicated relative to dosing:
x
Vital signs at 1, 2, 4, 8 and 12 hours (all ±10 minutes)
x
Dyspnoea scale at 30 (±10) minutes and 1, 1.5, 2, 4, 8, 11 and 12 hours (the latter
assessments all ±15 minutes)
x
PK sampling at 30 (±10) minutes and 1, 1.5, 2, 4, 8 and 12 hours (the latter assessments
all ±15 minutes)
x
Spirometry at 30 minutes (±10) and 1, 1.5, 2, 4, 8, 11.5 and 12 hours (the latter
assessments all ±15 minutes)
x
Question for adverse events
x
Weigh pMDI
Patients will be discharged from the study centre after the 12-hour assessments and instructed 
to return as follows: 1) for all but the final treatment period, 7 to 10 days later for Day 1 of the 
next treatment period, 2) for the final treatment period, 4 to 10 days later for the End of Study 
visit.    


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6.5
End of Study Visit
All completed and early terminated patients should complete the End of Study visit. The 
following will be performed:
x
Assess concomitant medications
x
Full physical examination
x
Vital signs
x
Blood samples for laboratory safety tests (haematology and blood chemistry)
x
Urinalysis
x
Urine pregnancy test (women of childbearing potential only)
x
Spirometry
x
Question for adverse events


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7
STUDY METHODOLOGY
7.1
Demographics, Baseline Characteristics and Eligibility Assessments 
Safety assessments (laboratory safety tests, vital signs, 12-lead ECG and physical examination) 
will be performed at Screening as part of the eligibility assessment as described in Section 7.4.3
to Section 7.4.6.
7.1.1
Demographic Variables 
Demographic 
variables, 
including 
date 
of 
birth, 
sex, 
height, 
weight, 
BMI 
(weight [kg]/height [m]2), race and smoking status will be collected at Screening. 
7.1.2
Medical and Disease History
All active medical conditions and all surgeries will be recorded at Screening. Disease history, 
including date of diagnosis will also be recorded.  
7.1.3
Reversibility Test
Reversibility in response to salbutamol will be assessed at Screening as an eligibility measure. 
Spirometry (FEV1 and FVC) assessment before and after four puffs (400 μg) of salbutamol,
administered using a pMDI, will be performed. 
Three technically acceptable measurements should be made and recorded in the eCRF. 
Spirometry assessments may be performed up to eight times to obtain three acceptable readings 
according to ATS guidelines (Miller et al, 2005). The highest reading from each assessment 
will be used for calculation of predicted values and increase from baseline.
The following must be confirmed for inclusion: 
x
Post-bronchodilator FEV1)9&UDWLRRI
x
Post-bronchodilator FEV1 4DQG80% of predicted normal*
x
'HPRQVWUDWHVP/LQFUHDVHIURPSUH-bronchodilator FEV1
*National Health and Nutrition Examination Survey (NHANES) III (Hankinson et al, 1999)
will be used as a reference for normal predicted values.
7.1.4
Screening Laboratory Assessments, Chest X-ray 
At Screening, blood samples will be taken and analysed for viral serology (human 
immunodeficiency virus, hepatitis B and hepatitis C). A serum pregnancy test will be 
performed on women of childbearing potential. An FSH test will be performed, if required to 
confirm post-menopausal status. Regarding viral serology, patients who received a hepatitis B 
vaccination and are positive for hepatitis B surface antibody, but are negative for both hepatitis 
B surface antigen and hepatitis B core antibody, do not need to be excluded from the study.
Samples will be taken and handled according to the laboratory manual and analysed locally.
A chest X-ray (posterior-anterior) must be performed at Screening or in the 12 months prior to 
Screening. 


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7.1.5
Prior and Concomitant Medications and Therapies
Prior COPD therapies and medications will be recorded at Screening and concomitant use 
during the study recorded as described in Section 5.8.1.
Other prior medications will be separately recorded at Screening and concomitant use during 
the study recorded as described in Section 5.8.2. 
7.1.6
Eligibility Check
Patients will be confirmed as eligible according to the Inclusion and Exclusion Criteria from 
assessments made at Screening with a final check of all results pre-dose in Part A.
7.2
Efficacy/Pharmacodynamic Assessments
7.2.1
Pulmonary Function Tests
Post-dose measurements will be taken in relation to the morning dose of RPL554 or placebo. 
Spirometry assessments (FEV1 and FVC) will be made in accordance with ATS/ERS 
guidelines (Miller et al, 2005). At all timepoints, three technically acceptable measurements 
will be made and recorded. Spirometry assessments may be performed up to eight times to 
obtain three acceptable readings. The highest FEV1 and FVC readings from each assessment 
will be used for analysis even if the FEV1 and FVC values come from two different forced 
exhalations. 
Spirometry will be performed using site-owned equipment and reviewed centrally, and sites 
will be instructed in proper use of the equipment prior to study initiation. 
7.2.2
Dyspnoea Scale 
Patients will be interviewed by a blinded member of study staff to assess their dyspnoea. An 
11-point Likert scale will be utilised, which will be anchored from 0 to 10 (Davis et al, 2006).
The interview will be worded as follows: “On a scale from zero to 10, please rate your current
shortness of breath, with zero indicating no shortness of breath and 10 indicating the worst
shortness of breath you can imagine.” This scale will be an instantaneous measurement of their
dyspnoea at that moment, and not reflective.
7.2.3
Rescue Medication 
The use of rescue medication will be assessed as follows: 1) during study visits, by recording 
the amount of and time that rescue was taken, and 2) between Days 1 and 7 of each treatment 
period, by recording the weight of the canister.  
7.3
Pharmacokinetic Assessments
Samples of 4 mL per time point will be collected by venepuncture or via indwelling cannula in 
the forearm into lithium heparin tubes and will be immediately chilled (ice bath). The blood 
will be centrifuged within 15 minutes of collection. The plasma will be separated in a 
refrigerated centrifuge (about 4°C) at 1100g for 15 minutes and transferred into polypropylene 
tubes. After each blood collection, the plasma will be dispensed into two aliquots. After 
appropriate labelling, the plasma samples will be stored at, or below -20°C. The plasma 
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at or below -20°C until they are submitted for analysis with a validated method. Analysis will 
be performed by a central laboratory.
7.4
Safety Assessments
7.4.1
Adverse Events 
7.4.1.1
Adverse Event Definitions
An adverse event is defined as any undesirable experience occurring to a patient, or worsening 
in a patient, during a clinical study, whether or not considered related to the study medication. 
An adverse event may be any of the following: 
x
A new illness
x
An exacerbation of a sign or symptom of the underlying condition under treatment or of
a concomitant illness
x
Unrelated to participation in the clinical study or an effect of the study medication
x
A combination of one or more of the above factors
No causal relationship with the study medication is implied by the use of the term “adverse 
event.” An exacerbation of a pre-existing condition or illness is defined as a more frequent 
occurrence or as an increase in the severity of the pre-existing condition or illness during the 
study. Planned or elective surgical or invasive procedures for pre-existing conditions that have 
not worsened are not adverse events. However, any complication that occurs during a planned 
or elective surgery is an adverse event (if the event fits the serious criteria, such as an extended 
hospitalisation, it will be considered to be serious). Conditions leading to unplanned surgical 
procedures may be adverse events.
An adverse reaction is defined as all untoward and unintended responses to study medication 
related to any dose administered. 
A serious adverse event (SAE) is any adverse experience that:
x
Results in death
x
Is life-threatening
x
Requires inpatient hospitalisation or prolongation of existing hospitalisation
x
Results in persistent or significant disability/incapacity, OR
x
Is a congenital anomaly/birth defect
x
Other medical events*
*Important medical events that may not be immediately life-threatening or result in death or
hospitalisation may be considered a SAE when, based on appropriate medical judgement, they
may jeopardise the patient or may require medical or surgical intervention to prevent one of
the outcomes listed above.
An unexpected adverse reaction is an adverse reaction in which the nature or severity of which 
is not consistent with the Investigator Brochure. 
A suspected unexpected serious adverse reactions (SUSAR) is any suspected adverse reaction 
related to the study medication that is both unexpected and serious. 
Standard procedures for emergency care should be followed for any individual adverse event, 
whenever clinically needed (decision to be taken by the Investigator). 


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7.4.1.2
Recording and Assessing Adverse Events
Any adverse events occurring during the following times are to be recorded in the eCRF: 
x
Part A:  From signing of the Informed Consent form until 28 days after administration
of the single dose.
x
Part B:  From 2 days prior to the start of Treatment Period 1 until the End of Study
Visit, which for patients who complete the study will occur 4 to 10 days after the
completion of the final treatment period
In view of the above, the period starting 29 days after Part A up to and including 3 days prior 
to the start of Part B (assuming they are separated by at least 29 days) will be considered to be 
outside the reporting period for adverse events, given the length of time between treatments 
with study medication.
All adverse events, whether reported spontaneously by the patient, in response to open 
questioning on treatment days or observed by the Investigator or his/her staff, will be recorded 
from informed consent until the End of Study Visit. The start and stop time will be recorded 
and adverse events will be assessed by the Investigator for the following:
7.4.1.2.1
Severity
Mild:
Resolved without treatment 
Moderate: 
Resolved or was tolerated with specific treatment without affecting study 
activities
Severe:
Did not resolve or was not tolerated with treatment
7.4.1.2.2
Chronicity 
Single occasion: 
Single event with limited duration
Intermittent:  
Several episodes of an event, each of limited duration 
Persistent: 
Event which remained indefinitely
7.4.1.2.3
Causality 
The Investigator will assess causal relationship between the study medication and each adverse 
event, and answer "yes" or "no" to the question, "Do you consider that there is a reasonable 
possibility that the event may have been caused by the study medication?"
For SAEs, causal relationship will also be assessed for study procedures, additional study 
medication, and other medication. Note that for SAEs that could be associated with any study 
procedure, the causal relationship is implied as "yes".
A guide to the interpretation of the causality question is found in Section 14.2.
7.4.1.2.4
Action and Outcome
x
Action taken with study medication (none, study medication stopped, study medication
temporarily interrupted)
x
Other actions (none, concomitant medication, study discontinuation, hospitalisation,
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x
The outcome and date of outcome according to the following definitions:
-
Recovered or resolved (adverse event disappeared)
-
Recovering or resolving (patient is recovering)
-
Not recovered or not resolved (adverse event remains without signs of
improvement)
-
Recovered or resolved with sequelae (adverse event has resulted in permanent
disability or incapacity)
-
Fatal
-
Unknown (only applicable if patient has been lost to follow-up)
x
Seriousness (yes or no)
7.4.1.3
Reporting Procedure for SAEs
The Investigator must report all SAEs to the Sponsor as soon as practical, but in call cases 
within 24 hours of awareness. Any fatal SAEs notified in the 28-day period after the last dose 
of study medication must also be reported. 
SUSARs will be determined by the Sponsor’s Medical Monitor. 
SAEs will be reported to the IEC and regulatory authority(ies) according to local requirements.
All adverse events will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical procedures 
as indicated, and/or referral to the patient’s general physician or a medical specialist.
It is the responsibility of the Investigator to ensure that any necessary additional therapeutic 
measures and follow-up procedures are performed. 
7.4.2
Pregnancy
In addition to the Screening serum pregnancy test (see Section 7.1.4), urine pregnancy tests 
will also be performed by the study centre on women of childbearing potential at Screening 
(confirmed to be negative prior to the chest X-ray) and during the study. 
Should a female patient become pregnant, or if a male patient fathers a child during the study 
or in the 30 days after the end of the study, the Investigator must be informed immediately. 
The Investigator will report this information to the Sponsor within 7 days of awareness. The 
Investigator will make all reasonable efforts to ascertain the progress and outcome of the 
pregnancy. If the outcome meets the criteria for immediate classification of a SAE 
(e.g. spontaneous or therapeutic abortion, stillbirth, neonatal death, congenital anomaly, birth 
defect), the Investigator must follow the procedure for reporting SAEs.
7.4.3
Laboratory Assessments
In addition to the laboratory tests detailed below, unscheduled and/or repeat testing may be 
performed at the discretion of the Investigator. Any additional laboratory results will also be 
merged into the final database. Laboratory results will be provided to the Investigator for each 
patient and each visit. The Investigator should assign whether each abnormal result is not 
clinically significant or a clinically significant. 
Samples will be taken and handled according to the laboratory manual and analysed locally. 


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7.4.3.1
Haematology
The following will be measured: haemoglobin, haematocrit, total white cell count, leucocyte 
differential count and platelet count.
For each assessment, a sample of venous blood will be collected in a collection tube containing 
ethylenediaminetetraacetic acid (EDTA). 
7.4.3.2
Blood Chemistry
The following will be measured: creatinine, total bilirubin, alkaline phosphatase, aspartate 
aminotransferase, alanine transaminase, gamma-glutamyl transferase, lactate dehydrogenase,
creatine kinase, thyroid stimulating hormone, triiodothyronine and thyroxine, glucose, 
potassium, sodium and calcium.  
For each assessment, a sample of venous blood will be collected in a vacutainer collection tube. 
7.4.3.3
Urinalysis
A midstream urine sample will be collected in a sterile container. The following will be tested: 
leucocytes, blood, ketones, bilirubin, urobilinogen, protein and glucose. If urinalysis on 
dipstick is positive for leucocytes and/or blood/haemoglobin, a microscopic examination 
including erythrocytes, leucocytes, bacteria, casts, epithelial cells and crystals will be 
performed. 
7.4.4
Vital Signs
The vital signs to be collected are blood pressure and pulse rate. 
Post-dose measurements will be taken in relation to the morning dose. Therefore, 12-hour 
measurements will be taken prior to the evening dose. 
For each assessment, supine vital signs will be assessed while the patient has been at rest for at 
least 5 minutes.
7.4.5
Physical Examination
A full physical examination, covering major body systems (assessments of the nose, throat, 
skin, thyroid gland, neurological system, respiratory system, cardiovascular system, abdomen 
[liver and spleen], lymph nodes and extremities) will be performed at Screening. Results will 
be recorded in the eCRF as normal, abnormal not clinically significant or abnormal clinically 
significant and abnormal results described. The full physical examination will be repeated at 
the End of Study Visit, and any changes only recorded. 
A brief physical examination, including assessments of the skin, respiratory system, 
cardiovascular system, and abdomen (liver and spleen) will be performed pre-dose for Part A, 
and pre-dose on Days 1 and 7 for Part B.
7.4.6
12-Lead ECG
Each 12-lead ECG should be taken after at least 5 minutes in the supine position. An overall 
assessment (normal, abnormal not clinically significant or abnormal clinically significant) will 
be recorded in the eCRF by the Investigator. ECG recordings will be assessed locally.


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Post-dose measurements in Part A will be taken in relation to the single, morning dose of 
RPL554 or placebo.  


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8
QUALITY ASSURANCE AND QUALITY CONTROL
The study will be conducted in accordance with the current approved protocol, standard 
operating procedures and all applicable guidelines and requirements (see Section 10).
8.1
Audit and Inspection 
The Sponsor, or its designee may conduct a quality assurance audit. An inspection of this study 
may also be carried out by regulatory authorities at their discretion. Such audits or inspections 
can occur at any time during or after completion of the study. If an audit or inspection occurs, 
the Investigator and institution agree to allow the auditor/inspector direct access to all relevant 
documents and to allocate his time and the time of his staff to the auditor or inspector to discuss 
findings and any relevant issues.
8.2
Monitoring and Source Document Verification
The study will be monitored by a monitor approved by the Sponsor. During these visits, all 
procedures will be monitored for compliance with the protocol. Source documents will be 
reviewed and compared with the data entries in the eCRFs to ensure consistency. The Sponsor 
will ensure that the study is monitored in accordance with the principles of ICH GCP. The 
frequency of monitoring visits will be determined, in part, by the rate of patient recruitment.
The following are examples of items that will be reviewed at these visits:
x
Compliance with the protocol
x
Consent procedure
x
Source documents
x
Adverse event procedures
x
Storage and accountability of materials
The monitoring visits also provide the Sponsor with the opportunity to ensure that timely 
patient accrual and the other Investigator’s obligations and all applicable requirements are 
being fulfilled.
The Investigator must permit the study monitor, the IEC, the Sponsor’s auditors and 
representatives from regulatory authorities’ direct access to all source documents for 
confirmation of the accuracy and reliability of data contained within the eCRFs (source 
document verification). Patient confidentiality will be protected at all times.
Source documents are defined as the results of original observations and activities of a clinical 
investigation, including medical notes. All source documents produced in this study will be 
maintained by the Investigator and made available for inspection. The original signed informed 
consent form for each patient will be retained by the Investigator and the second signed original 
given to the patient.
Source data include, but is not limited to, the following and will be identified in a source data 
location log: 
x
Screening/enrolment log
x
Medical notes - which should be updated after each visit to include visit dates, medical
history, diagnosis of COPD, concomitant medication, any clinically relevant findings of
clinical examinations or clinically relevant adverse events/medication changes, SAEs
and information on patient withdrawal


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x
Informed consent form
x
12-lead ECGs
x
Laboratory reports
x
Visit dates
x
Study medication accountability/inventory forms
The study monitor will carry out source document verification at regular intervals. This is an 
essential element of quality control, as it allows the rectification of transcription errors and 
omissions.
8.3
Data Management and Coding 
Data for each patient will be recorded in an eCRF. Data collection must be completed for each 
patient who signs an informed consent form and receives at least one dose of study medication. 
eCRFs will be designed and produced by the Sponsor or designee and should be completed in 
accordance with instructions. The Investigator is responsible for maintaining adequate and 
accurate medical records from which accurate information will be transcribed directly into the 
eCRFs using a secure internet connection. The eCRFs should be filled out completely by the 
Investigator or designee as stated on the delegation of responsibilities form. The eCRF system 
will be Food and Drug Administration Code of Federal Regulations 21 Part 11 compliant. 
The eCRFs must be reviewed, signed and dated by the Investigator. 
Data entered into the eCRF will be validated as defined in the data validation plan. Validation 
includes, but is not limited to, validity checks (e.g. range checks), consistency checks and 
customised checks (logical checks between variables to ensure that study data are accurately 
reported) for eCRF data and external data. A majority of edit checks will be triggered during 
data entry and will therefore facilitate efficient ‘point of entry’ data cleaning. 
Data management personnel will perform both manual eCRF review and review of additional 
electronic edit checks to ensure that the data are complete, consistent and reasonable. The 
electronic edit checks will run continually throughout the course of the study and the issues 
will be reviewed manually online to determine what action needs to be taken. 
Manual queries may be added to the system by clinical data management or study monitor. 
Clinical data managers and study monitors are able to remotely and proactively monitor the 
patient eCRFs to improve data quality. 
External data (laboratory safety, 12-lead ECG and PK data) will be transferred electronically 
into the study database. Discrepancies will be queried to the study centre and/or the laboratory 
until the electronic data and the database are reconciled. 
All updates to queried data will be made by authorised study centre personnel only and all 
modifications to the database will be recorded in an audit trail. Once all the queries have been 
resolved, eCRFs will be locked by password protection. Any changes to locked eCRFs will be 
approved by the Investigator. 
Once the full set of eCRFs have been completed and locked, the Sponsor will authorise
database lock and all electronic data will be sent to the designated statistician for analysis. 
Subsequent changes to the database will then only be made only by written agreement of the 
Sponsor. A copy of the eCRFs for each patient will be provided to the Investigator in uneditable 
format at the end of the study. 


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Adverse events will be coded from the verbatim description (Investigator term) using the 
Medical Dictionary for Regulatory Activities (MedDRA). Prior and concomitant medications 
will be coded according to the World Health Organisation drug code. An independent coding 
review will be performed by the Sponsor. 
The clinical database (in Statistical Analysis System [SAS] format) will be transferred to the 
Sponsor at the end of the study.  


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9
STATISTICAL METHODS
9.1
Statistical and Analytical Plans
This section presents a summary of the planned statistical analyses. A detailed plan describing 
the analyses to be conducted will be defined before the last patient is completed and will include 
the determination of rules for major and minor protocol deviations. Any deviation from the 
analysis specified in the protocol or the statistical analysis plan will be detailed and justified in 
the clinical study report. 
9.2
Populations to be Analysed 
Allocation of patients to the analysis populations (and whether any patients or specific data 
from a patient will be excluded) will be determined at the pre-database lock meeting.
Part A:
The full analysis set will consist of all randomised patients with sufficient data collected after 
intake of study treatment to compute the efficacy/pharmacodynamic parameters.
The safety set will consist of all randomised and treated patients. 
The PK data set will consist of all randomised patients with blood sampling performed after an
RPL554 treatment and with data sufficient to calculate PK parameters.
Part B:
The full analysis set will consist of all randomised patients with sufficient data collected after 
intake of study treatment to compute the efficacy/pharmacodynamic parameters on at least two 
treatment periods. 
The completer analysis set will consist of all randomised patients that complete all treatment
periods. 
The safety set will consist of all randomised patients who took at least one dose of study 
treatment during at least one period.  
The PK data set will consist of all randomised patients with blood sampling performed after at 
least one dose of RPL554 and with data sufficient to calculate PK parameters.
9.3
Study Endpoints  
9.3.1
Part A
9.3.1.1
Primary Endpoint 
The primary endpoints in Part A are the pharmacokinetic parameters AUC0-12 and AUC0-t
maximum concentration (Cmax), time to maximum concentration (tmax) and half-life.  
9.3.1.2
Secondary Endpoints 
x
Safety and tolerability:

Continuous monitoring of adverse events

Laboratory safety tests [haematology, blood chemistry and urinalysis]


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
12-lead ECG (including QTcF and heart rate), supine vital signs (blood pressure
and pulse rate)
x
Change from baseline in average FEV1 AUC0-4h measured after single dose
x
Change from baseline in average FEV1 AUC0-12h measured after single dose
x
Change from baseline in peak FEV1 measured after single dose
x
Change from baseline in peak pulse and peak heart rate measured after single dose
9.3.2
Part B
9.3.2.1
Primary Endpoint 
The primary endpoint in Part B is change from baseline in peak FEV1 measured after morning 
dosing on Day 7. 
9.3.2.2
Secondary Endpoints 
x
Safety and tolerability:

Continuous monitoring of adverse events

Laboratory safety tests [haematology, blood chemistry and urinalysis]

12-lead ECG (including QTcF and heart rate), supine vital signs (blood pressure
and pulse rate)
x
Change from baseline in (morning) trough FEV1 measured prior to morning dosing on
Day 7
x
Change from baseline in peak FEV1 measured after first dose
x
Change from baseline in average FEV1 AUC0-4h measured after morning dosing on Day 7
x
Change from baseline in average FEV1 AUC0-12h measured after first dose and after
morning dosing on Day 7
x
Determination of onset of action (>10% increase in FEV1 from pre- to post- first dose,
censored at 120 minutes) after first dose
x
RPL554 steady state pharmacokinetics (AUC0-12h, Cmax, tmax, accumulation ratio) after
dose 13 on Day 7
x
Change from baseline in peak pulse after first dose on Day 1 and after morning dosing
on Day 7
x
Change from baseline in, average FEV1 AUC0-4h and average FEV1 AUC0-12h on Day 1
x
Change from baseline in rescue medication use
9.3.2.3
Exploratory Endpoint 
x
Evaluation of dose response of RPL554 on peak and average FEV1 AUC0-12h after
morning dose on Day 7, and morning trough FEV1 prior to the last dose on Day 7
x
Change from baseline in Likert dyspnoea scale measured after single dose and after
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9.4
Statistical Methods
In general, unless stated otherwise, continuous variables will be summarised using descriptive 
statistics (number of patients, mean, standard deviation, median, minimum and maximum 
values) and for categorical (nominal) variables, the number and percentage of patients will be 
used.  
All hypothesis testing will be done using two-sided alternative hypotheses. P-values less than 
5% will be considered statistically significant. 
9.4.1
Patient Disposition
The number of patients enrolled, randomised, completed or withdrawn (with reason for 
withdrawal) will be summarised. 
9.4.2
Protocol Deviations 
All protocol deviations collected will be divided into critical, major or minor categories. Prior 
to database lock protocol deviations will be reviewed and consequences for inclusion of 
patients in various analysis population sets determined and documented. 
9.4.3
Demographics and Other Baseline Characteristics
Demographics and baseline characteristics (including pre- and post-bronchodilator FEV1 [both 
in litres and in percentage of predicted normal], post-bronchodilator FEV1/FVC, FEV1
reversibility, duration of COPD [time since diagnosis], smoking habits including number of 
pack-years, number of patients taking COPD medications by therapeutic class including ICS, 
LABA, LAMA or combinations thereof) will be listed and summarised appropriately. 
Medical history, prior and concomitant medications, viral serology results, pregnancy test 
results from females and chest X-ray findings will be listed. 
9.4.4
Extent of Exposure and Treatment Compliance
For Part A, all administration of study medication will be performed at the clinic under 
supervision of the study staff; therefore, no formal analysis of compliance will be performed. 
For Part B, compliance will be assessed based on: 1) patient-reported missed doses, and 2) the 
weights of pMDI units dispensed and returned. Total exposure will be based on the patient-
reported missed doses. 
9.4.5
Efficacy/Pharmacodynamics 
FEV1 and FVC will be summarised as actual value and change from baseline using descriptive 
statistics over time for all treatments and both study parts. 
The peak effect on FEV1 during these time intervals will be computed as the maximum value 
in the 4 hours after dosing. The average effect (average FEV1 AUC0-t) will be calculated as the 
AUC divided by the length of the time interval of interest. For analysis of the peak, average 
and trough FEV1, the change from baseline will be expressed as the parameter divided by the 
pre-dose Day 1 baseline value.  
In Part A, computed efficacy/pharmacodynamic parameters for FEV1 will be compared 
between the treatments using analysis of covariance models with fixed factor treatment, and 


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using 
the 
pre-dose 
baseline 
value 
as 
a 
covariate. 
In 
Part
B, 
computed 
efficacy/pharmacodynamic parameters (peak, AUC0-4, AUC0-12 and trough) for FEV1 will be 
compared between the treatments using analysis of covariance models adjusting for treatment 
period and patient, and using the pre-dose Day 1 baseline value as a covariate. FEV1 will be 
analysed using multiplicative models, which means that data (dependent and baseline) are 
logged prior to analysis and the result then transformed back to the linear scale giving treatment 
differences as ratios of geometric means. 
Primarily, active treatments will be compared to placebo. For RPL554 pMDI, the high dose 
will first be compared to placebo, and if found statistically significant then the next lower dose 
will be compared to placebo, and if found statistically significant then the subsequent lower 
dose will be compared to placebo, and this procedure repeated for all doses. Secondarily, the 
different doses of RPL554 pMDI will be compared. Results of the comparisons will be 
expressed as the mean geometric ratio with 95% confidence intervals and associated, 2-sided, 
p-value.
Onset of action will be calculated and summarised by treatment. In Part B, a Kaplan-Meier plot 
illustrating time to onset will be constructed and from the survival curves the median time to 
onset will be estimated. Placebo will not be included in summaries of onset of action.  
In Part B, the average use of rescue medication during the treatment periods will be summarised
by treatment group. In addition, all rescue medication used during the treatment visits (Day 1 
in Part A and Days 1 and 7 in Part B) will be listed to assess the accuracy of the FEV1
recordings. 
In Part B, change in Likert dyspnoea scale to each time point will be compared between the 
treatments using analysis of covariance models adjusting for factors for treatment, period and 
patient, and using the pre-dose Day 1 baseline value as a covariate. Additive models will be 
used for dyspnoea. 
9.4.6
Pharmacokinetics
The following PK parameters will be calculated from plasma concentrations of RPL554 using 
standard non-compartmental methods.
x
Part A: AUC0-t represents the area under the plasma concentration curve from time 0 to
last observed value above the lower limit of quantification
x
Part A: Half-OLIH OQȜz
x
Parts A and B: AUC0-12h represents the area under the plasma concentration curve from
time 0 to 12 hours. The AUC0-12h value after dose 13 in Part B is considered an
appropriate estimate of the AUC at steady state.
x
Cmax denotes the highest plasma concentration measured
x
tmax denotes the time point corresponding to Cmax
PK parameters will be summarised by dose level using descriptive statistics (n, geometric 
mean, coefficient of variation [CV], minimum, maximum and median for AUC parameters, 
Cmax, n, arithmetic mean, standard deviation, minimum, maximum and median for tmax).
In Part A, proportionality for AUC 0-12h and Cmax will be investigated by fitting a power model 
to data using linear regression on the log(parameter)-log(dose) scale. In Part B, 
dose-normalised AUC0-12h and Cmax will be compared using analysis of covariance models 
adjusting for factors treatment, period and patient 90% confidence intervals will be constructed 
for the geometric mean ratios. If appropriate, AUC0-12h data from Parts A and B belonging to 


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the same patient and the same dose of RPL554 may be combined to compute the accumulation 
index (repeat dose/single dose ratio). 
9.4.7
Safety 
Safety data including laboratory safety tests, 12-lead ECG, vital signs and physical 
examinations, will be summarised by treatment group and timepoint of collection, when 
appropriate, for each of the two parts separately. For continuous variables, the change from 
baseline (pre-dose at each treatment period) to each post-dose time point will also be calculated 
and summarised. Data will further be illustrated by shift tables (showing changes from 
low/normal/high) and shift plots for selected time points. Separate listings will be generated of 
abnormal values occurring after the first dose of study medication. 
In Part A, change from baseline in peak pulse and peak heart rate will be compared between 
the treatments using analysis of covariance models with fixed factor treatment, and using the 
pre-dose baseline value as a covariate. In Part B, change from baseline in peak pulse will be 
compared between the treatments using analysis of covariance models with fixed factors for 
treatment, period and patient, and using the pre-dose Day 1 baseline value as a covariate.
Additive model will be used for pulse and heart rate.
Coded adverse event terms will be presented by system organ class (SOC) and preferred term 
and summarised by treatment group for each part. Summary tables by treatment group with 
total number and number of patients with adverse events, SAEs, adverse events leading to 
discontinuation of study treatment, causally related adverse events and severe adverse events 
will be produced. Further SAEs, causally related adverse events and adverse events of each 
intensity will be summarised by SOC and preferred term. 
9.4.8
Handling of Withdrawals or Missing Data 
In Part B, patients withdrawn after only one treatment period will not be included in the 
efficacy/pharmacodynamic and PK analyses of parameters that can be computed in all planned 
treatment periods. Imputation of data for calculation of average (AUC) effects for FEV1 will 
be described in the statistical analysis plan. No other imputation of missing data will be 
performed. 
All available data from all dosed patients who have received study treatment will be listed and 
summarised. Any unscheduled or unplanned readings will be presented within the patient 
listings, but only the scheduled readings will be used in any summaries. If a visit is rescheduled 
due to variability in FEV1 or other reason, the rescheduled visit will be listed and summarised
as the valid visit. 
9.4.9
Interim Analyses
No formal interim analysis is currently planned. This study will consist of two separate and 
independent analyses. To avoid possible effects of the unblinding of data from Part A on the 
blinding in Part B, only aggregated data (i.e. treatment level, without individual patient 
identifiers) will be revealed at the time of the analysis of the Part A data. 
9.5
Determination of Sample Size
The sample size is determined for Part B. This is a complete block crossover study. Assuming 
a residual CV of 6% for peak FEV1, 30 patients will give an 80% power to detect a pairwise 
difference in peak FEV1 of 4.6%. Assuming a mean baseline FEV1 of 1.5 L this will correspond 


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to a difference of about 70 mL. To account for withdrawals, 36 patients will be randomised to 
Part A.  


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10
ETHICAL CONSIDERATIONS
10.1
Guidelines
The study will be performed in accordance with ICH GCP guidelines, the principles outlined 
in the Declaration of Helsinki (1996), the protocol and applicable regulatory requirements. 
10.2
Ethics and Regulatory Approval 
The Sponsor will supply all background data necessary to enable submission to the appropriate 
IECs and regulatory authorities. The study will not commence before formal ethical and 
regulatory approvals have been granted. 
All changes or revisions of this protocol will be documented. The reason for the amendment 
will be stated. The Sponsor will ensure ethical and regulatory approval is obtained for all 
substantial amendments to the original approved documents.
10.3
Informed Consent Process
It is the responsibility of the Investigator to obtain written informed consent from patients. All 
consent documentation must be in accordance with applicable regulations and ICH GCP. Each 
patient is requested to sign and date the informed consent form after (s)he has received and 
read the patient information sheet and received an explanation of what the study involves, 
including but not limited to: the objectives, potential benefits and risk, inconveniences and the 
patient’s rights and responsibilities. Patients will be given adequate time to evaluate the 
information given to them before signing the informed consent form. 
One original of the signed informed consent form must remain on file and must be available 
for verification by the study monitor at any time. A second original of the informed consent 
form plus the patient information sheet must be given to the patient or the patient’s legally 
authorised representative.
10.4
Patient Confidentiality
Data collected during this study may be used to support the development, registration or 
marketing of the study medication. The Sponsor will control all data collected during the study
and will abide by the European Union Directive on Data Privacy concerning the processing 
and use of patient’s personal data. For the purpose of data privacy legislation, the Sponsor will 
be the data controller. 
After patients have consented to take part in the study, their medical records and the data 
collected during the study will be reviewed by the Sponsor and/or its representatives. These 
records and data may, in addition, be reviewed by the following: independent auditors who 
validate the data on behalf of the Sponsor; regulatory authorities and the IEC which gave its 
approval for this study to proceed. 
Although patients will be known by a unique number, their initials will also be collected and 
used to assist the Investigator to reconcile data clarification forms, for example, that the results 
of study assessments are assigned to the correct patient. The results of this study containing the 
unique number, but not the patient’s initials and relevant medical information may be recorded 
and transferred to and used in other countries throughout the world, which may not afford the 
same level of protection that applies within the European Union. The purpose of any such 
transfer would be to support regulatory submissions made by the Sponsor in such countries. 


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10.5
Record Maintenance/Retention
The Investigator will retain the originals of all source documents generated at the location 
where the study is being conducted, either: 1) until after regulatory agency approval is obtained 
for the study medication in the country/countries in which the results of this study comprise 
the submission dossier, or 2) for a period of 2 years after the report of the study has been 
finalised, in the absence of a regulatory approval. After that time, all study-related documents 
will be archived according to ICH GCP regulations. 


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11
FINANCE AND 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.  


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12
PUBLICATION POLICY
The publication policy is detailed in the Investigator Agreement between the Sponsor and 
Investigator.


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13
REFERENCES
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):365-376. Doi: 10.1111/bcpt.12209. Epub 2014 Mar 6. 
Calverley PM, Sanchez-Toril F, McIvor A et al. Effect of 1-year treatment with roflumilast in 
severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 
176(2):154-161. 
Calzetta L, Page CP, Spina D, et al. The effect of the mixed phosphodiesterase 3/4 inhibitor 
RPL554 on human isolated bronchial smooth muscle tone. J Pharmacol Exp Ther 2013; 346: 
414–423.
Calzetta L, Cazzola M, Page CP, et al. Pharmacological characterization of the interaction 
between the dual phosphodiesterase (PDE) 3/4 inhibitor RPL554 and glycopyrronium on 
human isolated bronchi and small airways. Pulm Pharmacol Ther 2015 Apr 18. pii: 
S1094-5539(15)00042-5.
Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of 
patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J, 2004; 
2:932-946. 
Compton CH, Gubb J, Nieman R et al. Cilomilast, a selective phosphodiesterase-4 inhibitor 
for treatment of patients with chronic obstructive pulmonary disease: a randomised,
dose-ranging study. Lancet 2001; 358(9278):265-270. 
Davis AH, Carrieri-Kohlman V, Janson SL et al. Effects of treatment on two types of 
self-efficacy in people with chronic obstructive pulmonary disease. J Pain Symptom Manage 
2006; 32(1):60-70. 
EU Directive 95/46/EC: The Data Protection Directive.
Franciosi LG, Diamant Z, Banner KH, et al. Efficacy and safety of RPL554, a dual PDE3 and 
PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive 
pulmonary disease: findings from four clinical trials. Lancet Respiratory Medicine 2013; 
1(9):714-727. 
Gamble E, Grootendorst DC, Brightling CE et al. Anti-inflammatory effects of the 
phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am 
J Respir Crit Care Med 2003; 168(8):976-982. 
Grootendorst D, Gauw SA, Verhoosel RM, et al. Reduction in sputum neutrophil and 
eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007; 
62(12); 1081-1087. 
Hankinson JL, Odencrantz JR, Fedan KB. Spirometry reference values from a sample of the 
general U.S. Population. Am J Respir Crit Care 1999; 159:179-187. 
Harbinson PL, MacLeod D, Hawksworth R et al. The effect of a novel orally active selective 
PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects. Eur 
Respir J 1997; 10(5):1008-1014. 
International Council for Harmonisation (ICH) Integrated addendum to ICH E6(R1): Guideline 
for Good Clinical Practice E6(R2)


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Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 2005;
26(2):319-338. 
Rabe KF, Bateman ED, O'Donnell D, et al. Roflumilast--an oral anti-inflammatory treatment 
for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2005; 
366(9485):563-571. 
Recommendations related to contraception and pregnancy testing in clinical trials.  Clinical 
Trial Facilitation Group, Heads of Medicines Agencies, 2014. Downloaded from: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.
Rennard SI, Schachter N, Strek M, et al. Cilomilast for COPD: results of a 6-month placebo 
controlled study of a potent, selective inhibitor of phosphodiesterase 4. Chest 2006;
129(1):56-66.
Singh D. New combination bronchodilators for chronic obstructive pulmonary
disease: current evidence and future perspectives. Br J Clin Pharmacol 2015; 79(5): 695–708.  
Stuckler, D. Population causes and consequences of leading chronic diseases: a
comparative analysis of prevailing explanations. The Milbank Quarterly 2008; 86(2): 
273-326.
Ukena D, Rentz K, Reiber C, et al. Effects of the mixed phophodiesterase III/IV inhibitor, 
zardaverine, on airway function in patients with chronic airflow obstruction. Respir Med 1995;
89 (6):441-444. 
van Schalkwyk E, Strydom K, Williams Z et al. Roflumilast, an oral, once-daily 
phosphodiesterase 4 inhibitor, attenuates allergen-induced asthmatic reactions. J Allergy Clin 
Immunol 2005;116 (2):292-298.  
Verona Pharma plc RPL554 Investigator Brochure, version 17.0, May 2018.  
Verona Pharma plc RPL554 Investigational Medicinal Product Dossier current version. 
Vestbo J, Papi A, Corradi M et al. Single inhaler extrafine triple therapy versus long-acting 
muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double 
blind, parallel group, randomised controlled trial. Lancet 2017; 389(10082):1919-1929. 
World Medical Association, Declaration of Helsinki. Ethical Principles for Medical Research 
Involving Human Subjects. Last amended by the 48th World Medical Association General 
Assembly, Somerset West, 1996. 


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14
APPENDICES
14.1
Birth Control Methods For Women of Childbearing Potential Which May 
Be Considered As Highly Effective
(Adapted from the Clinical Trial Facilitation Group, Heads of Medicines Agencies, 2014)
I.
Definitions
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilisation
methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered women of childbearing potential: 
1.
Premenopausal female with one of the following:
x
Documented hysterectomy
x
Documented bilateral salpingectomy
x
Documented bilateral oophorectomy
Note: Documentation can come from the study centre staff’s: review of participant’s
medical records, medical examination, or medical history interview.
2.
Premenarchal
3.
Postmenopausal female
Females who are postmenopausal (age-UHODWHGDPHQRUUKHDFRQVHFXWLYHPRQWKVDQG
increased FSH >40 mIU/mL), or who have undergone hysterectomy or bilateral
oophorectomy are exempt from pregnancy testing. If necessary to confirm
postmenopausal status, an FSH will be drawn at Screening.
Females on hormone replacement therapy (HRT) and whose menopausal status is in
doubt will be required to use one of the non-hormonal highly effective contraception
methods if they wish to continue their HRT during the study. Otherwise, they must
discontinue HRT to allow confirmation of postmenopausal status before study enrolment.
II.
Methods
For the purpose of this guidance, methods that can achieve a failure rate of less than 1% per
year when used consistently and correctly are considered as highly effective birth control
methods. Such methods include: 
x
Combined (oestrogen and progestogen containing) hormonal contraception associated
with inhibition of ovulation:
-
Oral
-
Intravaginal
-
Transdermal
x
Progestogen-only hormonal contraception associated with inhibition of ovulation1:
-
Oral


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-
Injectable
-
Implantable1
x
Intrauterine device1
x
Intrauterine hormone-releasing system1
x
Bilateral tubal occlusion1
x
Vasectomised partner1,2
x
Sexual abstinence3
1 Contraception methods that in the context of this guidance are considered to have low user dependency
2 Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner 
of the trial participant and that the vasectomised partner has received medical assessment of the surgical success
3 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the patient


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14.2
Interpreting Adverse Event Causality
The following factors should be considered when deciding if there is a “reasonable possibility” 
that an adverse event may have been caused by the study medication. 
x
Time Course. Exposure to suspect study medication. Has the patient actually received
the suspect study medication? Did the adverse event occur in a reasonable temporal
relationship to the administration of the suspect study medication?
x
Consistency with known study medication profile. Was the adverse event consistent with
the previous knowledge of the suspect study medication (pharmacology and toxicology)
or drugs of the same pharmacological class? OR Could the adverse event be anticipated
from its pharmacological properties?
x
Dechallenge experience. Did the adverse event resolve or improve on stopping or
reducing the dose of the suspect study medication?
x
No alternative cause. The adverse event cannot be reasonably explained by another
aetiology such as the underlying disease, other drugs, other host or environmental factors
x
Rechallenge experience. Did the adverse event reoccur if the suspected study medication
was reintroduced after having been stopped Laboratory tests. A specific laboratory
investigation (if performed) has confirmed the relationship?
A "reasonable possibility" could be considered to exist for an adverse event where one or more 
of these factors exist.
In contrast, there would not be a "reasonable possibility" of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course, but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause of 
the adverse events.
In difficult cases, other factors could be considered such as:
x
Is this a recognised feature of overdose of the study medication?
x
Is there a known mechanism?
Ambiguous cases should be considered as being a "reasonable possibility" of a causal 
relationship unless further evidence becomes available to refute this. Causal relationship in 
cases where the disease under study has deteriorated due to lack of effect should be classified 
as no reasonable possibility. 

SAP_001.pdf: 
 
16.1.9 
Documentation of Statistical Methods 
Document
Date
Statistical Analysis Plan, Part A, Version 2.0 
13 January 2021 
Statistical Analysis Plan, Part B, Version 1.0 
13 January 2021 
Tables, Listings and Figures Shells, Part A, Version 2.0 
13 January 2021 
Tables, Listings and Figures Shells, Part B, Version 2.0 
22 January 2021 
Clinical Study Report
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Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v2.0 – Part A 
Page 1 of 43 
 
 
Document: 
Z:\ RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 SAP v2.0 – Part A 
Author: 
Nicholas Roubinis / Jennifer Allsopp 
Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN – PART A 
 
 
RPL554-MD-201 
A Phase II, Randomized Study to Assess the Pharmacokinetics, Safety 
and Pharmacodynamics of Single and Repeat Doses of RPL554 
Administered by Pressurised Metered Dose Inhaler in Patients with 
COPD 
 
 
 
 
 
AUTHOR: NICHOLAS ROUBINIS/JENNIFER ALLSOPP 
VERSION NUMBER AND DATE: V2.0, 13JAN2021 
 
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Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v2.0 – Part A 
Page 2 of 43 
 
 
Document: 
Z:\ RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 SAP v2.0 – Part A 
Author: 
Nicholas Roubinis / Jennifer Allsopp 
Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN – PART A SIGNATURE PAGE 
Statistical Analysis Plan V2.0 – Part A (Dated 13JAN2021) for Protocol RPL554-MD-201. 
 
 
Name 
Signature 
Date 
Author: 
Jennifer Allsopp 
 
 
 
Position: 
Senior Biostatistician 
 
Company: 
IQVIA 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan – Part A, 
authorizing that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
Mark Shaw 
 
 
 
Position: 
Manager, Biostatistics 
 
Company: 
IQVIA 
 
Approved By: 
Tara Rheault 
 
 
 
Position: 
VP, R&D  
 
Company: 
Verona Pharma 
 
Approved By: 
Thomas Bengtsson 
 
 
 
 
Position: 
Statistical Consultant to Verona 
 
Company: 
StatMind 
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Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v2.0 – Part A 
Page 3 of 43 
 
 
Document: 
Z:\ RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 SAP v2.0 – Part A 
Author: 
Nicholas Roubinis / Jennifer Allsopp 
Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
MODIFICATION HISTORY 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
1.0 
28AUG2019 
Nicholas Roubinis/ 
Jennifer Allsopp 
Not Applicable – First Version 
1.1 
01APR2020 
Jennifer Allsopp 
Update approver from Verona on signature 
page from Brian Maurer to Nancy Herje. 
Update protocol version SAP is based on in 
Section 1. 
1.2 
09DEC2020 
Jennifer Allsopp 
Update approver from Verona on signature 
page from Nancy Herje.to Tara Rheault 
2.0 
13JAN2021 
Jennifer Allsopp 
Add Thomas Bengtsson as an approver for 
Verona. 
 
 
 
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Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v2.0 – Part A 
Page 4 of 43 
 
 
Document: 
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Author: 
Nicholas Roubinis / Jennifer Allsopp 
Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION............................................................................................................... 8 
2. 
STUDY OBJECTIVES FOR PART A ............................................................................. 8 
2.1. 
Primary Objective ........................................................................................................................................... 8 
2.2. 
Secondary Objectives ...................................................................................................................................... 8 
3. 
STUDY DESIGN ................................................................................................................. 9 
3.1. 
General Description ......................................................................................................................................... 9 
3.2. 
Schedule of Events ......................................................................................................................................... 10 
3.3. 
Changes to Analysis from Protocol .............................................................................................................. 10 
4. 
PLANNED ANALYSES ................................................................................................... 10 
4.1. 
Data Monitoring Committee (DMC) ............................................................................................................ 11 
4.2. 
Interim Analysis ............................................................................................................................................. 11 
4.3. 
Part A Analysis .............................................................................................................................................. 11 
5. 
ANALYSIS SETS.............................................................................................................. 12 
5.2. 
All Patients Randomized Set [RND] ............................................................................................................ 12 
5.3. 
Safety Analysis Set [SAF] .............................................................................................................................. 12 
5.4. 
Full Analysis Set [FAS] ................................................................................................................................. 12 
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Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v2.0 – Part A 
Page 5 of 43 
 
 
Document: 
Z:\ RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 SAP v2.0 – Part A 
Author: 
Nicholas Roubinis / Jennifer Allsopp 
Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
5.5. 
Pharmacokinetics [PK] Analysis Set ............................................................................................................ 13 
6. 
GENERAL CONSIDERATIONS ................................................................................... 13 
6.1. 
Reference Start Date and Study Day ........................................................................................................... 13 
6.2. 
Baseline ........................................................................................................................................................... 14 
6.3. 
Repeat/reschedule, Unscheduled Visits and Early Termination Data ...................................................... 14 
6.4. 
Windowing Conventions ............................................................................................................................... 14 
6.5. 
Statistical Tests .............................................................................................................................................. 15 
6.6. 
Common Calculations ................................................................................................................................... 15 
6.7. 
Software Version ............................................................................................................................................ 16 
7. 
STATISTICAL CONSIDERATIONS ............................................................................ 16 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses ....................................................... 16 
7.2. 
Multicenter Studies ........................................................................................................................................ 16 
7.3. 
Missing data ................................................................................................................................................... 17 
7.4. 
Multiple Comparisons/ Multiplicity ............................................................................................................. 17 
7.5. 
Examination of Subgroups ............................................................................................................................ 18 
8. 
OUTPUT PRESENTATIONS ......................................................................................... 18 
9. 
DISPOSITION AND WITHDRAWALS ........................................................................ 18 
10. 
DEMOGRAPHIC AND OTHER SCREENING CHARACTERISTICS ................... 19 
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Statistical Analysis Plan v2.0 – Part A 
Page 6 of 43 
 
 
Document: 
Z:\ RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 SAP v2.0 – Part A 
Author: 
Nicholas Roubinis / Jennifer Allsopp 
Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
10.1. 
Derivations ................................................................................................................................................. 20 
11. 
SURGICAL, MEDICAL AND CHRONIC OBSTRUCTIVE PULMONARY 
DISEASE/SMOKING HISTORY ............................................................................................. 21 
12. 
MEDICATIONS ............................................................................................................... 21 
13. 
STUDY MEDICATION EXPOSURE ............................................................................ 23 
14. 
STUDY MEDICATION COMPLIANCE ...................................................................... 23 
15. 
EFFICACY OUTCOMES................................................................................................ 23 
15.1. 
Primary Efficacy ........................................................................................................................................ 23 
15.1.1. 
Primary Efficacy Variable(s) & Derivation(s) ......................................................................................... 23 
15.1.2. 
Missing Data Methods for Primary Efficacy Variable(s) ........................................................................ 23 
15.1.3. 
Primary Analysis of Primary Efficacy Variable(s) .................................................................................. 23 
15.2. 
Secondary Efficacy .................................................................................................................................... 24 
15.2.1. 
Secondary Efficacy Variables & Derivations .......................................................................................... 24 
15.2.1.1. 
Change in baseline in average FEV1 of AUC0-4h (Average FEV1 over 4 hours) after single dose 
(Secondary variable 1) ......................................................................................................................................... 24 
15.2.1.2. 
Change in baseline in average FEV1 AUC0-12h (Average FEV1 over 12 hours) after single dose 
(Secondary variable 2) ......................................................................................................................................... 25 
15.2.1.3. 
Change from baseline in peak FEV1 (measured in first 4 hours) after single dose (Secondary 
variable 3) 25 
15.2.2. 
Missing Data Methods for Secondary Efficacy Variable(s) .................................................................... 26 
15.2.3. 
Analysis of Secondary Efficacy Variables............................................................................................... 26 
16. 
SAFETY OUTCOMES .................................................................................................... 27 
16.1. 
Adverse Events ........................................................................................................................................... 27 
16.1.1. 
All TEAEs ............................................................................................................................................... 28 
16.1.1.1. 
Severity ............................................................................................................................................ 28 
16.1.1.2. 
Relationship to Study Medication .................................................................................................... 28 
16.1.2. 
TEAEs Leading to Discontinuation of Study Medication ....................................................................... 28 
16.1.3. 
Serious Adverse Events ........................................................................................................................... 29 
16.1.4. 
Adverse Events Leading to Death............................................................................................................ 29 
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16.2. 
Laboratory Evaluations ............................................................................................................................ 29 
16.2.1. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ............................................................ 30 
16.3. 
ECG Evaluations ....................................................................................................................................... 30 
16.4. 
Vital Signs ................................................................................................................................................... 31 
16.5. 
Physical Examination ................................................................................................................................ 32 
16.6. 
Other Safety Assessments ......................................................................................................................... 33 
17. 
PHARMACOKINETIC EVALUATIONS ..................................................................... 33 
18. 
REFERENCES .................................................................................................................. 34 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS .............................. 35 
IQVIA Output Conventions...................................................................................................................................... 35 
Table and Listing Output Conventions ................................................................................................................... 35 
Figure Output Conventions ...................................................................................................................................... 38 
Dates & Times ............................................................................................................................................................ 38 
Spelling Format.......................................................................................................................................................... 38 
Presentation of Treatment Groups .......................................................................................................................... 38 
Presentation of Visits ................................................................................................................................................. 39 
Listings ....................................................................................................................................................................... 39 
APPENDIX 2. PARTIAL DATE CONVENTIONS ............................................................. 40 
Algorithm for Treatment Emergence of Adverse Events ....................................................................................... 40 
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Algorithm for Prior / Concomitant Medications .................................................................................................... 41 
1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy, safety and 
pharmacokinetic (PK)/pharmacodynamic (PD) data for Part A of protocol RPL554-MD-201. It describes the data to 
be summarized and analyzed, including specifics of the statistical analyses to be performed. This statistical analysis 
plan (SAP) is based on the protocol version 3.0, dated 24DEC2019. The study will consist of two parts (A and B) 
and Part A will be described in this SAP while a separate SAP for Part B will be created prior to the start of Part B. 
Only the protocol sections applicable to Part A will be described in this SAP.  
2. STUDY OBJECTIVES FOR PART A 
2.1. PRIMARY OBJECTIVE 
The primary objective of Part A is to investigate the PK profile of single doses of RPL554, administered by 
pressurized metered dose inhaler (pMDI), in patients with moderate to severe chronic obstructive pulmonary disease 
(COPD). 
2.2. SECONDARY OBJECTIVES 
The secondary objectives of this part are as follows: 
x 
To investigate the safety and tolerability of single doses of RPL554 administered by pMDI, including effects on 
peak pulse and heart rate.  
x 
To investigate the bronchodilator effect of single doses of RPL554 administered by pMDI, in terms of peak 
FEV1 (forced expiratory volume in one second), average FEV1 area under the curve (AUC)0-4h and average 
FEV1 AUC0-12h.  
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3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
This is a Phase II, randomized, double-blind, placebo-controlled, two-part study. Part A is a parallel group, single 
dose assessment of RPL554 administered by pMDI to evaluate the safety and terminal PK profile of a range of doses 
of RPL554. Five dose levels, 100 g, 300 g, 1000 g, 3000 g and 6000 g (single-blind) were selected, covering 
a 60-fold increase in doses. A total of approximately 36 COPD patients (as defined by the American Thoracic 
Society [ATS]/European Respiratory Society [ERS] guidelines with symptoms compatible with COPD for at least 1 
year prior to Screening) aged 40 to 80 years (inclusive) will be randomized at two study centres in the United 
Kingdom (UK). At the end of Part A, a data cut-off will be used, selected data unblinded and analyzed prior to 
commencing Part B. Up to four active doses will be selected for Part B, which will include all Part A patients. Part 
B is designed as a complete block crossover, repeat dose assessment of RPL554 administered by pMDI to evaluate 
the steady state efficacy/PD effect of the doses compared to the effect with placebo pMDI. The patients in Part B 
will undergo up to five treatment periods. 
 
In Part A, patients will be screened for eligibility, including a reversibility test with albuterol between 7 and 14 days 
before the single dose of study treatment. Eligible patients will then be given a single dose of RPL554 or placebo 
and assessed for 12 hours. They will then return to the clinic the following day for a 24-hour post-dose assessment 
of PK and lung function.  
 
In Part B, the patients from Part A will be randomly assigned in crossover fashion to one of 4 treatment sequences 
(if there are 4 treatment groups in Part B), or 10 treatment sequences (if there are 5 treatment groups in Part B) each 
consisting of up to five 1-week treatment periods separated by a 7 to 10-day washout. Each treatment period consists 
of 6 days of twice daily doses of RPL554, and a single morning dose on Day 7. In each treatment period, patients 
will undergo assessments over 12 hours on Days 1 and 7. Figure 1 below and Figure 1 in the protocol summarize 
these details. 
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Figure 1 Study Flow Chart 
 
3.2. SCHEDULE OF EVENTS 
Schedule of events can be found in Section 6 of the protocol. 
3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
Not applicable. 
4. PLANNED ANALYSES 
There are no data monitoring committee (DMC) or formal interim analyses to be performed for this study. The study 
will consist of two separate and independent analyses, Part A and Part B. At the end of Part A, a data cut-off will be 
used, selected data unblinded and analyzed prior to commencing Part B. At the end of Part B, the database will be 
locked and unblinded, and the full analyses for each part will be performed. 
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4.1. DATA MONITORING COMMITTEE (DMC)  
There will be no DMC analyses for this study. 
4.2. INTERIM ANALYSIS  
No formal interim analysis is planned for the study. 
4.3. PART A ANALYSIS  
Selected Part A analysis will be performed by IQVIA Biostatistics following the data cut-off. All Part A analyses 
identified in this SAP will be performed by IQVIA Biostatistics following the Part B Database Lock on a clean 
database:  
x 
All outstanding data issues and queries resolved. 
x 
All irresolvable data issues documented in the Data Handling Report (DHR) from Data Management. 
x 
All coding of medications and adverse events (AEs) completed. 
x 
Serious AE (SAE) reconciliation completed. 
x 
All reconciliation of vendor data with electronic case report form (eCRF) data completed successfully. 
x 
Analysis sets authorized. 
 
It should be noted that the main teams performing the Part A analysis will remain blinded at the time of the Part A 
data cut-off. This is to avoid any potential risk they could trace what study medication a patient might be receiving 
in Part B (e.g. if they know they experienced certain AEs while on one treatment in Part A and identify this in Part 
B). 
 
All verbatim text from the eCRF will be presented in outputs “as is” with no “manual hard coding” corrections for 
such data. Also, PK analysis will be performed by another party (third party vendor). 
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5. ANALYSIS SETS 
Agreement and authorization of patients included/excluded from each analysis set will be conducted prior to the 
unblinding of the study for Part A.  
5.1. ALL PATIENTS ENROLLED SET [ENR] 
The all patients enrolled (ENR) set will contain all patients who provide informed consent for this study. 
5.2. ALL PATIENTS RANDOMIZED SET [RND] 
The all patients randomized (RND) set will contain all patients who provide informed consent and who are 
randomized to study medication. For analyses and displays based on RND, patients will be classified according to 
randomized treatment.  
5.3. SAFETY ANALYSIS SET [SAF] 
The safety analysis set (SAF) will contain all patients in the RND set who received the single dose of study 
medication during Part A. Patients will be classified according to actual treatment received. If there is any doubt 
whether a patient was treated or not, they will be assumed treated for the purposes of analysis.  
5.4. FULL ANALYSIS SET [FAS] 
The full analysis set (FAS) will contain all patients in the RND set with data collected after intake of study 
medication to compute the pharmacodynamic parameters (FEV1 measurements pre-dose and at least one post-
baseline). For analyses and displays based on FAS, patients will be classified according to planned treatment.  
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5.5. PHARMACOKINETICS [PK] ANALYSIS SET 
The PK analysis set will contain all patients in the RND analysis set who have a blood sampling performed after the 
single dose of RPL554 and PK parameter data.  The PK analysis set will be determined by a third-party vendor and 
the data will be provided to IQVIA. 
6. GENERAL CONSIDERATIONS 
6.1. REFERENCE START DATE AND STUDY DAY 
Study day will be calculated from the reference start date and will be used to show start/stop day of assessments and 
events. Reference start date is defined as the day of the single dose of study medication and will appear in every 
listing where an assessment date or event date appears. 
 
If the date of the event is on or after the reference date, then:  
x 
Study day = (date of event – reference date) + 1. 
 
If the date of the event is prior to the reference date, then:  
x 
Study day = (date of event – reference date). 
 
In the situation where the event date is partial or missing, the date will appear partial or missing in the listings, and 
study day, and any corresponding durations will be presented based on the imputations specified in Appendix 2; 
Partial Date Conventions. 
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6.2. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to the single dose 
assessment (including unscheduled assessments). For FEV1 and forced vital capacity (FVC), baseline is defined as 
the average of the two pre-dose assessments (at 1-hour [±5 minutes] and immediately [within 5 minutes] pre-dose). 
6.3. REPEAT/RESCHEDULE, UNSCHEDULED VISITS AND EARLY 
TERMINATION DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. If a visit is 
repeated/rescheduled due to variability in FEV1 or other reason, the repeated/rescheduled visit, will be listed and 
summarized as the valid visit (same visit number assigned). Unscheduled measurements will not be included in by-
visit summaries, but will contribute to the endpoint value. For example, if an unscheduled visit occurred at 10 hours 
post-dose on the day of the single dose, then this value will be considered in the calculation of the average FEV1 
over 12 hours (AUC0-12h FEV1). Any unscheduled or unplanned readings will be presented within the patient listings. 
 
Early termination data will be mapped according to the visit number the termination occurred for by-visit 
summaries. In Part A early terminations can occur at Screening, Day 1 and Day 2. If termination is between Part A 
and Part B, data are to be considered in the Part B SAP. Subject will be a completer of Part A. 
 
Listings will include scheduled, unscheduled, repeat/reschedule and early discontinuation data. 
6.4. WINDOWING CONVENTIONS  
No visit windows will be applied in this study and the scheduled assessments will be reported and analyzed as per 
eCRF collection. 
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6.5. STATISTICAL TESTS 
The default significant level will be (5%); confidence intervals will be 95% and all tests will be 2-sided, unless 
otherwise specified in the description of the analyses. All significant p-values (i.e. < 5%) will be flagged by means 
of a “*” for ease of review. 
 
For presentation of summary statistics for quantitative and qualitative variables see Appendix 1; Programming 
conventions for outputs.  
6.6. COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
x 
Test value at post-dose timepoint – baseline value. 
For quantitative measurement values of FEV1 and FEV1 AUCs will be calculated based on: 
x 
The highest FEV1 reading from each assessment. 
x 
The baseline value (average of the two pre-dose values [at 1-hour {±5 minutes} and immediately {within 5 
minutes}} pre-dose) must be within ± 20% of the pre-albuterol value at Screening; otherwise, the patient will be 
a screen failure. 
Peak effect will be calculated as: 
x 
Maximum value in the first 4 hours after dosing. 
Average effect will be calculated as: 
x 
FEV1 AUC divided by the length of the time interval of interest. 
Log-transformations will be performed on FEV1 data: 
x 
FEV1 will be analyzed using multiplicative models, which means that data will be logged prior to analysis. The 
results will then be back-transformed to linear scale (treatment differences will thus be ratios of geometric 
means). 
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6.7. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4.  
7. STATISTICAL CONSIDERATIONS 
7.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
The following covariates are used in the analyses. For details of their inclusion in the models, see the specific 
analysis section. 
x 
Randomized treatment (fixed). 
o 
RPL554 100g 
o 
RPL554 300g 
o 
RPL554 1000g 
o 
RPL554 3000g 
o 
RPL554 6000g 
o 
Placebo 
 
x 
Baseline value of analyzed variable (covariate). 
7.2. MULTICENTER STUDIES 
This study will be conducted at 2 study centers, in the UK.  
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7.3. MISSING DATA 
Missing safety data will not be imputed, apart from partial date imputations as specified in Appendix 2.  
Missing efficacy data will be handled as described in Section 15.1.2 and Section 15.2.2 of this SAP.  
7.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
Significance of treatment effect will be tested for the primary and secondary efficacy endpoints in Part A and will be 
done for each of the doses of RPL554 against placebo, starting with the highest dose (6000 g). To this end, the 
fixed-sequence testing approach (Maurer et al., 1995; Westfall & Krishen, 2001) will be used. 
 
For the endpoints, let i = 0, 1, 2, 3, 4 and 5 represent increasing dose levels, 0 denoting placebo. Also, let i, i = 0, 1, 
2, 3, 4 and 5 denote the mean change from baseline for the endpoint of interest for placebo and each increasing 
active dose level, respectively.  The null hypotheses are defined as: Hi: j - 0 = 0 and will be tested against the  
2-sided alternative Ki: j - 0  0, j = 1, 2, 3, 4 and 5. 
 
Finally, let p1, p2, p3, p4, p5 denote the marginal p-values obtained from the statistical tests associated with H1, H2, 
H3, H4, H5 (obtained from the model). 
The fixed-sequence testing will begin with the null hypothesis corresponding to the highest dose versus placebo. If a 
statistically significant difference is found at the 2-sided Į level of 5%, the testing will proceed with the next highest 
dose. Otherwise, testing stops, and the remaining null hypotheses are considered as failed to reject, without testing. 
This testing strategy can be written as the following stepwise algorithm: 
x 
Step 1: If p5  Į reject H5 and go to Step 2. Otherwise, fail to reject H5, H4, H3, H2 and H1 and stop. 
x 
Step 2: If p4  Į reject H4 and go to Step 3. Otherwise, fail to reject H4, H3, H2 and H1 and stop. 
x 
Step 3: If p3  Į reject H3 and go to Step 4. Otherwise, fail to reject H3, H2 and H1 and stop. 
x 
Step 4: If p2  Į reject H2 and go to Step 5. Otherwise, fail to reject H2 and H1 and stop. 
x 
Step 5: If p1  Į reject H1. Otherwise, accept H1. 
 
The fixed-sequence procedure controls the family-wise error rate in the strong sense because, for each null 
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Version Number: 
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Version Date:  
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Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
hypothesis, the testing is conditional upon rejecting all hypotheses earlier in the sequence (Dmitrienko, et al., 2009). 
 
Each secondary endpoint will be tested independently and nominally following a hierarchical testing of doses like 
the one used for the primary endpoint.  
7.5. EXAMINATION OF SUBGROUPS 
No subgroup analyses will be performed for this study. 
8. OUTPUT PRESENTATIONS 
Appendix 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP describe the presentations for this study and therefore the format and content 
of the summary tables, figures, and listings to be provided by IQVIA Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
All patients who provide informed consent will be accounted for in this study.  
 
Patient disposition, withdrawals and reasons for exclusion from each analysis set and protocol deviations, 
including exception to the inclusion and exclusion criteria will be presented for all patients, including those with 
screen failures and summarized by treatment group for the RND analysis set. Number of patients treated and 
discontinued will also be presented. If the patient discontinued/withdraws, he/she will be allocated to the single dose 
treatment group administered.  
 
All protocol deviations collected in Part A will be divided into critical, major or minor categories and will be 
assigned to the single dose treatment group. These which will be summarized by treatment and presented in a listing 
for the RND analysis set. Protocol deviations affect the integrity of the drug activity data and will be obtained by the 
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Version Number: 
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Version Date:  
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Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
clinical research associates (CRAs) and documented in the clinical trial management system (CTMS). 
Each protocol deviation is categorized into one of the following types, based on CTMS: 
1. Informed Consent Criteria 
2. Eligibility and Entry Criteria 
3. Concomitant Medication Criteria 
4. Laboratory Assessment Criteria 
5. Study Procedures Criteria 
6. Serious Adverse Event Criteria 
7. Randomization Criteria 
8. Visit Schedule Criteria 
9. Investigation Product (IP) Compliance 
10. Efficacy Criteria 
11. Administrative Criteria 
12. Source Document Criteria 
13. Regulatory or Ethics Approvals Criteria 
14. Other Criteria 
 
Preliminary assignment to each analysis population, therefore whether a patient is included/excluded in each 
analysis population (excluding the PK analysis population) will be recorded in an EXCEL sheet by the IQVIA 
Biostatistician, with the reason for exclusion from each population indicated. The EXCEL sheet should then be 
authorized by means of a customer authorization form (CAF) and prior to the Database Lock of the study.   
10. DEMOGRAPHIC AND OTHER SCREENING CHARACTERISTICS 
Demographic data and other baseline characteristics (including screening disease characteristics) will be presented 
for all analysis sets (RND, SAF, FAS, PK), by treatment groups, if the analysis sets differ to each other. If these are 
the same, as is expected for Part A, the presentation will be limited to just the RND analysis set, or to those that are 
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Version Number: 
2.0 
 
Version Date:  
13JAN2021 
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Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
different. No statistical testing will be carried out for demographic or other baseline characteristics. The following 
demographic and other baseline characteristics will be reported for Part A: 
x 
Age (years) 
x 
Sex 
x 
Childbearing potential 
x 
Race  
x 
Ethnicity 
x 
Height (cm) 
x 
Weight (kg) 
x 
BMI (kg/m2) 
x 
Pre (prior to dosing at baseline)/post (post dosing at baseline) bronchodilator FEV1 (both in liters and in 
percentage of predicted normal) 
x 
Pre/Post-bronchodilator FEV1/FVC 
x 
FEV1 reversibility test (mL and %) 
x 
Reversibility assessment performed with four puffs of Albuterol 
x 
Met requirements of reversibility test 
10.1. DERIVATIONS 
x 
Age (years) = (Informed consent date – date of birth) 
x 
BMI (kg/ m2) = weight (kg)/ height (m)2 
 
Demographic and other screening characteristics recorded on the eCRF will be used as is on the eCRF, without any 
derivations or adjustments. 
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Version Number: 
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Version Date:  
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Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
11. SURGICAL, MEDICAL AND CHRONIC OBSTRUCTIVE 
PULMONARY DISEASE/SMOKING HISTORY 
Surgical and Medical History information will be presented in table summaries and listings, for the RND analysis 
set.  
x 
Surgical History will not be coded. 
o 
Surgical History conditions are defined as those conditions which stop prior to or at Screening.  
x 
Medical History will be coded by MedDRA dictionary using the version specified in the data management plan. 
o 
Medical History conditions are defined as those conditions which stop prior to or at Screening.  
o 
Data captured on the Medical History page of the eCRF will be presented by SOC and PT.  
x 
COPD/Smoking History data captured on the COPD and Smoking History page of the eCRF will be presented 
for the RND analysis set. 
o 
COPD history (Duration of COPD [calculated relative to date of first diagnosis {Randomization date – 
first COPD diagnosis date}], date of most recent exacerbation, known to have chronic 
bronchitis/emphysema) 
o 
Smoking history (current or former smoker, number of packs per day, number of years smoking and 
number of pack-years [calculated as number of packs per day x number of years smoking]) 
12. MEDICATIONS 
Medications will be coded using the World Health Organization – Drug Dictionary (WHO-DD) version specified in 
the data management plan and will be presented in a listing by Anatomical Therapeutic Chemical (ATC) (the 1st 
level of the ATC code) and PT for the RND analysis set. Certain medications (or a special grouping of medications) 
will be classified in a list during the study and signed-off prior to lock by a medical advisor. As this list, may change 
prior to sign-off they will not be defined in this section of the SAP. Potential medications include, but are not limited 
to, inhaled corticosteroids (ICS), LAMAs (long-acting muscarinic antagonists), LABAs (long-acting beta2-agonists) 
etc. 
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Version Number: 
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Version Date:  
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Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
 
See Appendix 2 for handling of partial dates for medications, in the case where it is not possible to define a 
medication as prior, concomitant, or post treatment, the medication will be classified by the worst case; i.e. 
concomitant.  
x 
‘Prior’ medications are medications which started and stopped in the 3 months prior to the single dose of study 
medication and are recorded at Screening.  
x 
‘Concomitant’ medications are medications which:  
o Had an onset date on or after the single dose of study medication. 
o AND ended on or after the date of single dose of medication or were ongoing at the end of Part A. 
o A patient can report more than 1 concomitant medication with the same PT.  
Prior and concomitant medications will be presented in a listing only, by treatment group. 
 
Rescue medications will be recorded on the Rescue Medication/Rescue Medication Canister Collection/Rescue 
Medication Canister Dispensed/Rescue Medication Canister Weight pages of the eCRF. These are short acting 
bronchodilators and will be sourced by the study center and dispensed at the Screening visit and end of Part A (Day 
2). Rescue medication used during study visits will be documented on the eCRF pages. Protocol procedures must 
continue even if rescue medication has been taken. Salbutamol/albuterol is to be used for primary rescue use. 
  
Rescue medications used during study visits (by recording the time it was dispensed and collected) and the amount 
taken between Day 1 and Day 2 (by recording the weight of the canisters), will be presented in a listing for the RND 
analysis set.  
 
When a rescue medication is used less than 8 or 6 hours (for protocol version 1 or 2 respectively) prior to pre-dose 
spirometry or between the pre-dose and 12-hour post-dose spirometry a sensitivity analysis will be carried out. For 
the analysis detailed in Section 15.2.1.2 patients who took rescue medication will be removed. This will only be 
carried out if at least 1 patient has taken rescue medication less than 8 or 6 hours (for protocol version 1 or 2 
respectively) prior to pre-dose spirometry or between the pre-dose and 12-hour post-dose spirometry. 
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Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
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Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
13. STUDY MEDICATION EXPOSURE 
Date and time of exposure to the single dose of study medication and the date of completion/discontinuation will be 
presented in a listing for the RND analysis set. Duration of exposure will not be calculated as this is expected to be 
one day for all patients in Part A. The information to be listed will be taken from the Drug Exposure and Disposition 
eCRF pages.  
14. STUDY MEDICATION COMPLIANCE  
All administration of study treatment will be done at the clinic under supervision of the study staff; therefore, no 
formal analysis of compliance will be performed.  
15. EFFICACY OUTCOMES  
15.1. PRIMARY EFFICACY 
15.1.1. PRIMARY EFFICACY VARIABLE(S) & DERIVATION(S) 
x 
Not applicable – The primary endpoint of Part A will be described in Section 17.  
15.1.2. MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE(S) 
Not applicable. 
15.1.3. PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
Not applicable. 
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Version Number: 
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Version Date:  
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
15.2. SECONDARY EFFICACY 
The secondary efficacy analyses will be performed for the FAS.  
15.2.1. SECONDARY EFFICACY VARIABLES & DERIVATIONS 
15.2.1.1. Change in baseline in average FEV1 of AUC0-4h (Average FEV1 over 4 hours) after single 
dose (Secondary variable 1) 
 
Average FEV1 after single dose is defined as the AUC0-4h FEV1 collected, divided by the length of the time (in 
hours). AUC0-4h FEV1 is derived using the following formula: 
ܣܷܥൌͳ
ʹ ሺݐଵെݐ଴ሻሺݕଵ൅ݕ଴ሻ൅ͳ
ʹ ሺݐଶെݐଵሻሺݕଶ൅ݕଵሻ൅ڮ ൅ͳ
ʹ ሺݐ௜െݐ௜ିଵሻሺݕ௜൅ݕ௜ାଵሻ 
where i are the number of intervals, ti are the time values or time intervals (in actual hours) between assessments and 
yi the FEV1 values at ti. The AUC result will then be divided by the actual time (the time elapsed since dosing, until 
the time of assessment) at 4-hour assessment (as this can occur ± 10 minutes) to obtain the average FEV1. If the 
assessment at 4-hour is missing, the AUC result will be divided by the actual time of the last collected assessment. 
For analysis purposes, it will be assumed that the pre-dose value (immediately pre-dose) occurred at time 0 when 
computing PD parameters. If a patient misses hour 2 and 4 then the AUC0-4 is set to missing. 
 
Descriptive statistics (see Appendix 1 [Programming conventions for outputs]) for AUC0-4 will be presented for all 
patients assigned to FAS, at each assessment and change from baseline at each assessment as relevant. All 
summaries will be presented for each treatment group. In addition, a figure (bar graph) representing mean change 
from baseline FEV1 to FEV1 AUC0-4 by treatment will be presented, including the standard error of the mean.   
 
Change from baseline FEV1 to FEV1 AUC0-4 will be derived to test the hypothesis described in Section 15.2.3 with 
baseline defined as the average of the FEV1 pre-dose assessments (-60 minutes and -5 minutes) collected.  
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Version Number: 
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Version Date:  
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
15.2.1.2. Change in baseline in average FEV1 AUC0-12h (Average FEV1 over 12 hours) after single 
dose (Secondary variable 2) 
 
AUC0-12h FEV1 after single dose is defined and derived similarly to secondary endpoint above (see Section 15.2.1.1), 
but over 12-hours post-dose. If the assessment at 12-hours is missing, the AUC result will be divided by the actual 
time of the last collected assessment. If patient misses hours 11 and 12 then the AUC0-12h is set to missing.  
15.2.1.3. Change from baseline in peak FEV1 (measured in first 4 hours) after single dose 
(Secondary variable 3) 
 
Peak FEV1 is measured in the first 4 hours after single dose. It is collected on the Spirometry Study measurements 
eCRF page. 
 
Three acceptable readings are performed at each of the timepoints in first 4 hours after the single dose (5, 15 and 30 
minutes and 1, 1.5, 2 and 4 hours) and the highest of the 3 is used for analysis purposes. Hence peak FEV1 is derived 
as the highest of all these readings.  
 
Descriptive statistics (see Appendix 1 [Programming conventions for outputs]) for peak FEV1 will be presented for 
all patients assigned to FAS, at each assessment and change from baseline as relevant. All summaries will be 
presented for each treatment group. In addition, a figure (bar graph) representing mean change from baseline FEV1 
to peak FEV1 by treatment will be presented, including the standard error of the mean. A figure also displaying the 
mean change over time on Day 1 will be presented.  
 
Change from baseline FEV1 to peak FEV1 (over 4 hours) will be derived to test the hypothesis described in Section 
15.2.3 with baseline defined as the average of the FEV1 pre-dose assessments (-60 minutes and -5 minutes) 
collected.  
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Document: 
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Version Number: 
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Version Date:  
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
15.2.2. MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLE(S) 
No imputation will be applied. 
15.2.3. ANALYSIS OF SECONDARY EFFICACY VARIABLES 
The secondary variables will be analyzed by comparing the RPL554 treatment groups to each other and placebo by 
rejecting the null hypothesis described below at significance level Į=0.05 level (2-sided): 
H0: j = 0 versus H1: j  0 
 
where j and 0 are the mean change from Baseline for each parameter (Peak FEV1, AUC0-4h and AUC0-12h) after 
single dose for each respective dose of RPL554 and placebo.  
 
ANCOVA analyses will be implemented using the SAS® procedure MIXED as follows:  
 
PROC MIXED DATA = …; 
 
CLASS TREATMENT; 
 
MODEL CHG = TREATMENT BASELINE; 
 
LSMEANS TREATMENT / CL DIFF; 
RUN; 
 
where CHG = difference in log (parameter) – log (baseline parameter) i.e. log (parameter / baseline parameter) 
TREATMENT = treatment group (Respective dose of RPL554, 100g, 300g, 1000g, 3000g and 6000g and 
placebo) 
BASELINE = log (baseline parameter) 
 
The primary comparison will be the contrast (difference in least squares mean [LSMEAN]) between 6000ȝg 
RPL554 and placebo. The parameter value and its baseline will be log-transformed prior to analysis using natural 
logarithm. The difference between the two (log [parameter] – log [baseline parameter] equals log (parameter / 
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Version Number: 
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Version Date:  
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baseline parameter). The covariate, baseline parameter, will also be log transformed. Therefore, the LSMEAN 
statement between treatments in the above PROC MIXED will provide the log of the contrasts. Prior to 
presentations, the antilog of these point estimates and associated 95% confidence intervals will be performed, giving 
ratios of geometric means on the linear scale. The 2-sided p-value for the exponential (exp)least squares mean, 
exp(LSM), ratio between each of the 2 treatment groups and placebo will be reported.  
 
Summary statistics for each parameter (Peak FEV1, AUC0-4h and AUC0-12h) will be presented for baseline, at point of 
interest and change from baseline by treatment group on patients with both assessments, on the original scale. 
16. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the SAF.  
There will be no statistical comparisons between the treatment groups for safety data, unless otherwise specified 
with the relevant section.  
16.1. ADVERSE EVENTS 
Adverse Events (AEs) will be coded by MedDRA dictionary using the version specified in the data management 
plan.  
 
Treatment emergent adverse events (TEAEs) are defined as AEs that started or worsened in severity on or after the 
single dose of study medication, based on the investigator assessment of severity. TEAEs will be assigned to 
treatment groups based on actual treatment received.  
 
See Appendix 2 for handling of partial dates for AEs.  In the case where it is not possible to define an AE as 
treatment emergent or not, the AE will be classified by the worst case; i.e. treatment emergent.  
 
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An overall summary of number of patients within each of the categories described in the sub-section below, will be 
provided as specified in the templates.  
 
Listings will include TEAEs and Non-TEAEs. 
16.1.1. ALL TEAES  
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) and broken down 
further by maximum severity and relationship to study medication. 
16.1.1.1. Severity 
Severity is classed as mild/ moderate/ severe (increasing severity). TEAEs starting after the single dose of study 
medication with a missing severity will be classified as severe. If a patient reports a TEAE more than once within 
that SOC/ PT, the AE with the worst-case severity will be used in the corresponding severity summaries. 
16.1.1.2. Relationship to Study Medication 
Relationship, as indicated by the Investigator, is classed as “yes” or “no”. A related TEAE is defined as a TEAE 
with a relationship to study medication as “yes”. TEAEs with a missing relationship to study medication will be 
regarded as relationship = “yes” to study medication. If a patient reports the same AE more than once within that 
SOC/ PT, the AE with the worst-case relationship to study medication will be used in the corresponding relationship 
summaries.  
16.1.2. TEAES LEADING TO DISCONTINUATION OF STUDY 
TEAEs leading to discontinuation from the study will be identified by using the question “Did the AE cause the 
Patient to discontinue from the study?” from the AE page of the eCRF. 
 
For TEAEs leading to discontinuation from the study, summaries of incidence rates (frequencies and percentages) 
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Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 29 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v2.0 – Part A 
Page 29 of 43 
 
 
Document: 
Z:\ RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 SAP v2.0 – Part A 
Author: 
Nicholas Roubinis / Jennifer Allsopp 
Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
by SOC and PT will be prepared. 
16.1.3. SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse Events page of the eCRF. A 
summary of serious TEAEs by SOC and PT will be prepared, similarly to Section 16.1.1 and Section 16.1.2. 
16.1.4. ADVERSE EVENTS LEADING TO DEATH 
TEAEs leading to Death are those events which are recorded as “Death” on the Adverse Events page of the eCRF. A 
summary of TEAEs leading to death by SOC and PT will be prepared. 
16.2. LABORATORY EVALUATIONS 
Results from the local laboratory will be included in the reporting of this study for hematology, blood chemistry, 
urinalysis and viral serology. A list of laboratory assessments to be included in the outputs is included in the 
protocol, Sections 7.4.3.1, 7.4.3.2,7.4.3.3 and 7.1.4 for hematology, blood chemistry, urinalysis and viral serology, 
respectively. Presentations will use International system (SI) units.  
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of quantification (BLQ), or 
“> X”, i.e. above the upper limit of quantification (ULQ), will be converted to X for quantitative summaries, but will 
be presented as recorded, i.e. as “< X” or “> X” in the listings. 
The following summaries will be provided for laboratory data: 
x 
Actual results at Screening. 
x 
Incidence of abnormal values at Screening according to normal range criteria 
x 
Listing of all laboratory evaluations and abnormal values at Screening. 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 30 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v2.0 – Part A 
Page 30 of 43 
 
 
Document: 
Z:\ RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 SAP v2.0 – Part A 
Author: 
Nicholas Roubinis / Jennifer Allsopp 
Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
16.2.1. LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges in SI units and 
categorized as: 
x 
Low: Below the lower limit of the laboratory reference range.  
x 
Normal: Within the laboratory reference range (upper and lower limit included). 
x 
High: Above the upper limit of the laboratory reference range. 
 
In addition to the high and low quantitative laboratory assignments (as identified by means of the laboratory 
reference ranges), markedly abnormal quantitative blood chemistry values per the table below will also be identified 
by the Investigator. 
 
 
Blood Chemistry –  
Markedly Abnormal Definition 
Alanine Aminotransferase (ALT) 
> 3 x ULN 
Alkaline Phosphatase (ALP) 
> 3 x ULN 
Aspartate Aminotransferase (AST) 
> 3 x ULN 
Creatinine 
> 221 mol/L 
Gamma Glutamyl Transferase (GGT) 
> 3 x ULN 
Bilirubin (TBL) 
> 3 x ULN 
ULN: Upper limit of normal. ALT: Alanine aminotransferase. AST: Aspartate aminotransferase.  
ALP: Alkaline phosphatase. TBL: Total bilirubin. 
 
16.3. ECG EVALUATIONS 
Overall results from the local ECG (Electrocardiogram) lab will be included in the reporting of this study. The 
overall assessment of ECG parameters will be reported for this study: 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v2.0 – Part A 
Page 31 of 43 
 
 
Document: 
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Author: 
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Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
x 
Normal 
x 
Abnormal not Clinically Significant (ANCS) 
x 
Abnormal Clinically Significant (ACS) 
x 
Incomplete 
x 
Uninterpretable 
 
The following summaries will be provided for quantitative ECG data, for example heart rate: 
x 
Actual assessments at screening, baseline (pre-dose of single dose) and each post-dose timepoint (1, 2, 4 and 8 
hours) 
x 
Change from Baseline at each post-dose timepoint assessment 
x 
Shift of overall assessment baseline to post-dose timepoints according to Normal, ANCS and ACS overall 
assessment criteria 
x 
Listing of all ECG evaluations and abnormal values 
 
Peak heart rate after single dose is defined as the maximum value measured in the first 4 hours post-dose. Peak heart 
rate and change from baseline to peak will be summarized similarly to Section 15.2.1.3, including the figure 
presentations. In addition, hypothesis testing as per Section 15.2.3, will be repeated for this endpoint. 
16.4. VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
x 
Supine Systolic Blood Pressure (mmHg) 
x 
Supine Diastolic Blood Pressure (mmHg) 
x 
Supine Pulse Rate (bpm) 
 
The following summaries will be provided for vital signs data: 
x 
Actual assessments at screening, baseline (pre-dose of single dose) and each post-dose timepoint (1, 2, 4, 8, 12 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v2.0 – Part A 
Page 32 of 43 
 
 
Document: 
Z:\ RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 SAP v2.0 – Part A 
Author: 
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Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
and 24 hours [Day 2]) 
x 
Change from Baseline at each post-dose timepoint assessment 
x 
Incidence of markedly abnormal values based on the criteria presented in the table below: 
 
Low 
High 
Systolic blood pressure (mmHg)  
Value  90 mmHg 
Value  180 mmHg 
Decrease from Baseline of  
40 mmHg 
Increase from Baseline of  40 
mmHg 
Diastolic blood pressure (mmHg)  
Value  50 mmHg 
Value  110 mmHg 
Decrease from Baseline of  
20 mmHg 
Increase from Baseline of  20 
mmHg 
Pulse rate (bpm)   
Value  50 bpm  
Value  110 bpm 
Decrease from Baseline of  
30 bpm 
Increase from Baseline of  30 bpm 
 
Peak supine pulse rate after single dose is defined as the maximum value measured in the first 4 hours post-dose. 
Peak pulse rate and change from baseline to peak will be summarized similarly to Section 15.2.1.3, including the 
figure presentations. In addition, hypothesis testing as per Section 15.2.3, will be repeated for these endpoints. 
16.5. PHYSICAL EXAMINATION 
The following summaries will be provided for the full physical examination data, covering major body systems 
(nose, throat, skin, thyroid gland, neurological system, respiratory system, cardiovascular system, abdomen [liver 
and spleen], lymph nodes and extremities): 
x 
Incidence of abnormalities at screening 
 
The following summaries will be provided for a brief physical examination to be also performed, on skin, 
respiratory system, cardiovascular system, and abdomen (liver and spleen): 
x 
Incidence of abnormalities pre-dose. 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v2.0 – Part A 
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Document: 
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Author: 
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Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
16.6. OTHER SAFETY ASSESSMENTS 
Chest X-ray and inhalation training results will be presented in a listing only. In addition, screening serum and urine 
pregnancy test results, as well as pregnancy report data (current pregnancy, pregnancy history and details of the 
mother), will be listed for women of childbearing potential at Screening. 
 
17. PHARMACOKINETIC EVALUATIONS 
PK concentrations are measured at the time of the single dosing and are collected on the Pharmacokinetic Samples 
eCRF page. Based on this information the PK parameters are then derived. All PK analysis will be carried out by a 
third party and will not be detailed in this SAP. 
 
 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v2.0 – Part A 
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Document: 
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Author: 
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Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
18. REFERENCES  
Dobson, A. J. (2002). An introduction to generalized linear models, 2nd ed. Chapman & Hall/CRC. 
Dmitrienko, A., Bretz, F., Westfall, P. H., Troendle, J., Wiens, B. L., Tamhane, A. C., & Hsu, J. C. (2009). Multiple 
testing methodology. Multiple Testing Problems in Pharmaceutical Statistics. Chapman and Hall/CRC 
Press, New York. 
Maurer, W., Hothorn, L. A., & Lehmacher, W. (1995). Multiple Comparisons in Drug Clinical Trials and Preclinical 
Assays: A-priori ordered Hypotheses. Testing Principles in Clinical and Preclinical Trials (J. Vollmar, 
editor) STuttgart, Gustav Fisher Verlag, 3-18. 
SAS Institute, Inc. (1999). SAS Procedures Guide, version 8. Cary, NC: SAS Institute. 
 
 
 
 
 
 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v2.0 – Part A 
Page 35 of 43 
 
 
Document: 
Z:\ RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 SAP v2.0 – Part A 
Author: 
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Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
IQVIA OUTPUT CONVENTIONS 
Outputs will be presented according to the following: 
TABLE AND LISTING OUTPUT CONVENTIONS 
General: 
• The first row in the body of the table or listing should be blank 
• The left-hand column should start in column 1. No indenting or centering of the output should occur. 
• Rounding should be done with the SAS function ROUND. 
• Numbers in tables should be rounded, not truncated. 
• Alphanumeric output should be left aligned. 
• Numbers should be decimal point aligned. 
• Whole numbers should be right aligned. 
• Text values should be left aligned. 
• The first letter of a text entry should be capitalized 
• Listings of adverse events, concomitant medications, medical histories etc. should be sorted in chronological order, 
with earliest adverse event, medication or history coming first. 
• The study drug should appear first in tables with treatments as columns 
• In general, only present totals (across treatment groups) at baseline/randomization, and do not present them post 
randomization, unless the customer specifically requests it. 
• All listing outputs should be sorted (preferably by Treatment, Site Number and Patient Number). 
• Exponentiation will be expressed using a superscript with ODS RTF. 
• All variables that are output in the CRF (which have data present) should appear in the listings, along with all 
derived data appearing in the corresponding tables 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 36 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v2.0 – Part A 
Page 36 of 43 
 
 
Document: 
Z:\ RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 SAP v2.0 – Part A 
Author: 
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Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
• The width of the entire output should match the linesize. 
 
Univariate Statistics: 
• Statistics should be presented in the same order across tables (i.e., n, Mean, SD, Minimum, Median, Maximum and 
equivalently, n, GeoMean, CV, Minimum, Median, Maximum) 
• Table statistics should line up under the N part of the (N=XXX) in the table header. All decimal points should line 
up. If the minimum and maximum are output on 1 line as Minimum, Maximum then the comma should line up with 
the decimal point. 
• If the original data has N decimal places, then the summary statistics should have the following decimal places: 
Minimum and maximum: N 
Mean, median and CV%: N + 1 
SD: N + 2 
 
Frequencies and percentages (n and %): 
• Percent values should be reported inside parentheses, with 1 space between the count and the left parenthesis of the 
percentage. Parentheses should be justified to accept a maximum of 100.0 as a value and padded with blank space if 
the percent is less than 100.0. An example is given below: 
77 (100.0%) 
50 ( 64.9%) 
0 ( 0.0%) 
• Percentages will be reported to 1 decimal place, except percentages <100.0% but >99.9% will be presented as 
‘>99.9%’ (e.g., 99.99% is presented as >99.9%); and percentages < 0.1% will be presented as ‘<0.1%’ (e.g., 0.08% 
is presented as <0.1%). Rounding will be applied after the <0.1% and >99.9% rule. 
e.g. ( <0.1%) 
( 6.8%) 
(>99.9%) 
Percentages may be reported to 0 decimal places as appropriate (for example, where the denominator is relatively 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v2.0 – Part A 
Page 37 of 43 
 
 
Document: 
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Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
small). 
• Where counts are zero, percentages of 0.0% should appear in the output. 
 
Confidence Intervals: 
• As a rule, confidence intervals are output to 1 place more than the raw data, and standard deviations and standard 
errors to 2 places more than the raw data 
• Confidence intervals should be justified so that parentheses displayed on consecutive lines of a table “line up”. 
• Boundary values of confidence intervals should be separated by a comma. 
• Boundary values should be padded as necessary to accept negative values and to allow alignment of the decimal 
place. 
• An example is given below: 
(-0.12, -0.10) 
( 9.54, 12.91) 
 
P-values: 
• P-values should be reported to 4 decimal places, except values <1.000 but >0.9999 will be presented as ‘>0.9999’ 
(e.g., 0.9999 is presented as >0.9999); and values <0.0001 will be presented as ‘<0.0001’ (e.g., 0.00009 is presented 
as <0.0001). Rounding will be applied after the <0.0001 and >0.9999 rule 
 
Ratios: 
• Ratios should be reported to 1 more decimal place than the original data. 
 
Spacing: 
• There must be a minimum of 1 blank space between columns (preferably 2) 
 
Denominators: 
• If a different count other than the population count is used for a denominator (within the table) to calculate 
percentages, there should be a row in the table that identifies that number “n”. 
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Clinical Study Report
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Version 1.0; 17 May 2021
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CONFIDENTIAL
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Statistical Analysis Plan v2.0 – Part A 
Page 38 of 43 
 
 
Document: 
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Author: 
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Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
• Alternatively, a footnote should be included in each table with percentages to indicate the denominator for 
percentages. 
 
Missing values 
• A “0” should be used to indicate a zero frequency. 
• A blank will be used to indicate missing data in an end-of-text table or patient listing. 
FIGURE OUTPUT CONVENTIONS 
• Figures should be provided in RTF files generated by SAS. 
• Should contain the title or footer. 
• The image should be clear and of high quality when viewed in the Word document, and when printed. 
• In general, boxes around the figures should be used. 
DATES & TIMES 
Depending on data available, dates and times will take the form DDMMMYYY THH:MM:SS. 
SPELLING FORMAT 
English US.  
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in this order: 
 
Treatment Group 
For Tables, Graphs and Listings 
RPL554 100 g double blind  
RPL554 100g 
RPL554 300 g double blind 
RPL554 300g 
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Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Statistical Analysis Plan v2.0 – Part A 
Page 39 of 43 
 
 
Document: 
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Author: 
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Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
Treatment Group 
For Tables, Graphs and Listings 
RPL554 1000 g double blind  
RPL554 1000g 
RPL554 3000 g double blind  
RPL554 3000g 
RPL554 6000 g single blind  
RPL554 6000g 
Placebo 
Placebo 
Non-randomized (where applicable) 
Non-randomized  
PRESENTATION OF VISITS 
For outputs, visits will be represented as follows and in that order: 
 
Long Name (default) 
Short Name  
Screening 
Scr 
Day 1 
Day 1 
Day 2 
Day 2 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
Randomized treatment group (or treatment received if it’s a safety output), first by active dose [by ascending dose 
group] and then placebo.  
Center-patient ID,  
Date (where applicable), 
For listings where non-randomized patients are included, these will appear in a category after the randomized 
treatment groups labeled ‘Non-randomized’. 
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Statistical Analysis Plan v2.0 – Part A 
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Document: 
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Version Number: 
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Version Date:  
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Template No.:  CS_TP_BS016 Revision 5 
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Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Partial 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Missing 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
 
 
Partial, but known 
components show that it 
cannot be on or after study 
med start date 
Known 
Not TEAE 
 
Partial 
Not TEAE 
 
Missing 
Not TEAE 
 
 
 
Partial, could be on or after 
study med start date 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month 
if day unknown or 31st December if day and month are 
unknown), then: 
If stop date < study med start date, then not TEAE 
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Version 1.0; 17 May 2021
Verona Pharma plc
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Statistical Analysis Plan v2.0 – Part A 
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Document: 
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Author: 
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Version Number: 
2.0 
 
Version Date:  
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
START DATE 
STOP DATE 
ACTION 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month 
if day unknown or 31st December if day and month are 
unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS  
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior  
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant  
If stop date >= study med start date and start date > end of treatment, assign 
as post study  

	
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 42 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v2.0 – Part A 
Page 42 of 43 
 
 
Document: 
Z:\ RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 SAP v2.0 – Part A 
Author: 
Nicholas Roubinis / Jennifer Allsopp 
Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
START DATE 
STOP DATE 
ACTION 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, assign 
as post treatment 
 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, assign 
as post treatment 

	
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 43 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v2.0 – Part A 
Page 43 of 43 
 
 
Document: 
Z:\ RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 SAP v2.0 – Part A 
Author: 
Nicholas Roubinis / Jennifer Allsopp 
Version Number: 
2.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
START DATE 
STOP DATE 
ACTION 
 
Partial 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown) and impute stop 
date as latest possible date (i.e. last day of month if day unknown or 31st 
December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, assign 
as post treatment 
 
Missing 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Missing 
Known 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Missing 
Assign as concomitant 
 

	
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 44 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 1 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN – PART B 
 
 
RPL554-MD-201 
A Phase II, Randomized Study to Assess the Pharmacokinetics, Safety 
and Pharmacodynamics of Single and Repeat Doses of RPL554 
Administered by Pressurised Metered Dose Inhaler in Patients with 
COPD 
 
 
 
 
AUTHOR: JENNIFER ALLSOPP 
VERSION NUMBER AND DATE: V1.0, 13JAN2021 
 
 
 
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		


Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 45 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 2 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
STATISTICAL ANALYSIS PLAN – PART B SIGNATURE PAGE 
Statistical Analysis Plan V1.0 – Part B (Dated 13JAN2021) for Protocol RPL554-MD-201. 
 
 
Name 
Signature 
Date 
Author: 
Jennifer Allsopp 
 
 
 
 
Position: 
Senior Biostatistician  
 
Company: 
IQVIA 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan – Part B, 
authorizing that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
Mark Shaw 
 
 
 
 
Position: 
Associate Director 
 
Company: 
IQVIA 
 
 
 
 
Approved By: 
Tara Rheault 
 
 
 
Position: 
VP, R&D  
 
Company: 
Verona Pharma 
 
 
Approved By: 
Thomas Bengtsson 
 
 
 
 
Position: 
Statistical Consultant to Verona 
 
Company: 
StatMind 
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		






Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 46 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 3 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
MODIFICATION HISTORY 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
1.0 
13JAN2021 
Jennifer Allsopp 
Not Applicable – First Version 
 
 
 
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		


Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 47 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 4 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION 9 
2. 
STUDY OBJECTIVES FOR PART B 
9 
2.1. 
Primary Objective ........................................................................................................................................... 9 
2.2. 
Secondary Objectives ...................................................................................................................................... 9 
2.3. 
Exploratory Objectives ................................................................................................................................. 10 
3. 
STUDY DESIGN 
10 
3.1. 
General Description ....................................................................................................................................... 10 
3.2. 
Schedule of Events ......................................................................................................................................... 11 
3.3. 
Changes to Analysis from Protocol .............................................................................................................. 11 
4. 
PLANNED ANALYSES 
11 
4.1. 
Data Monitoring Committee (DMC) ............................................................................................................ 12 
4.2. 
Interim Analysis ............................................................................................................................................. 12 
4.3. 
Part B Analysis ............................................................................................................................................... 12 
5. 
ANALYSIS SETS 
13 
5.2. 
All Patients Randomized Set in Part B [RND] ............................................................................................ 13 
5.3. 
Safety Analysis Set [SAF] .............................................................................................................................. 13 
5.4. 
Full Analysis Set [FAS] ................................................................................................................................. 14 
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		

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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 48 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 5 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
5.5. 
Completers Analysis Set [CAS] .................................................................................................................... 14 
5.6. 
Pharmacokinetics [PK] Analysis Set ............................................................................................................ 14 
6. 
GENERAL CONSIDERATIONS 14 
6.1. 
Reference Start Date and Study Day ........................................................................................................... 14 
6.2. 
Baseline ........................................................................................................................................................... 15 
6.3. 
Repeat/reschedule, Unscheduled Visits and Early Termination Data ...................................................... 15 
6.4. 
Windowing Conventions ............................................................................................................................... 16 
6.5. 
Statistical Tests .............................................................................................................................................. 16 
6.6. 
Common Calculations ................................................................................................................................... 16 
6.7. 
Software Version ............................................................................................................................................ 17 
7. 
STATISTICAL CONSIDERATIONS 
18 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses ....................................................... 18 
7.2. 
Multicenter Studies ........................................................................................................................................ 18 
7.3. 
Missing data ................................................................................................................................................... 18 
7.4. 
Multiple Comparisons/ Multiplicity ............................................................................................................. 19 
7.5. 
Examination of Subgroups ............................................................................................................................ 19 
8. 
OUTPUT PRESENTATIONS 
20 
9. 
DISPOSITION AND WITHDRAWALS 20 
10. 
DEMOGRAPHIC AND OTHER SCREENING CHARACTERISTICS 
21 
10.1. 
Derivations ................................................................................................................................................. 22 
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		
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 49 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 6 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
11. 
SURGICAL, MEDICAL AND CHRONIC OBSTRUCTIVE PULMONARY 
DISEASE/SMOKING HISTORY 22 
12. 
MEDICATIONS 
23 
13. 
STUDY MEDICATION EXPOSURE 
24 
14. 
STUDY MEDICATION COMPLIANCE 25 
15. 
EFFICACY OUTCOMES 25 
15.1. 
Primary Efficacy ........................................................................................................................................ 25 
15.1.1. 
Primary Efficacy Variable(s) & Derivation(s) ......................................................................................... 25 
15.1.2. 
Missing Data Methods for Primary Efficacy Variable(s) ........................................................................ 26 
15.1.3. 
Primary Analysis of Primary Efficacy Variable(s) .................................................................................. 26 
15.2. 
Secondary Efficacy .................................................................................................................................... 28 
15.2.1. 
Secondary Efficacy Variables & Derivations .......................................................................................... 28 
15.2.1.1. 
Change in baseline in average FEV1 of AUC0-4h (Average FEV1 over 4 hours), average FEV1 of 
AUC0-12h (Average FEV1 over 12 hours) and (morning) trough FEV1 on Day 7 (Secondary variables 1, 2 and 3)
 
28 
15.2.1.2. 
Change in baseline in peak FEV1 measured after first dose, average FEV1 of AUC0-4h on Day 1 and 
average FEV1 of AUC0-12h FEV1 on Day 1 (Secondary variables 4, 5 and 6) ....................................................... 29 
15.2.1.5. 
Change from baseline in rescue medication use (Secondary variable 9) ......................................... 30 
15.2.2. 
Missing Data Methods for Secondary Efficacy Variable(s) .................................................................... 31 
15.2.3. 
Analysis of Secondary Efficacy Variables............................................................................................... 31 
15.2.3.1. 
Analysis of Secondary Variables 1, 2, 3, 4, 5 and 6......................................................................... 31 
15.2.3.2. 
Analysis of Secondary Variable 7 .................................................................................................... 32 
15.2.3.3. 
Analysis of Secondary Variable 8 .................................................................................................... 33 
15.2.3.4. 
Analysis of Secondary Variable 9 .................................................................................................... 33 
15.3. 
Exploratory Efficacy ................................................................................................................................. 33 
15.3.1. 
Exploratory Efficacy Variables & Derivations ........................................................................................ 33 
15.3.1.1. 
Evaluation of dose response of RPL554 on peak and average FEV1 AUC0-12h after morning dose 
on Day 7, and morning trough FEV1 prior to the last dose on Day 7.................................................................. 33 
15.3.1.2. 
Change from baseline in Likert dyspnea scale measured after morning dose on Day 7 .................. 33 
15.3.2. 
Missing Data Methods for Exploratory Efficacy Variable(s) .................................................................. 34 
15.3.3. 
Analysis of Exploratory Efficacy Variables ............................................................................................ 34 
16. 
SAFETY OUTCOMES 
34 
16.1. 
Adverse Events ........................................................................................................................................... 34 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 50 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 7 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
16.1.1. 
All TEAEs ............................................................................................................................................... 35 
16.1.1.1. 
Severity ............................................................................................................................................ 35 
16.1.1.2. 
Relationship to Study Medication .................................................................................................... 35 
16.1.2. 
TEAEs Leading to Discontinuation from Study medication ................................................................... 36 
16.1.3. 
Serious Adverse Events ........................................................................................................................... 36 
16.1.4. 
Adverse Events Leading to Death............................................................................................................ 36 
16.2. 
Laboratory Evaluations ............................................................................................................................ 36 
16.2.1. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ............................................................ 37 
16.3. 
ECG Evaluations ....................................................................................................................................... 38 
16.4. 
Vital Signs ................................................................................................................................................... 38 
16.5. 
Physical Examination ................................................................................................................................ 39 
16.6. 
Other Safety Assessments ......................................................................................................................... 40 
17. 
REFERENCES 
41 
APPENDIX 1. 
PROGRAMMING CONVENTIONS FOR OUTPUTS 42 
IQVIA Output Conventions...................................................................................................................................... 42 
Table and Listing Output Conventions ................................................................................................................... 42 
Figure Output Conventions ...................................................................................................................................... 45 
Dates & Times ............................................................................................................................................................ 45 
Spelling Format.......................................................................................................................................................... 45 
Presentation of Treatment Groups .......................................................................................................................... 45 
Presentation of Visits ................................................................................................................................................. 46 
Listings ....................................................................................................................................................................... 46 
APPENDIX 2. 
PARTIAL DATE CONVENTIONS 
47 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 51 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 8 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
Algorithm for Treatment Emergence of Adverse Events ....................................................................................... 47 
Algorithm for Prior / Concomitant Medications .................................................................................................... 48 
 
 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 52 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 9 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy, safety and 
pharmacokinetic (PK)/pharmacodynamic (PD) data for Part B of protocol RPL554-MD-201. It describes the data to 
be summarized and analyzed, including specifics of the statistical analyses to be performed. This statistical analysis 
plan (SAP) is based on the protocol version 3.0, dated 24DEC2019. The study will consist of two parts (A and B) 
and Part B will be described in this SAP. Only the protocol sections applicable to Part B will be described in this 
SAP.  
2. STUDY OBJECTIVES FOR PART B 
2.1. PRIMARY OBJECTIVE 
The primary objective of Part B is to investigate the bronchodilator effect of repeat doses of RPL554 administered 
by pMDI (pressurized metered dose inhaler), assessed in terms of peak FEV1 (forced expiratory volume in one 
second). 
2.2. SECONDARY OBJECTIVES 
The secondary objectives of this part are as follows: 
x 
To investigate the safety and tolerability of repeat doses of RPL554 administered by pMDI.  
x 
To investigate the bronchodilator effect of RPL554 administered by pMDI, in terms of average FEV1 area under 
the curve (AUC)0-4h, average FEV1 AUC0-12h and trough FEV1. 
x 
To determine the onset of action of RPL554 administered by pMDI. 
x 
To evaluate the PK profile of RPL554 administered by pMDI. 
x 
To evaluate the amount of rescue medication use during treatment periods. 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 53 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 10 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
2.3. EXPLORATORY OBJECTIVES 
The exploratory objectives of this part are as follows: 
x 
To assess the dose response of RPL554 on peak and FEV1 AUC0-12h after morning dose on Day 7, and morning 
trough FEV1 prior to the last dose on Day 7. 
x 
To examine the effect of RPL554 administered by pMDI on a Likert dyspnea scale. 
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
This is a Phase II, randomized, double-blind, placebo-controlled, two-part study. Part A was a parallel group, single 
dose assessment of RPL554 administered by pMDI to evaluate the safety and terminal PK profile of a range of doses 
of RPL554. Five dose levels, 100 g, 300 g, 1000 g, 3000 g and 6000 g (single-blind) were selected, covering 
a 60-fold increase in doses. A total of approximately 36 COPD patients (as defined by the American Thoracic 
Society [ATS]/European Respiratory Society [ERS] guidelines with symptoms compatible with COPD for at least 1 
year prior to Screening) aged 40 to 80 years (inclusive) were randomized at two study centres in the United 
Kingdom (UK). At the end of Part A, a data cut-off will be used, selected data unblinded and analyzed prior to 
commencing Part B.  Three dose levels, 300 g, 1000 g, 3000 g were selected for Part B, using the same Part A 
patients. Part B is designed as a complete-block crossover, repeat dose assessment of RPL554 administered by 
pMDI to evaluate the steady state efficacy/PD effect of the three RPL554 doses compared to the effect with placebo 
pMDI. The patients in Part B will be expected to complete four treatment periods. 
 
In Part B, the patients from Part A will be randomly assigned in crossover fashion to one of 4 treatment sequences 
(see Appendix 1; Presentation of Treatment Sequences) each consisting of four 1-week treatment periods separated 
by a 7 to 10-day washout. Each treatment period consists of 6 days of twice daily doses of RPL554, and a single 
morning dose on Day 7. In each treatment period, patients will undergo assessments over 12 hours on Days 1 and 7.  
 
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Document: 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
3.2. SCHEDULE OF EVENTS 
Schedule of events can be found in Section 6 of the protocol. 
3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
The secondary analysis of change from baseline in rescue medication collected via patient diaries will not be carried 
out as rescue medication data is only collected during the treatment periods. The rescue medication will be 
summarized by treatment group for the between visit periods.  
An initial formal sample size computation was made for Part B. This was a complete block crossover study. 
Assuming a residual CV of 6% for peak FEV1, it was estimated that 30 evaluable patients would give an 80% power 
to detect a pairwise difference in peak FEV1 of 4.6%. Assuming a mean baseline FEV1 of 1.5 L this corresponded 
to a difference of about 70 mL. To account for withdrawals, 36 patients were to be randomized to Part A. 
Due to the COVID-19 pandemic, there was a longer than expected period between the completion of Part A and the 
start of Part B. The long pause made it difficult to re-recruit all patients from Part A and further study conduct with 
long clinic visits would be more difficult to perform in an ongoing pandemic. It was therefore decided to decrease 
the patient numbers for Part B to a minimum needed to show efficacy of ensifentrine MDI at doses giving at least 
110 mL benefit over placebo on peak FEV1. With 14 fully evaluable patients it was estimated that Part B would 
have 80% power to fulfill this revised objective. 
 
4. PLANNED ANALYSES 
There are no data monitoring committee (DMC) or formal interim analyses to be performed for this study. The study 
will consist of two separate and independent analyses, Part A and Part B. At the end of each part, the database will 
be locked and unblinded, and the analyses for each part will be performed. 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
4.1. DATA MONITORING COMMITTEE (DMC)  
There will be no DMC analyses for this study. 
4.2. INTERIM ANALYSIS  
No formal interim analysis is planned for the study. 
4.3. PART B ANALYSIS  
All Part B analyses identified in this SAP will be performed by IQVIA Biostatistics following Database Lock on a 
clean database:  
x 
All outstanding data issues and queries resolved. 
x 
All irresolvable data issues documented in the Data Handling Report (DHR) from Data Management. 
x 
All coding of medications, medical history and adverse events (AEs) completed. 
x 
Serious AE (SAE) reconciliation completed. 
x 
All reconciliation of vendor data with electronic case report form (eCRF) data completed successfully. 
x 
Analysis sets authorized. 
 
It should be noted that the main teams that worked with the Part A analysis remained blinded at the time of the Part 
A data cut-off, an independent unblinded team performed the Part A unblinded analysis. This was to avoid any 
potential risk they could trace what study medication a patient might be receiving in Part B (e.g. if they know they 
experienced certain AEs while on one treatment in Part A and this was identifiable in Part B). Summary data tables 
for the Part A dose finding analysis were generated. Individual data listings were not provided to the Verona or 
IQVIA clinical teams to avoid any potential unblinding. 
 
All verbatim text from the eCRF will be presented in outputs “as is” with no “manual hard coding” corrections for 
such data. Also, PK analysis will be performed by another party (third party vendor), and details of this analysis will 
not be specified in this SAP. 
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Document: 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
5. ANALYSIS SETS 
Agreement and authorization of patients included/excluded from each analysis set will be conducted prior to the 
unblinding of the study for Part B.  
In the case of dosing errors leading to duplication of treatment period or that treatment during period is 
undetermined, the period data for a patient could be excluded from the analysis. These will be agreed and 
documented prior to unblinding. 
5.1. PART A COMPLETERS SET 
This set will contain all patients who completed Part A of the study. 
5.2. ALL PATIENTS RANDOMIZED SET IN PART B [RND] 
The all patients randomized (RND) set will contain all patients who completed Part A and who are randomized to 
study medication in Part B (two randomizations are expected for this study, one for each part). For analyses and 
displays based on RND, patients will be classified per randomized sequence/treatment.  
5.3. SAFETY ANALYSIS SET [SAF] 
The safety analysis set (SAF) will contain all patients in the RND set who received at least one dose of study 
medication during Part B. Patients will be classified per actual sequence/treatment received. If there is any doubt 
whether a patient was treated or not, they will be assumed treated for the purposes of analysis. If a patient is treated 
based on a non-pre-specified sequence, which is not one of the 4 listed treatment sequence, this will be reported as 
‘Undefined’ for analysis by actual sequence/ treatment per Appendix 1; Presentation of Treatment Sequences. For 
analysis by treatment group a patient should be counted once for each time a specific treatment was received.  
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Document: 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
5.4. FULL ANALYSIS SET [FAS] 
The full analysis set (FAS) will contain all patients in the RND set with sufficient data (pre-dose and at least one 
post-dose assessment of spirometry) collected after intake of study medication to compute the pharmacodynamic 
parameters (FEV1, FVC measurements) on at least 2 treatment periods in Part B. For analyses and displays based on 
FAS, patients will be classified per randomized sequence/treatment. 
5.5. COMPLETERS ANALYSIS SET [CAS] 
The completers analysis set (CAS) will contain all patients in the SAF analysis set who complete all treatment 
periods i.e., a patient who receives a first and last dose intake plus 1 day for all 4 treatment periods per schedule of 
events (see section 6 of the protocol for schedule details). In the case of dosing errors leading to duplication of 
treatment period or that treatment during period is undetermined, the patient will be excluded from the completer 
analysis set. These will be agreed and documented prior to unblinding. 
5.6. PHARMACOKINETICS [PK] ANALYSIS SET 
The PK analysis set will contain all patients in the RND analysis set who have a blood sampling performed after at 
least one dose of RPL554 in Part B and with data sufficient to calculate PK parameter data. The PK analysis set will 
be determined by a third-party vendor and the data will be provided to IQVIA. 
6. GENERAL CONSIDERATIONS 
6.1. REFERENCE START DATE AND STUDY DAY 
Study day will be calculated from the reference start date (treatment period [TP] 1, day 1) and will be used to show 
start/stop day of assessments and events. Relative day will be calculated from the reference start date (each TP, day 
1) and will be used to show start/stop day of assessments and events relative to each treatment period. Reference 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
start date is defined as the day of the study medication and will appear in every listing where an assessment date or 
event date appears.  
 
If the date of the event is on or after the reference date, then:  
x 
Study day = (date of event – reference date) + 1. 
 
If the date of the event is prior to the reference date, then:  
x 
Study day = (date of event – reference date). 
 
In the situation where the event date is partial or missing, the date will appear partial or missing in the listings, and 
study day, and any corresponding durations will be presented based on the imputations specified in Appendix 2; 
Partial Date Conventions. 
6.2. BASELINE 
Baseline definitions are related to the treatment period the patient enters. For majority of endpoints (primary 
endpoint, relevant secondary/exploratory endpoints and safety endpoints assessed post-dose in the treatment 
periods), this will be the pre-dose assessment on Day 1 of each treatment period (treatment period 1 to treatment 
period 4). Baseline for peak FEV1, FEV1 AUC0-4h, FEV1 AUC0-12h and morning trough is defined as the average of 
the FEV1 pre-dose assessment (-60 minutes and -5 minutes) collected on relevant day of each treatment period. 
Baseline pre-dose FEV1/FVC will be derived from 3 acceptable readings (performed up to 8 times to obtain these), 
with the highest result from each assessment being used for analysis. For safety assessments with pre-dose 
assessments, baseline will be defined as the pre-dose assessment for each treatment period. 
6.3. REPEAT/RESCHEDULE, UNSCHEDULED VISITS AND EARLY 
TERMINATION DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. If a visit is 
repeated/rescheduled due to variability in FEV1 or other reason, the repeated/rescheduled visit, will be listed and 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
summarized as the valid visit (same visit number assigned). Unscheduled measurements will not be included in by-
visit summaries, but will contribute to the endpoint value. For example, if an unscheduled visit occurred at 10 hours 
post-dose on Day 1, then this value will be considered in the calculation of the average FEV1 over 12 hours (AUC0-
12h FEV1). Any unscheduled or unplanned readings will be presented within the patient listings. 
 
Early termination data will be mapped according to the visit number the termination occurred for by-visit 
summaries. If termination is between the end of Part A and the beginning of Part B, data are to be considered in the 
Part B SAP and patient is considered a Part A completer. 
 
Listings will include scheduled, unscheduled, repeat/reschedule and early discontinuation data. 
6.4. WINDOWING CONVENTIONS  
No visit windows will be applied in this study and the scheduled assessments will be reported and analyzed as per 
eCRF collection. 
6.5. STATISTICAL TESTS 
The default significant level will be (5%); confidence intervals will be 95% and all tests will be 2-sided, unless 
otherwise specified in the description of the analyses. All significant p-values (i.e. < 5%) will be flagged by means 
of a “*” for ease of review. 
 
For presentation of summary statistics for quantitative and qualitative variables see Appendix 1; Programming 
conventions for outputs.  
6.6. COMMON CALCULATIONS 
Assessments assigned to treatment periods: 
x 
Based on the day of assessment relative to the start date of each treatment period as defined by the first 
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Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
treatment administration for that specific treatment period:  
o 
Treatment period 1  
o 
Treatment period 2 
o 
Treatment period 3 
o 
Treatment period 4  
For quantitative measurements, change from baseline will be calculated as: 
x 
Test value at post-dose timepoint – baseline value. 
For quantitative measurement values of FEV1 and FEV1 AUCs will be calculated based on: 
x 
The highest FEV1 reading from each assessment. 
x 
The baseline value (average of the two pre-dose values [at 1-hour {±5 minutes} and immediately {within 5 
minutes}} pre-dose) must be within ± 20% of the pre-albuterol value at Screening; otherwise, the patient will be 
a screen failure. 
Peak effect will be calculated as: 
x 
Maximum value in the first 4 hours after dosing. 
Average effect will be calculated as: 
x 
FEV1 AUC divided by the length of the time interval of interest. 
Log-transformations will be performed on FEV1 data: 
x 
FEV1 will be analyzed using multiplicative models, which means that data will be logged prior to analysis. The 
results will then be back-transformed to linear scale (treatment differences will thus be ratios of geometric 
means). 
6.7. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4.  
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
7. STATISTICAL CONSIDERATIONS 
7.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
The following covariates are used in the analyses. For details of their inclusion in the models, see the specific 
analysis section. 
x 
Randomized treatment (fixed). 
o 
RPL554 300g 
o 
RPL554 1000g 
o 
RPL554 3000g 
o 
Placebo 
x 
Treatment period (fixed). 
o 
Treatment period 1 
o 
Treatment period 2 
o 
Treatment period 3 
o 
Treatment period 4 
x 
Baseline value of analyzed variable (covariate). 
7.2. MULTICENTER STUDIES 
This study is being conducted at 2 study centers in the UK.  
7.3. MISSING DATA 
Missing safety data will not be imputed, apart from partial date imputations as specified in Appendix 2.  
Missing efficacy data will be handled as described in Section 15.1.2 and Section 15.2.2 of this SAP.  
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
7.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
Significance of treatment effect will be tested for the primary and secondary efficacy endpoints in Part B and will be 
done for each of the doses of RPL554 against placebo, starting with the highest dose (3000 g). To this end, the 
fixed-sequence testing approach (Maurer et al., 1995; Westfall & Krishen, 2001) will be used. 
 
For the endpoints, let i = 0, 1, 2 and 3 represent increasing dose levels, 0 denoting placebo. Also, let i, i = 0, 1, 2 
and 3 denote the mean change from baseline for the endpoint of interest for placebo and each increasing active dose 
level, respectively.  The null hypotheses are defined as: Hi: j - 0 = 0 and will be tested against the  
2-sided alternative Ki: j - 0  0, j = 1, 2 and 3. 
 
Finally, let p1, p2, p3 denote the marginal p-values obtained from the statistical tests associated with H1, H2, H3 
(obtained from the model). 
The fixed-sequence testing will begin with the null hypothesis corresponding to the highest dose versus placebo. If a 
statistically significant difference is found at the 2-sided Į level of 5%, the testing will proceed with the next highest 
dose. Otherwise, testing stops, and the remaining null hypotheses are considered as failed to reject, without testing. 
This testing strategy can be written as the following stepwise algorithm: 
x 
Step 1: If p3  Į reject H3 and go to Step 2. Otherwise, fail to reject H3, H2 and H1 and stop. 
x 
Step 2: If p2  Į reject H2 and go to Step 3. Otherwise, fail to reject H2 and H1 and stop. 
x 
Step 3: If p1  Į reject H1. Otherwise, accept H1. 
 
The fixed-sequence procedure controls the family-wise error rate in the strong sense because, for each null 
hypothesis, the testing is conditional upon rejecting all hypotheses earlier in the sequence (Dmitrienko, et al., 2009). 
 
Each secondary endpoint will be tested independently and nominally following a hierarchical testing of doses like 
the one used for the primary endpoint.  
7.5. EXAMINATION OF SUBGROUPS 
No pre-planned subgroup analyses will be performed for this study. 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
8. OUTPUT PRESENTATIONS 
Appendix 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP describe the presentations for this study and therefore the format and content 
of the summary tables, figures, and listings to be provided by IQVIA Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
All patients who completed Part A of the study will be accounted for in Part B of the study.  
 
Patient disposition, withdrawals and reasons for exclusion from each analysis set will be presented for all patients, 
summarized by treatment sequence for the patients who completed Part A and were randomized in Part B. Number 
of patients treated and discontinued in each treatment period will also be presented. If the patient 
discontinued/withdrew, he/she will be allocated to the last treatment period attended.  
 
All protocol deviations collected in Part B will be divided into critical, major or minor categories and will be 
assigned to the actual treatment group. The major and critical protocol deviations (PD) will be summarized by 
treatment and all PDs will be presented in a listing for the RND analysis set. Protocol deviations affect the integrity 
of the drug activity data and will be obtained by the clinical research associates (CRAs) and documented in the 
clinical trial management system (CTMS). 
Each protocol deviation is categorized into one of the following types, as reported in CTMS: 
1. Informed Consent Criteria 
2. Eligibility and Entry Criteria 
3. Concomitant Medication Criteria 
4. Laboratory Assessment Criteria 
5. Study Procedures Criteria 
6. Serious Adverse Event Criteria 
7. Randomization Criteria 
8. Visit Schedule Criteria 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
9. Investigation Product (IP) Compliance 
10. Efficacy Criteria 
11. Administrative Criteria 
12. Source Document Criteria 
13. Regulatory or Ethics Approvals Criteria 
14. Other Criteria 
 
Preliminary assignment to each analysis set, therefore whether a patient is included/excluded in each analysis set 
(excluding the PK analysis set, as this set will be defined later in a separate authorization with input, as required, 
from the PK scientist) will be recorded in an EXCEL sheet by the IQVIA Biostatistician, with the reason for 
exclusion from each population indicated. The EXCEL sheet should then be authorized by means of a customer 
authorization form (CAF) and prior to the Database Lock of the study.   
10. DEMOGRAPHIC AND OTHER SCREENING CHARACTERISTICS 
Demographic data and other screening characteristics (including screening disease characteristics) will be presented 
for each unique set, as described in Section 5. No statistical testing will be carried out for demographic or other 
screening characteristics. The following demographic and other screening characteristics will be reported for Part B: 
x 
Age (years) 
x 
Sex 
x 
Childbearing potential 
x 
Race  
x 
Ethnicity 
x 
Height (cm) 
x 
Weight (kg) 
x 
BMI (kg/m2) 
x 
Pre (prior to dosing at screening)/post (post dosing at screening) bronchodilator FEV1 (both in liters and in 
percentage of predicted normal) 
x 
Post-bronchodilator FEV1/FVC 
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Statistical Analysis Plan v1.0 – Part B 
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Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
x 
Reversibility test (mL and %) 
x 
Reversibility assessment performed with four puffs of Albuterol 
x 
Met requirements of reversibility test 
10.1. DERIVATIONS 
Demographic and other screening characteristics recorded on the eCRF will be used as is on the eCRF, without any 
derivations or adjustments. 
11. SURGICAL, MEDICAL AND CHRONIC OBSTRUCTIVE 
PULMONARY DISEASE/SMOKING HISTORY 
Surgical and Medical History information will be presented in listings, for the RND analysis set.  
x 
Surgical History will be coded by Medical Dictionary for Regulatory Activities (MedDRA) dictionary using the 
version specified in the data management plan. 
o 
Surgical History conditions are defined as those conditions which stop prior to or at Screening.  
o 
Data captured on the Surgical Procedure History page of the eCRF will be presented by SOC (System 
Organ Class) and PT (Preferred Term).  
x 
Medical History will be coded by MedDRA dictionary using the version specified in the data management plan. 
o 
Medical History conditions are defined as those conditions which stop prior to or at Screening.  
o 
Data captured on the Medical History page of the eCRF will be presented by SOC and PT.  
x 
COPD/Smoking History data captured on the COPD and Smoking History page of the eCRF will be presented 
for each unique set, as described in Section 5. 
o 
COPD history (Duration of COPD (years) [calculated relative to date of first diagnosis {Randomization 
date, as recorded in Part A – first COPD diagnosis date}/365.25], date of most recent exacerbation, known 
to have chronic bronchitis/emphysema). 
o 
Smoking history (current or former smoker, number of packs per day, number of years smoking and 
number of pack-years [calculated as number of packs per day x number of years smoking]) 
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CONFIDENTIAL
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Statistical Analysis Plan v1.0 – Part B 
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Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
12. MEDICATIONS 
Medications will be coded using the World Health Organization – Drug Dictionary (WHO-DD) version specified in 
the data management plan and will be presented in a listing by Anatomical Therapeutic Chemical (ATC) (the 1st 
level of the ATC code) and PT for the RND analysis set. Certain medications (or a special grouping of medications) 
will be classified in a list during the study and signed-off prior to lock by a medical advisor. As this list, may change 
prior to sign-off they will not be defined in this section of the SAP. Potential medications include, but are not limited 
to, inhaled corticosteroids (ICS), LAMAs (long-acting muscarinic antagonists), LABAs (long-acting beta2-agonists) 
etc. 
 
See Appendix 2 for handling of partial dates for medications. In the case where it is not possible to define a 
medication as prior or concomitant, the medication will be classified by the worst case; i.e. concomitant.  
x 
‘Prior’ medications are medications which started and stopped in the time between Part A and Part B (prior to 
the study medication at TP1, Day 1) and have Started prior to start of study medication? = “Yes” on the 
Concomitant medications eCRF page.  
 
x 
‘Concomitant’ medications are medications which:  
o 
Had an onset date on or after the start of study medication for Part B (TP1, Day 1). 
o 
AND ended on or after the date of medication or were ongoing at the end of Part B. 
o 
A patient can report more than 1 concomitant medication with the same PT.  
Prior and concomitant medications will be presented in a listing only, by treatment sequence. For concomitant 
medications, the treatment period when the medication was taken will also be reported in the listing. 
 
Rescue medications will be recorded on the Rescue Medication/Rescue Medication Inhaler Dispensed/Rescue 
Medication Inhaler Weight/Rescue Medication Inhaler Collection/Rescue Medication Diary Dispense/Patient Diary 
for Rescue Medication pages of the eCRF. These are short acting bronchodilators and will be sourced by the study 
center and dispensed as needed during the Screening, treatment and washout periods. Rescue medication used 
during the study will be documented on the eCRF pages. Protocol procedures must continue even if rescue 
medication has been taken. Salbutamol/albuterol is to be used for primary rescue use, but others are also permitted 
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Statistical Analysis Plan v1.0 – Part B 
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Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
(e.g. ipratropium). Rescue medications must be withheld for at least 6 hours prior to pre-dose spirometry until 
completion of the 12-hour post-dose spirometry (per below), and this is to be confirmed in the eCRF at the start of 
each treatment period. If this withhold is not met, the patient should be rescheduled for a repeat visit within 
permitted windows. 
  
Rescue medications used during study visits in Part B will be primarily provided by patients on paper diaries, which 
will be transcribed into the eCRF. In the event of missing or incomplete diaries, rescue medication will be 
determined analytically (by recording the weight of the canister dispensed at the end of Day 1 and start of Day 7 per 
period). Rescue medication analysis will be described in Section 15.2.1.5. 
 
When a rescue medication is used less than 6 hours prior to study medication a sensitivity analysis will be carried 
out for the AUC0-12h FEV1 analysis detailed in Section 15.2.1.1 and 15.2.1.2 which will remove patients from the 
treatment periods where rescue medication was taken less than 6 hours prior to study medication or patients who 
took rescue medication during the 12 hour assessments. This will only be carried out if at least 1 patient has taken 
rescue medication less than 6-hours prior to study medications. 
13. STUDY MEDICATION EXPOSURE 
Exposure to study medication in days will be presented by treatment for the SAF analysis set. The date of first study 
medication inhalation, per treatment, will be taken from the Drug Exposure eCRF page for treatment period 1. The 
date of last study medication inhalation, per treatment sequence, will also be taken from the Drug Exposure eCRF 
page, based on the last end time of inhalation for the last treatment period of a patient.  
  
Drug accountability i.e. the number of pMDIs used per treatment period, as measured on the Drug Exposure eCRF 
page will be summed to get the total number of pMDIs used and presented similarly to exposure, by treatment 
sequence for the SAF analysis set. 
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Clinical Study Report
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Version 1.0; 17 May 2021
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CONFIDENTIAL
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PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 25 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
13.1. DERIVATIONS 
x 
Duration of exposure per treatment period (days) in Part B = date of last study medication administration, per 
treatment – date of first study medication administration, per treatment +1.  
x 
Duration of exposure per treatment sequence (days) in Part B = Duration of exposure for period 1 + Duration of 
exposure for period 2 + Duration of exposure for period 3 + Duration of exposure for period 4. 
x 
Drug accountability (number of capsules) = Number of pMDIs dispensed – number of pMDIs returned by 
treatment period. 
14. STUDY MEDICATION COMPLIANCE  
In Part B, patients will be dosed at the study center on the morning and evening of Day 1 and on the morning of Day 
7. Patients will self-administer study medication for the other dosing times (i.e. on Days 2 through 6). Compliance 
will be assessed by recording the number of pMDIs dispensed and returned, as per drug accountability described in 
Section 13. 
15. EFFICACY OUTCOMES  
The primary efficacy analyses will be performed for the FAS. Patients withdrawn after only one treatment period 
will not be included in the analyses of the primary efficacy variable. If the CAS differs from the FAS, the primary 
efficacy analysis will also be carried out on the CAS. 
15.1. PRIMARY EFFICACY 
15.1.1. PRIMARY EFFICACY VARIABLE(S) & DERIVATION(S)   
The primary efficacy variable is peak FEV1 (measured in first 4 hours after morning dosing). This will be measured 
after dosing on Day 7 and is collected on the Spirometry Study measurements eCRF page. The primary efficacy 
endpoint is change from baseline in peak FEV1. 
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Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
Three acceptable readings are performed at each of the timepoints in first 4 hours after morning dosing on Day 7 (5, 
15 and 30 minutes and 1, 1.5, 2 and 4 hours) and the highest of the 3 is used for analysis purposes. Hence, peak 
FEV1 is derived as the highest of all these readings. Patients withdrawn after only one treatment period will not be 
included in the analysis. 
 
Descriptive statistics (see Appendix 1 [Programming conventions for outputs]) for FEV1 will be presented for all 
patients assigned to FAS, at each assessment and change from baseline at each assessment. All summaries will be 
presented for each treatment group by day and timepoint. In addition, a figure (bar graph) representing mean change 
from baseline FEV1 to peak FEV1 by treatment will be presented, including the standard error of the mean.   
 
Change from baseline FEV1 to peak FEV1 (over 4 hours) at Day 7 will be derived to test the hypothesis described in 
section 15.1.3 with baseline defined as the average of the FEV1 pre-dose assessment (-60 minutes and -5 minutes) 
collected on Day 1 of each treatment period. Peak FEV1 at Day 7 is defined as the maximum post-dose value among 
the 5, 15, 30 minutes, 1, 1.5, 2 and 4-hour assessments collected at after morning dose on Day 7 of each treatment 
period.  
15.1.2. MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE(S) 
No imputation will be applied. 
15.1.3.  PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
The primary efficacy objective of the study is to show that at least 1 RPL554 treatment group (RPL554 3000g, 
RPL554 1000g, RPL554 300g) will increase peak FEV1 (change from Baseline) compared to placebo at Day 7 
(measured in first 4 hours after morning dosing) by rejecting the null hypothesis described below at significance 
level Į=0.05 level (2-sided): 
H0: j = 0 versus H1: j  0 
 
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Statistical Analysis Plan v1.0 – Part B 
Page 27 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
where j and 0 are the mean change from Baseline in peak FEV1 at Day 7 (measured in first 4 hours after morning 
dosing) for 1 RPL554 treatment group (RPL554 3000g, RPL554 1000g, RPL554 300g) and placebo 
respectively.  
 
An ANCOVA will be used to test the hypothesis with change from baseline FEV1 to peak FEV1 (measured in first 4 
hours after morning dosing) on Day 7 as response variable, and treatment and treatment period as fixed factors, 
patient as random and baseline FEV1 as covariates. Analyses will be implemented using the SAS® procedure 
MIXED as follows:  
 
PROC MIXED DATA = …; 
 
CLASS USUBJID PERIOD TREATMENT; 
 
MODEL CHG = TREATMENT PERIOD BASELINE; 
 
RANDOM USUBJID; 
 
LSMEANS TREATMENT / CL DIFF; 
RUN; 
where CHG = difference in log (peak FEV1 - baseline FEV1) 
TREATMENT = treatment group (RPL554 3000g, RPL554 1000g, RPL554 300g, and placebo) 
PERIOD = treatment period (treatment period 1, 2, 3, and 4) 
BASELINE = log (baseline FEV1) 
USUBJID = subject ID   
 
The primary comparison will be the contrast (difference in least squares mean [LSMEAN]) between RPL554 
3000g and placebo on Day 7 (in first 4 hours after morning dosing). 
Peak FEV1 and the covariate, baseline FEV1, will be log-transformed prior to analysis using natural logarithm. The 
difference between the two is log (peak FEV1) – log (baseline FEV1). Therefore, the LSMEAN statement between 
treatments in the above PROC MIXED will provide the log of the contrasts. Prior to presentations, the antilog of 
these point estimates and associated 95% confidence intervals will be performed, giving ratios of geometric means 
on the linear scale. The 2-sided p-value for the exponential (exp) least squares mean, exp(LSM), ratio between each 
of the 2 treatment groups and placebo will be reported. 
 
Summary statistics for FEV1 will be presented for baseline, peak on Day 7 (in first 4 hours after morning dosing) 
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Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
and change from baseline to peak by treatment group on patients with both assessments, on the original scale. A 
figure displaying the mean change from baseline FEV1 over time by treatment and day will also be presented. 
15.2. SECONDARY EFFICACY    
The secondary efficacy analyses will be performed for the FAS. Patients withdrawn after only one treatment period 
will not be included in the analyses of any of the secondary efficacy variables. 
15.2.1. SECONDARY EFFICACY VARIABLES & DERIVATIONS 
15.2.1.1. 
Change in baseline in average FEV1 of AUC0-4h (Average FEV1 over 4 hours), average 
FEV1 of AUC0-12h (Average FEV1 over 12 hours) and (morning) trough FEV1 on Day 7 
(Secondary variables 1, 2 and 3) 
 
Average FEV1 is defined as the AUC0-4h FEV1, divided by the length of the time (in hours). AUC0-4h FEV1 is derived 
using the following formula: 
ܣܷܥ= 1
2 (ݐଵെݐ଴)(ݕଵ+ ݕ଴) + 1
2 (ݐଶെݐଵ)(ݕଶ+ ݕଵ) + ڮ + 1
2 (ݐ௜െݐ௜ିଵ)(ݕ௜+ ݕ௜ାଵ) 
where i are the number of intervals, ti are the time values or time intervals (in actual hours) between assessments and 
yi the FEV1 values (highest of the three acceptable readings) at ti. The AUC result will then be divided by the actual 
time (the time elapsed since dosing, until the time of assessment) at 4-hour assessment (as this can occur ± 10 
minutes) to obtain the average FEV1. If the assessment at 4-hour is missing, the AUC result will be divided by the 
actual time of the last collected assessment.  For analysis purposes, it will be assumed that the pre-dose value 
(immediately pre-dose) occurred at time 0 when computing PD parameters. If a patient misses hour 2 and 4 then the 
AUC0-4 is set to missing. 
 
Descriptive statistics (see Appendix 1 [Programming conventions for outputs]) for AUC0-4 will be presented for all 
patients assigned to FAS, at each assessment and change from baseline at each assessment as relevant. All 
summaries will be presented for each treatment group. 
 
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Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
Change from baseline FEV1 to FEV1 AUC0-4 will be derived to test the hypothesis described in Section 15.2.3 with 
baseline defined as the average of the FEV1 pre-dose assessments (-60 minutes and -5 minutes) collected. 
 
AUC0-12h FEV1 is defined and derived similarly to AUC0-4h above, but over 12-hours post-dose. If patient misses 
hours 11 and 12 then the AUC0-12h is set to missing. If the assessment at 12-hours is missing, the AUC result will be 
divided by the actual time of the last collected assessment. 
 
Morning trough FEV1 is the average of the FEV1 pre-dose assessments (-60 minutes and -5 minutes) on Day 7 and 
the change from baseline will be analyzed similarly to AUC0-4h and AUC0-12h. 
15.2.1.2. 
Change in baseline in peak FEV1 measured after first dose, average FEV1 of AUC0-4h on 
Day 1 and average FEV1 of AUC0-12h FEV1 on Day 1 (Secondary variables 4, 5 and 6) 
 
Peak FEV1 measured after first dose is defined as the peak FEV1 (after 4 hours of dosing) on Day 1. It is defined as 
the change from baseline to peak FEV1 and derived similarly to primary analysis (see section 15.1.1), but instead at 
Day 1.  
 
AUC0-4h FEV1 and AUC0-12h FEV1 on Day 1 are defined and derived similarly to secondary endpoint above (see 
section 15.2.1.1), but at Day 1. Parameters will be calculated over 4 and 12 hours, respectively (on Day 1 of each 
treatment period). If patient misses hours 2 and 4 then the AUC0-4h is set to missing. Similarly, if patient misses 
hours 11 and 12 then the AUC0-12h is set to missing. If the assessment at 12-hours is missing, the AUC result will be 
divided by the actual time of the last collected assessment. 
15.2.1.3. Determination of onset of action (>10% increase in FEV1, from pre-first dose, censored at 
120 minutes) on Day 1 (Secondary variable 7) 
 
Onset of action is defined as a >10% increase in FEV1 from pre-dose on Day 1 over the next 120 minutes (2 hours) 
after morning dosing on Day 1 (5, 15 and 30 minutes and 1, 1.5, 2 hours). Time to onset will be derived as the time 
to onset of action is achieved. For analysis purposes, it will be assumed that the pre-dose value occurred at time 0. 
Patients not experiencing an onset of action will be censored at 120 minutes (2 hours) or at time of premature 
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Document: 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
discontinuation (if withdrawn before 120 minutes). If the number of patients censored regarding onset of action is 
deemed to be too high (number of patients with onset of action censored >50%), the Kaplan-Meier estimates and 
accompanying figure will not be presented. Patients receiving placebo will not be summarized in either tables or 
figure. 
15.2.1.4. RPL554 steady state pharmacokinetics (AUC0-12h, Cmax, time to maximum concentration 
[tmax]) (Secondary variable 8) 
 
Concentration of RPL554 and computed PK parameters (AUC0-12h, Cmax [maximum concentration], tmax [time to 
maximum concentration]) on Day 7 of each treatment period (pre-dose, 30 minutes and 1, 1.5, 2, 4, 8 and 12-hours 
post dose).  
15.2.1.5. 
Rescue medication use during treatment periods (Secondary variable 9) 
 
Use of medication per treatment period is calculated as the mean use daily over the treatment period, (Day 1 to Day 
7) calculated only based on the days data was recorded/verified in the patient diary for rescue mediation.  
If less than 4 days of data are available for the treatment period, the weekly mean is set to missing, e.g. if data is 
entered for less than 4 days between Day 1 and Day 7 then no result will be presented for that treatment period.  
This will be documented in the “Rescue Medication Diary Dispense” page of the eCRF, as well as in the “Patient 
Diary for Rescue Medication” entry.  
The rescue medication use will be confirmed in the diary using the following rules:  
1. If patient has put in rescue medication use then analyse as expected.  
2. If patient has not put in rescue medication use, then to confirm that there was no diary compliance issue, 
question “Rescue medication taken?” will be answered “No” to make sure it is filled in correctly.  
3. If patient has not put in rescue medication use and question “Rescue medication taken?” was not filled in 
correctly then this will be treated as diary compliance issue and therefore this day will not be used as the 
day recorded for the weekly means calculation.  
 
Rescue medication use, in terms of weight (mcg) of rescue medication during the treatment periods will be collected 
from the Rescue Medication Inhaler Dispensed, Rescue Medication Inhaler Collected and Rescue Medication 
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Document: 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
Inhaler Weight eCRF pages and will be summarized by treatment group in a listing.  
15.2.2. MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLE(S) 
No imputation will be applied. 
15.2.3. ANALYSIS OF SECONDARY EFFICACY VARIABLES 
15.2.3.1. Analysis of Secondary Variables 1, 2, 3, 4, 5 and 6 
 
The secondary variables listed above will be analyzed by comparing the RPL554 treatment groups to each other and 
placebo by rejecting the null hypothesis described below at significance level Į=0.05 level (2-sided): 
H0: j = 0 versus H1: j  0 
 
where j and 0 are the mean change from Baseline for each parameter for each respective dose of RPL554 and 
placebo.  
 
ANCOVA analyses will be implemented using the SAS® procedure MIXED as follows:  
 
PROC MIXED DATA = …; 
 
CLASS USUBJID PERIOD TREATMENT; 
 
MODEL CHG = TREATMENT PERIOD BASELINE; 
 
LSMEANS TREATMENT / CL DIFF; 
 
RANDOM USUBJID; 
RUN; 
 
where CHG = difference in log (parameter – baseline parameter) 
TREATMENT = treatment group (Respective dose of RPL554, 300g, 1000g and 3000g and placebo) 
PERIOD = treatment period (treatment period 1, 2, 3, and 4) 
BASELINE = log (baseline parameter) 
USUBJID = subject ID 
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Document: 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
The primary comparison will be the contrast (difference in least squares mean [LSMEAN]) between 3000ȝg 
RPL554 and placebo using hierarchical testing. The parameter value and its baseline covariate will be log-
transformed prior to analysis using natural logarithm. The difference between the two log (parameter) – log 
(baseline parameter). Therefore, the LSMEAN statement between treatments in the above PROC MIXED will 
provide the log of the contrasts. Prior to presentations, the antilog of these point estimates and associated 95% 
confidence intervals will be performed, giving ratios of geometric means on the linear scale. The 2-sided p-value for 
the exponential (exp)least squares mean, exp(LSM), ratio between each of the 2 treatment groups and placebo will 
be reported.  
 
Summary statistics for each parameter will be presented for baseline, at point of interest (if applicable) and change 
from baseline by treatment group on patients with both assessments, on the original scale. 
15.2.3.2. Analysis of Secondary Variable 7 
Onset of action will be summarized by treatment and a Kaplan-Meier plot illustrating time to onset constructed. The 
SAS® procedure LIFETEST, will be used as follows to calculate the median, 25th and 75th percentile:  
 
PROC LIFETEST DATA=...  OUTSURV =... CONFTYPE = LINEAR METHOD = 
KM ALPHA = 0.05 ALPHAQT = 0.05 PLOTS = (SURVIVAL (FAILURE NOCENSOR));  
 
TIME ONSET*STATUS (1); 
 
STRATA TREATMENT; 
RUN; 
 
where ONSET = time to onset of action 
TREATMENT = treatment group (Respective dose of RPL554, 300g, 1000g and 3000g) 
STATUS (1) = indicates an event of onset of action 
 
To calculate the mean difference to RPL554 3000g, the SAS procedure LIFETEST will be carried for each 
treatment comparison pair individually. 
If a patient does not have onset of action from pre-dose on Day 1 over the next 120 minutes (2 hours) the data will 
be censored at 120 minutes or if a patient prematurely discontinued before 120 minutes, the last available 
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Document: 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
assessment time post-dose (1 indicates censored variables). Median differences to the highest dose (RPL554 3000 
g) will be estimated and the p-value based on the PROC LIFETEST above (Wilcoxon signed rank sum test) 
between each treatment groups and the highest dose will also be presented. 
15.2.3.3. Analysis of Secondary Variable 8 
As described in section 4.3, this SAP will not summarise the analyses related to the PK concentrations and 
parameters and this will be handled by a third-party vendor. 
15.2.3.4. Analysis of Secondary Variable 9 
 
Summary statistics will be presented by treatment group. In addition, all rescue medication used during the serial 
spirometry assessments (Days 1 and 7) will be listed to assess the accuracy of the FEV1 recordings. 
15.3. EXPLORATORY EFFICACY  
15.3.1. 
EXPLORATORY EFFICACY VARIABLES & DERIVATIONS 
15.3.1.1. 
Evaluation of dose response of RPL554 on peak and average FEV1 AUC0-12h after 
morning dose on Day 7, and morning trough FEV1 prior to the last dose on Day 7 
 
The association of dose response for the primary and secondary endpoints listed in this section title will be 
performed by pairwise comparisons of RPL554 doses (ie, 1000g vs 300g, and 3000g vs 1000g) using 
ANCOVA models in the same ways as the primary endpoint detailed in Section 15.1.3. 
15.3.1.2. 
Change from baseline in Likert dyspnea scale measured after morning dose on Day 7 
 
An 11-point Likert scale will be utilized, with patients being asked the following question by a blinded member of 
staff: “On a scale of zero to ten, please rate your current shortness of breath, with zero indicating no shortness of 
breath and ten indicating the worst shortness of breath that you can imagine”. This scale will be an instantaneous 
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Document: 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
measurement of their dyspnea at that moment, and not reflective. It will be administered on Day 7 pre-dose and 30 
minutes, 1, 1.5, 2, 4, 8, 11 and 12 hours post-dose of each treatment period. Baseline will be considered the pre-dose 
assessment on Day 1 of each treatment period and change from baseline will be assessed at each timepoint on Day 1 
and Day 7.  
15.3.2. 
MISSING DATA METHODS FOR EXPLORATORY EFFICACY VARIABLE(S) 
No imputation will be applied. 
15.3.3. 
ANALYSIS OF EXPLORATORY EFFICACY VARIABLES 
Dyspnea score and the change in dyspnea score will be summarized at each timepoint of interest on Day 7 (pre-dose 
and 30 minutes, 1, 1.5, 2, 4, 8, 11 and 12 hours post-dose). Treatment comparisons of change from baseline will be 
performed using an ANCOVA adjusting for treatment, treatment period and patient, and using pre-dose Day 1 
baseline value as a covariate, like the hypothesis described in section 15.1.3. The model will be additive; therefore 
no log-transformation will be applied. 
16. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the SAF.  
There will be no statistical comparisons between the treatment groups for safety data, unless otherwise specified 
with the relevant section.  
16.1. ADVERSE EVENTS 
Adverse Events (AEs) will be coded by MedDRA dictionary using the version specified in the data management 
plan.  
 
Treatment emergent adverse events (TEAEs) are defined as AEs that started or worsened in severity on or after the 
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Document: 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
first dose of study medication in Part B, based on the investigator assessment of severity. TEAEs will be assigned to 
treatment groups based on actual treatment received. TEAEs, like medications, may be assigned to multiple 
treatment groups due to the cross-over design of the study. This will depend on the occurrence date and duration of 
each TEAE. 
 
See Appendix 2 for handling of partial dates for AEs.  In the case where it is not possible to define an AE as 
treatment emergent or not, the AE will be classified by the worst case; i.e. treatment emergent.  
An overall summary of number of patients within each of the categories described in the sub-section below, will be 
provided as specified in the templates.  
 
Listings will include TEAEs and Non-TEAEs. 
16.1.1. ALL TEAES  
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) and broken down 
further by maximum severity and relationship to study medication. 
16.1.1.1. 
Severity 
Severity is classed as mild/ moderate/ severe (increasing severity). TEAEs starting after the first dose of study 
medication with a missing severity will be classified as severe. If a patient reports a TEAE more than once within 
that SOC/ PT, the AE with the worst-case severity will be used in the corresponding severity summaries. 
16.1.1.2. 
Relationship to Study Medication 
Relationship, as indicated by the Investigator, is classed as “yes” or “no”. A related TEAE is defined as a TEAE 
with a relationship to study medication as “yes”. TEAEs with a missing relationship to study medication will be 
regarded as relationship = “yes” to study medication. If a patient reports the same AE more than once within that 
SOC/ PT, the AE with the worst-case relationship to study medication will be used in the corresponding relationship 
summaries.  
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Document: 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
16.1.2. TEAES LEADING TO DISCONTINUATION FROM STUDY  
TEAEs leading to discontinuation from the study will be identified by using the question “Did the AE cause the 
Patient to discontinue from the study?” from the AE page of the eCRF. 
 
For TEAEs leading to discontinuation from the study, summaries of incidence rates (frequencies and percentages) 
by SOC and PT will be prepared. 
16.1.3. SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse Events page of the eCRF. A 
summary of serious TEAEs by SOC and PT will be prepared, similarly to Section 16.1.1 and Section 16.1.2. 
16.1.4. ADVERSE EVENTS LEADING TO DEATH 
TEAEs leading to Death are those events which are recorded as “Death” on the Adverse Events page of the eCRF. A 
summary of TEAEs leading to death by SOC and PT will be prepared. 
16.2. LABORATORY EVALUATIONS 
Results from the local laboratory will be included in the reporting of this study for hematology, blood chemistry, and 
urinalysis. A list of laboratory assessments to be included in the outputs is included in the protocol, Sections 7.4.3.1, 
7.4.3.2, and 7.4.3.3 for hematology, blood chemistry, and urinalysis, respectively. Presentations will use 
International system (SI) units.  
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of quantification (BLQ), or 
“> X”, i.e. above the upper limit of quantification (ULQ), will be converted to X for quantitative summaries, but will 
be presented as recorded, i.e. as “< X” or “> X” in the listings. 
The following summaries will be provided for laboratory data: 
x 
Actual and change from baseline (pre-dose at Day 1 for each treatment period) to each pre-dose time point at 
Day 7 (for quantitative measurements), including overall (where overall is regardless of treatment period, day 
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Document: 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
and timepoint to assess treatment group, as a whole). 
x 
Shift from baseline based on normal range criteria (for quantitative measurements and categorical 
measurements) 
x 
Incidence of abnormal values according to normal range criteria (in the case of Biochemistry only). 
x 
Listing of all abnormal values occurring after the first dose of study medication. 
16.2.1. LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges in SI units and 
categorized as: 
x 
Low: Below the lower limit of the laboratory reference range.  
x 
Normal: Within the laboratory reference range (upper and lower limit included). 
x 
High: Above the upper limit of the laboratory reference range. 
 
In addition to the high and low quantitative laboratory assignments (as identified by means of the laboratory 
reference ranges), markedly abnormal quantitative blood chemistry values per the table below will also be identified 
by the Investigator. 
 
 
Blood Chemistry –  
Markedly Abnormal Definition 
Alanine Aminotransferase (ALT) 
> 3 x ULN 
Alkaline Phosphatase (ALP) 
> 3 x ULN 
Aspartate Aminotransferase (AST) 
> 3 x ULN 
Creatinine 
> 221 mol/L 
Gamma Glutamyl Transferase (GGT) 
> 3 x ULN 
Bilirubin (TBL) 
> 3 x ULN 
ULN: Upper limit of normal.  
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Document: 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
16.3. ECG EVALUATIONS 
Overall results from the local ECG lab will be included in the reporting of this study. The overall assessment of 
ECG parameters will be reported for this study: 
x 
Normal 
x 
Abnormal not Clinically Significant (ANCS) 
x 
Abnormal Clinically Significant (ACS) 
x 
Incomplete Analysis 
x 
Uninterpretable 
 
The following summaries will be provided for quantitative ECG data, for example heart rate: 
x 
Actual assessments at baseline (pre-dose at Day 1 for each treatment period) and each pre-dose time point at 
Day 7, including overall (where overall is regardless of treatment period, day and timepoint to assess treatment 
group as a whole). 
x 
Shift of overall assessment baseline to post-dose timepoints per Normal, ANCS and ACS overall 
assessment criteria. 
x 
Listing of all ECG evaluations and abnormal values occurring after the first dose of study 
medication. 
16.4. VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
x 
Supine Systolic Blood Pressure (mmHg) 
x 
Supine Diastolic Blood Pressure (mmHg) 
x 
Supine Pulse Rate (bpm) 
 
The following summaries will be provided for vital signs data: 
x 
Actual assessments at screening, baseline (pre-dose at each treatment period) and each post-dose time points, 
including end of study visit and overall (where overall is regardless of treatment period, day and timepoint to 
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Document: 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
assess treatment group as a whole). 
x 
Incidence of markedly abnormal values (number and percent) based on the criteria presented in the table below: 
 
 
Low 
High 
Systolic blood pressure (mmHg)  
Value  90 mmHg 
Value  180 mmHg 
Decrease from Baseline of  
40 mmHg 
Increase from Baseline of  40 
mmHg 
Diastolic blood pressure (mmHg)  
Value  50 mmHg 
Value  110 mmHg 
Decrease from Baseline of  
20 mmHg 
Increase from Baseline of  20 
mmHg 
Pulse rate (bpm)   
Value  50 bpm 
Value  110 bpm 
Decrease from Baseline of  
30 bpm 
Increase from Baseline of  30 bpm 
 
Peak supine pulse rate after study medication is defined as the maximum value measured in the first 4 hours post-
dose. Peak pulse rate and change from baseline to peak on Day 1 and after morning dosing on Day 7 will be 
summarized similarly to Section 15.1.3, including the figure presentation described in the same section. Treatment 
comparisons of change from baseline will be performed using an ANCOVA adjusting for treatment, treatment 
period and patient, and using pre-dose pulse rate as a covariate, like the hypothesis described in Section 15.1.3. The 
model will be additive; therefore no log-transformation will be applied. 
16.5. PHYSICAL EXAMINATION 
The following summaries will be provided for the full physical examination data, covering major body systems 
(nose, throat, skin, thyroid gland, neurological system, respiratory system, cardiovascular system, abdomen [liver 
and spleen], lymph nodes and extremities): 
x 
Incidence of abnormalities at end of study visit (4-10 days after last treatment period). 
x 
Shifts from baseline at end of study visit. 
 
The following summaries will be provided for a brief physical examination to be also performed, on skin, 
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Document: 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
respiratory system, cardiovascular system, and abdomen (liver and spleen): 
x 
Incidence of abnormalities pre-dose on Day 1 and 7 by treatment period. 
x 
Shifts from baseline by treatment period and timepoint. 
16.6. OTHER SAFETY ASSESSMENTS 
Inhalation training results on Day 1 pre-dose will be presented in a listing only. In addition, urine pregnancy test 
results will be listed for women of childbearing potential at Day 1 pre-dose and end of study visits. 
 
 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
17. REFERENCES  
Dobson, A. J. (2002). An introduction to generalized linear models, 2nd ed. Chapman & Hall/CRC. 
Dmitrienko, A., Bretz, F., Westfall, P. H., Troendle, J., Wiens, B. L., Tamhane, A. C., & Hsu, J. C. (2009). Multiple 
testing methodology. Multiple Testing Problems in Pharmaceutical Statistics. Chapman and Hall/CRC 
Press, New York. 
Maurer, W., Hothorn, L. A., & Lehmacher, W. (1995). Multiple Comparisons in Drug Clinical Trials and Preclinical 
Assays: A-priori ordered Hypotheses. Testing Principles in Clinical and Preclinical Trials (J. Vollmar, 
editor) STuttgart, Gustav Fisher Verlag, 3-18. 
SAS Institute, Inc. (1999). SAS Procedures Guide, version 8. Cary, NC: SAS Institute. 
 
 
 
 
 
 
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Document: 
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SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
IQVIA OUTPUT CONVENTIONS 
Outputs will be presented according to the following: 
TABLE AND LISTING OUTPUT CONVENTIONS 
General: 
• The first row in the body of the table or listing should be blank 
• The left-hand column should start in column 1. No indenting or centering of the output should occur. 
• Rounding should be done with the SAS function ROUND. 
• Numbers in tables should be rounded, not truncated. 
• Alphanumeric output should be left aligned. 
• Numbers should be decimal point aligned. 
• Whole numbers should be right aligned. 
• Text values should be left aligned. 
• The first letter of a text entry should be capitalized 
• Listings of adverse events, concomitant medications, medical histories etc. should be sorted in chronological order, 
with earliest adverse event, medication or history coming first. 
• The study drug should appear first in tables with treatments as columns 
• In general, only present totals (across treatment groups) at baseline/randomization, and do not present them post 
randomization, unless the customer specifically requests it. 
• All listing outputs should be sorted (preferably by Treatment, Site Number and Patient Number). 
• Exponentiation will be expressed using a superscript with ODS RTF. 
• All variables that are output in the CRF (which have data present) should appear in the listings, along with all 
derived data appearing in the corresponding tables 
• The width of the entire output should match the line size. 
 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 43 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
Univariate Statistics: 
• Statistics should be presented in the same order across tables (i.e., n, Mean, SD, Minimum, Median, Maximum and 
equivalently, n, GeoMean, CV, Minimum, Median, Maximum) 
• Table statistics should line up under the N part of the (N=XXX) in the table header. All decimal points should line 
up. If the minimum and maximum are output on 1 line as Minimum, Maximum then the comma should line up with 
the decimal point. 
• If the original data has N decimal places, then the summary statistics should have the following decimal places: 
Minimum and maximum: N 
Mean, median and CV%: N + 1 
SD: N + 2 
 
Frequencies and percentages (n and %): 
• Percent values should be reported inside parentheses, with 1 space between the count and the left parenthesis of the 
percentage. Parentheses should be justified to accept a maximum of 100.0 as a value and padded with blank space if 
the percent is less than 100.0. An example is given below: 
77 (100.0%) 
50 ( 64.9%) 
0 ( 0.0%) 
• Percentages will be reported to 1 decimal place, except percentages <100.0% but >99.9% will be presented as 
‘>99.9%’ (e.g., 99.99% is presented as >99.9%); and percentages < 0.1% will be presented as ‘<0.1%’ (e.g., 0.08% 
is presented as <0.1%). Rounding will be applied after the <0.1% and >99.9% rule. 
e.g. ( <0.1%) 
( 6.8%) 
(>99.9%) 
Percentages may be reported to 0 decimal places as appropriate (for example, where the denominator is relatively 
small). 
• Where counts are zero, percentages of 0.0% should appear in the output. 
 
Confidence Intervals: 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 87 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 44 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
• As a rule, confidence intervals are output to 1 place more than the raw data, and standard deviations and standard 
errors to 2 places more than the raw data 
• Confidence intervals should be justified so that parentheses displayed on consecutive lines of a table “line up”. 
• Boundary values of confidence intervals should be separated by a comma. 
• Boundary values should be padded as necessary to accept negative values and to allow alignment of the decimal 
place. 
• An example is given below: 
(-0.12, -0.10) 
( 9.54, 12.91) 
 
P-values: 
• P-values should be reported to 4 decimal places, except values <1.0000 but >0.9999 will be presented as ‘>0.9999’ 
(e.g., 0.9998 is presented as >0.9999); and values <0.0001 will be presented as ‘<0.0001’ (e.g., 0.0000 is presented 
as <0.0001). Rounding will be applied after the <0.0001 and >0.9999 rule 
 
Ratios: 
• Ratios should be reported to 1 more decimal place than the original data. 
 
Spacing: 
• There must be a minimum of 1 blank space between columns (preferably 2) 
 
Denominators: 
• If a different count other than the population count is used for a denominator (within the table) to calculate 
percentages, there should be a row in the table that identifies that number “n”. 
• Alternatively, a footnote should be included in each table with percentages to indicate the denominator for 
percentages. 
 
Missing values:  
• A “0” should be used to indicate a zero frequency. 
• A blank will be used to indicate missing data in an end-of-text table or patient listing. 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 88 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 45 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
FIGURE OUTPUT CONVENTIONS 
• Figures should be provided in RTF files generated by SAS. 
• Should contain the title or footer. 
• The image should be clear and of high quality when viewed in the Word document, and when printed. 
• In general, boxes around the figures should be used. 
DATES & TIMES 
Depending on data available, dates and times will take the form DDMMMYYY THH:MM:SS. 
SPELLING FORMAT 
English US.  
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in this order: 
 
Treatment Group 
For Tables, Graphs and Listings 
RPL554 300 g double blind 
RPL554 300g 
RPL554 1000 g double blind  
RPL554 1000g 
RPL554 3000 g double blind  
RPL554 3000g 
Placebo 
Placebo 
Non-randomized (where applicable) 
Non-randomized  
PRESENTATION OF TREATMENT SEQUENCES 
For outputs, treatment sequences will be represented as follows and in that order: 
Treatment Group 
For Tables, Graphs and Listings 
RPL554 300 mcg db/RPL554 3000 mcg db/Placebo/RPL554 1000 
mcg db 
Seq 1 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 89 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 46 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
Treatment Group 
For Tables, Graphs and Listings 
RPL554 1000 mcg db/Placebo/RPL554 3000 mcg db/RPL554 300 
mcg db 
Seq 2 
RPL554 3000 mcg db/RPL554 1000 mcg db/RPL554 300 mcg 
db/Placebo 
Seq 3 
Placebo/RPL554 300 mcg db/RPL554 1000 mcg db/RPL554 3000 
mcg db 
Seq 4 
Undefined sequence, not mentioned above 
Undefined 
Non-randomized (where applicable) 
Non-randomized  
db = double blind  
 
PRESENTATION OF VISITS 
For outputs, visits will be represented as follows and in that order, considering there will be 4 treatment periods (1 to 
4): 
Long Name (default) 
Short Name  
Screening 
Scr 
Day 1 
Day 1 
Day 7 
Day 7 
End of Study 
EOS 
Overall (where applicable) 
Overall 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
Randomized treatment group (or treatment received if it’s a safety output), first by active dose [by ascending dose 
group] and then placebo.  
Center-patient ID,  
Date (where applicable), 
For listings where non-randomized patients are included, these will appear in a category after the randomized 
treatment groups labeled ‘Non-randomized’. 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 90 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 47 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS 
START DATE 
STOP DATE 
ACTION 
Known 
Known, 
Partial or 
Missing 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
 
 
Partial, but known 
components show that it 
cannot be on or after study 
med start date 
Known, 
Partial or 
Missing 
Not TEAE 
 
 
 
Partial, could be on or after 
study med start date 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month 
if day unknown or 31st December if day and month are 
unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month 
if day unknown or 31st December if day and month are 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 91 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 48 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
START DATE 
STOP DATE 
ACTION 
unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS  
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior  
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant  
If stop date >= study med start date and start date > end of treatment, assign 
as post study  
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
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		
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 92 of 291


 
Verona Pharma 
PROTOCOL RPL554-MD-201 
 
Statistical Analysis Plan v1.0 – Part B 
Page 49 of 49 
 
 
Document: 
\\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 
SAP v1.0 – Part B 
Author: 
Jennifer Allsopp 
Version Number: 
1.0 
 
Version Date:  
13JAN2021 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
START DATE 
STOP DATE 
ACTION 
 
Partial 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown) and impute stop 
date as latest possible date (i.e. last day of month if day unknown or 31st 
December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
 
Missing 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
 
 
 
Missing 
Known 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
 
Missing 
Assign as concomitant 
 
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RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
 
 
 
 
TABLES, LISTINGS AND FIGURES SHELLS – PART A 
 
 
RPL554-MD-201 
A Phase II, Randomized Study to Assess the Pharmacokinetics, Safety and Pharmacodynamics of 
Single and Repeat Doses of RPL554 Administered by Pressurised Metered Inhaler in Patients with 
COPD 
 
 
 
 
 
AUTHOR: NICHOLAS ROUBINIS/JENNIFER ALLSOPP 
VERSION NUMBER AND DATE: V2.0, 13JAN2021 
 

 
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Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
TABLES, LISTINGS AND FIGURES SHELLS – PART A SIGNATURE PAGE 
Tables, Listings and Figures Shells V2.0 – Part A (Dated 13JAN2021) for Protocol RPL554-MD-201. 
 
Name 
Signature 
Date 
Author: 
Jennifer Allsopp  
 
 
Position: 
Senior Biostatistician 
Company: 
IQVIA  
 
Upon review of this document, the undersigned approves this version of the Tables, Listings and Figures Shells – Part A, authorizing that the content 
is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved by: 
Mark Shaw 
 
 
Position: 
Manager, Biostatistics 
Company: 
IQVIA 
 
 
Customer Representative 
 
Approved by: 
Tara Rheault 
 
 
Position: 
VP, R&D  
Company: 
Verona Pharma 
 
Approved by: 
Thomas Bengtsson 
 
 
 
Position: 
Statistical Consultant to Verona 
Company: 
StatMind 
 
 

 
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Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Modification History 
 
Unique Identifier for 
this Version 
Date of the Document 
Version 
Author 
Significant Changes from Previous Authorized Version 
1.0 
27SEP2019 
Nicholas 
Roubinis/  
Jennifer 
Allsopp 
Not Applicable – First Draft Version 
1.1 
04MAY2020 
Jennifer 
Allsopp 
1. Update figure numbering from Figure 14.2.5-14.2.8 to 14.3.1-14.3.4. 
2. Update listing numbering from Listing 16.2.2.1 to 16.2.3.1. 
3. Update lisitng numbering from Listing 16.2.3.1 to 16.2.2.1. 
4. Remove DOB from the demographic listing. 
5. Update customer representative from Brian Maurer to Nancy Herje. 
6. Update footnotes following review of Part A dose finding analysis. 
7. Add shell for F14.2.5 – requested as part of the additional dose finding outputs. 
1.2 
09DEC2020 
Jennifer 
Allsopp 
1. Update customer representative from Nancy Herje to Tara Rheault. 
2. Aded footnote to table 14.1.5.1 detailing how patients met protocol requirements of 
the reversibility test. 
3. Update title for tables 14.3.5 and 14.3.9 to clarify that the tables are displaying 
discontinuation of study rather than study medication. 
4. Added column for patients who discontinued between Part A and Part B to listing 
16.2.1.1. 
2.0 
13JAN2021 
Jennifer 
Allsopp 
Add Thomas Bengtsson as an approver for Verona. 
 
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Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
 
Table of Contents 
Tables............................................................................................................................... 7 
14.1 Demographic Data .............................................................................................................. 7 
Table 14.1.1 Patient Disposition (All Patients Enrolled in Part A) ............................................................... 7 
Table 14.1.2 Analysis Sets (All Patients Enrolled in Part A) ..................................................................... 9 
Table 14.1.3 Critical/Major/Minor Protocol Deviations (ALL Randomised Analysis Set in Part A) ................................... 10 
Table 14.1.4.1 Demographic Characteristics (All Randomized Analysis Set in Part A) .............................................. 11 
Table 14.1.4.2 Demographic Characteristics (Safety Analysis Set in Part A) ...................................................... 14 
Table 14.1.4.3 Demographic Characteristics (Full Analysis Set in Part A) ........................................................ 14 
Table 14.1.4.4 Demographic Characteristics (Pharmacokinetics Analysis Set in Part A) ............................................ 14 
Table 14.1.5.1 Screening Disease Characteristics (All Randomized Analysis Set in Part A) ........................................ 15 
Table 14.1.5.2 Screening Disease Characteristics (Safety Analysis Set in Part A) ................................................ 19 
Table 14.1.5.3 Screening Disease Characteristics (Full Analysis Set in Part A) .................................................. 19 
Table 14.1.5.4 Screening Disease Characteristics (Pharmacokinetics Analysis Set in Part A) ...................................... 20 
Table 14.1.6 COPD and Smoking History (All Randomized Analysis Set in Part A) ................................................... 21 
14.2 Efficacy ..................................................................................................................... 24 
Secondary Efficacy ................................................................................................................ 24 
Table 14.2.1 FEV1 by Treatment and Timepoint Pre- and Post- Single Dose (Full Analysis Set in Part A) ........................... 24 
Table 14.2.2 Change from Baseline FEV1 to Average FEV1 (over 4 hours) After Single Dose (Full Analysis Set in Part A) ............ 25 
Table 14.2.3 Change from Baseline FEV1 to Average FEV1 (over 12 hours) After Single Dose (Full Analysis Set in Part A) ........... 26 
Table 14.2.3a Change from Baseline FEV1 to Average FEV1 (over 12 hours) After Single Dose – Sensitivity Analysis (Full Analysis Set 
in Part A) ...................................................................................................................... 26 
Table 14.2.4 Change from Baseline FEV1 to Peak FEV1 (over 4 hours) After Single Dose (Full Analysis Set in Part A) ............... 27 
14.3 Safety ....................................................................................................................... 29 
Adverse Event ..................................................................................................................... 29 
Table 14.3.1 Treatment-emergent Adverse Events Summary (Safety Analysis Set in Part A) .......................................... 29 
Table 14.3.2 Treatment-emergent Adverse Events by System Organ Class and Preferred Term (Safety Analysis Set in Part A) ......... 31 
Table 14.3.3 Treatment-emergent Adverse Events Related to Study Medication by System Organ Class and Preferred Term (Safety 
Analysis Set in Part A) ......................................................................................................... 32 
Table 14.3.4 Treatment-emergent Adverse Events by System Organ Class, Preferred Term and Maximum Severity (Safety Analysis Set in 
Part A) ......................................................................................................................... 33 
Table 14.3.5 Treatment-emergent Adverse Events Leading to Discontinuation of Study by System Organ Class and Preferred Term (Safety 
Analysis Set in Part A) ......................................................................................................... 34 
Table 14.3.6 Serious treatment-emergent Adverse Events by System Organ Class and Preferred Term (Safety Analysis Set in Part A) . 35 
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Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.3.7 Serious treatment-emergent Adverse Events Related to Study Medication by System Organ Class and Preferred Term (Safety 
Analysis Set in Part A) ......................................................................................................... 35 
Table 14.3.8 Serious treatment-emergent Adverse Events by System Organ Class, Preferred Term and Maximum Severity (Safety Analysis 
Set in Part A) .................................................................................................................. 35 
Table 14.3.9 Serious treatment-emergent Adverse Events Leading to Discontinuation of Sutdy by System Organ Class and Preferred Term 
(Safety Analysis Set in Part A) ................................................................................................. 36 
Table 14.3.10 Treatment-emergent Adverse Events with Outcome of Death by System Organ Class and Preferred Term (Safety Analysis Set 
in Part A) ...................................................................................................................... 36 
Laboratory ........................................................................................................................ 37 
Table 14.3.11 Hematology Laboratroy Data at Screening (Safety Analysis Set in Part A) ........................................... 37 
Table 14.3.12 Biochemistry Laboratroy Data at Screening (Safety Analysis Set in Part A) ......................................... 38 
Table 14.3.13 Urinalysis Laboratroy Data at Screening (Safety Analysis Set in Part A) ........................................... 39 
Table 14.3.14 Viral Serology Laboratroy Data at Screening (Safety Analysis Set in Part A) ....................................... 40 
Table 14.3.15 Hematology Laboratroy Data at Screening – Normal Reference Ranges (Safety Analysis Set in Part A) ................. 41 
Table 14.3.16 Biochemistry Laboratroy Data at Screening – Normal Reference Ranges (Safety Analysis Set in Part A) ............... 42 
Table 14.3.17 Urinalysis Laboratroy Data at Screening – Normal Reference Ranges (Safety Analysis Set in Part A) ................. 42 
Table 14.3.18 Viral Serology Laboratroy Data at Screening – Normal Reference Ranges (Safety Analysis Set in Part A) ............. 42 
Table 14.3.19 Hematology Laboratroy Data at Screening – Markedly Abnormal Values (Safety Analysis Set in Part A) ................ 43 
ECG ............................................................................................................................... 44 
Table 14.3.20 12-Lead Electrocardiogram Data by Timepoint (Safety Analysis Set in Part A) ....................................... 44 
Table 14.3.21 12-Lead Electrocardiogram – Shifts from Pre-Dose Local Lab Assessment by Timepoint (Safety Analysis Set in Part A) 46 
Table 14.3.22 Change from Baseline Heart Rate to peak Heart Rate (over 4 hours) After Single Dose (Safety Analysis Set in Part A) 47 
Vital Signs ....................................................................................................................... 48 
Table 14.3.23 Vital Sign Data – Change from Pre- to Post- dose by Timepoint (Safety Analysis Set in Part A) ..................... 48 
Table 14.3.24 Vital Sign Data – Markedly Abnormal Values (Safety Analysis Set in Part A) ........................................ 50 
Table 14.3.25 Change from Baseline Pulse Rate to Peak Pulse Rate (over 4 hours) After Single Dose (Safety Analysis Set in Part A) 52 
Physical Examination .............................................................................................................. 53 
Table 14.3.26 Physical Examination Data by Timepoint (Safety Analysis Set in Part A) ............................................ 53 
Figures ............................................................................................................................ 54 
Figure 14.2.1 Geometric Mean of ratios of Average FEV1 (over 4 hours)to pre-dose FEV1 by Treatment (Full Analysis Set in Part A) . 54 
Figure 14.2.2 Geometric Mean of ratios of Average FEV1 (over 12 hours) to pre-dose FEV1 by Treatment (Full Analysis Set in Part A) 54 
Figure 14.2.3 Geometric Mean of ratios to Peak FEV1 (over 4 hours) to pre-dose FEV1 by Treatment (Full Analysis Set in Part A) ... 55 
Figure 14.2.4 Mean Change from pre-dose FEV1 during spirometry over Time by Treatment (Full Analysis Set in Part A) .............. 56 
Figure 14.2.5 Change from Pre-dose FEV1 over Time by Treatment by Subject (Full Analysis Set in Part A) .......................... 57 
Figure 14.3.1 Mean Change from Baseline in Heart Rate by Treatment (Safety Analysis Set in Part A) .............................. 58 
Figure 14.3.2 Mean Change from Baseline in Heart Rate over Time by Treatment (Safety Analysis Set in Part A) .................... 58 
Figure 14.3.3 Mean Change from Baseline in Pulse Rate by Treatment (Safety Analysis Set in Part A) .............................. 59 
Figure 14.3.4 Mean Change from Baseline in Pulse Rate over Time by Treatment (Safety Analysis Set in Part A) .................... 59 
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Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listings ........................................................................................................................... 60 
Listing 16.2.1.1 Completed/Discontinued Patients (All Randomized Analysis Set in Part A) ........................................ 60 
Listing 16.2.2.1 Protocol Deviations (All Randomized Analysis Set in Part A) .................................................... 61 
Listing 16.2.3.1 Patients Excluded from Analysis Sets (All Randomized Analysis Set in Part A) ................................... 62 
Listing 16.2.4.1 Demographic Characteristics (All Randomized Analysis Set in Part A) ............................................ 63 
Listing 16.2.4.2 Screening Disease Characteristics (All Randomized Analysis Set in Part A) ...................................... 64 
Listing 16.2.4.3 COPD and Smoking History (All Randomized Analysis Set in Part A) ............................................... 65 
Listing 16.2.4.4 Medical History (All Randomized Analysis Set in Part A) ........................................................ 66 
Listing 16.2.4.5 Surgical Procedure History (All Randomized Analysis Set in Part A) ............................................. 67 
Listing 16.2.4.6 Prior and Concomitant Medications (All Randomized Analysis Set in Part A) ...................................... 68 
Listing 16.2.5.1 Drug Exposure and Accountability (All Randomized Analysis Set in Part A) ....................................... 69 
Listing 16.2.6.1 Spirometry: FEV1 Results (Full Analysis Set in Part A) ......................................................... 70 
Listing 16.2.6.2 Spirometry: FEV1 Derived Measurements (Full Analysis Set in Part A) ............................................ 71 
Listing 16.2.6.3 Rescue Medications Taken at Site (All Randomized Analysis Set in Part A) ....................................... 72 
Listing 16.2.6.4 Rescue Medication Taken between Visits (All Randomized Analysis Set in Part A) ................................. 73 
Listing 16.2.7.1 All Adverse Events (Safety Analysis Set in Part A) ............................................................. 74 
Listing 16.2.7.2 Treatment-emergent Adverse Events Leading to Study Discontinuation (Safety Analysis Set in Part A) ............. 75 
Listing 16.2.7.3 Treatment-emergent Adverce Events Leading to Death (Safety Analysis Set in Part A) ............................. 75 
Listing 16.2.7.4 Serious Treatment-emergent Adverse Events (Safety Analysis Set in Part A) ...................................... 75 
Listing 16.2.7.5 Serious Treatment-emergent Adverse Events - Details (Safety Analysis Set in Part A) ............................ 76 
Listing 16.2.8.1 Hematology (Safety Analysis Set in Part A) ..................................................................... 78 
Listing 16.2.8.2 Biochemistry (Safety Analysis Set in Part A) ................................................................... 78 
Listing 16.2.8.3 Urinalysis (Safety Analysis Set in Part A) ..................................................................... 79 
Listing 16.2.8.4 Viral Serology (Safety Analysis Set in Part A) ................................................................. 79 
Listing 16.2.9.1 Electrocardiogram Local Reading Overall Evaluation (Safety Analysis Set in Part A) ............................. 80 
Listing 16.2.9.2 12-Lead ECG (Safety Analysis Set in Part A) .................................................................... 81 
Listing 16.2.9.3 Vital Signs (Safety Analysis Set in Part A) .................................................................... 82 
Listing 16.2.9.4 Derived Safety Measurements (Safety Analysis Set in Part A) .................................................... 83 
Listing 16.2.9.5 Brief Physical Examination (Safety Analysis Set in Part A) ..................................................... 84 
Listing 16.2.9.6 Full Physical Examination (Safety Analysis Set in Part A) ...................................................... 85 
Listing 16.2.9.7 Chest X-ray (All Randomized Analysis Set in Part A) ............................................................ 86 
Listing 16.2.9.8 Inhalation Training (All Randomized Analysis Set in Part A) .................................................... 87 
Listing 16.2.9.9 Pregnancy Serum and Urine Test at Screening (All Randomized Analysis Set in Part A) ............................ 88 
Listing 16.2.9.10 Pregnancy Report at Screening (All Randomized Analysis Set in Part A) ......................................... 89 
 
 
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Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Tables 
14.1 Demographic Data 
Table 14.1.1 Patient Disposition (All Patients Enrolled in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.1.1  
Patient Disposition  
(All Patients Enrolled in Part A) 
  
RPL554 
100g 
RPL554 
300g 
RPL554 
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
Overall 
Description, n (%) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
  
Number of patients enrolled 
xx 
Screen failures 
xx 
Number of patients randomized 
xx (100.0) 
xx (100.0) 
xx (100.0) 
xx (100.0) 
xx (100.0) 
xx (100.0) 
xx (100.0) 
Number of patients treated 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Number of patients who completed  
Part A 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Number of patients who discontinued  
Part A 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Number of patients who discontinued between 
Part A and Part B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary reason for early study  
discontinuation  
 
 
 
 
 
 
 
  Adverse event 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Death 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Lost to follow-up 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Pregnancy 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Protocol violation 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Physician decision 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Study terminated by sponsor 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Withdrawal by patient 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Other 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
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Verona Pharma plc
CONFIDENTIAL
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Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
 
 

 
  
  
  
  
  
  
  
  
n = number of patients. N = Number of patients randomized. % = percentage of patients calculated relative to the total number of 
patients in the All Randomized Analysis Set. Percentage for early discontinuation reasons is calculated based on the number of 
patients who had early discontinuation data. 
 
Source: Listing 16.2.1.1 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
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Verona Pharma plc
CONFIDENTIAL
Page 101 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.1.2 Analysis Sets (All Patients Enrolled in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.1.2  
Analysis Sets  
(All Patients Enrolled in Part A) 
  
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
Overall 
Analysis Set, n (%) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
  
All Enrolled Analysis Set 
xx  
xx  
xx  
xx  
xx  
xx  
xx  
All Randomized Analysis Set 
xx (100.0) 
xx (100.0) 
xx (100.0) 
xx (100.0) 
xx (100.0) 
xx (100.0) 
xx (100.0) 
Safety Analysis Set 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Full Analysis Set 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Pharmacokinetics Analysis 
Set 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 NA 
xx (xx.x) 
  
  
  
  
  
  
  
  
FEV1: Forced expiratory volume in one second. NA: Not applicable. n = number of patients. N = number of patients randomized. % = 
percentage of patients calculated relative to the total number of patients in All Randomized Analysis Set. All Enrolled Analysis Set: 
All patients enrolled. All Randomized Analysis Set: All patients enrolled who are randomized. Safety Analysis Set: Randomized patients 
who received the single dose of study medication. Full Analysis Set: Patients included in the Safety Analysis Set with sufficient data 
to compute the pharmacodynamic parameters (FEV1 measurement pre-dose and at least one post-dose). Pharmacokinetics Analysis Set: 
Patients included in the All Randomized Analysis Set who have a blood sampling performed after at least one dose of study medication 
and pharmacokinetic parameter data. 
 
Source: Listing 16.2.2.1 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
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RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 102 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.1.3 Critical/Major/Minor Protocol Deviations (ALL Randomised Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.1.3  
Critical/Major/Minor Protocol Deviations  
(All Randomized Analysis Set in Part A)  
Severity/ 
RPL554  
100g 
RPL554  
300g 
RPL554 
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
Overall 
  Deviation type 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
Patients with at least one 
critical/major/minor  
protocol deviation, n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Critical 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Type 1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Type 2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  … 
 
 
 
 
 
 
 
Major 
 
 
 
 
 
 
 
  …  
  
  
  
  
  
  
  
CTMS: Clinical trial management system. n = number of patients. N = Number of patients in the analysis set. % = percentage of patients 
calculated relative to the total number of patients in the analysis set. Protocol deviations were obtained from CTMS. 
 
Source: Listing 16.2.3.1 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes: 
Deviation types are sorted in descending order of frequency of the Overall column. A patient may have multiple critical/major/minor 
protocol deviations within and is counted once at each level of summarization.   
 
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CONFIDENTIAL
Page 103 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.1.4.1 Demographic Characteristics (All Randomized Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.1.4.1  
Demographic Characteristics  
(All Randomized Analysis Set in Part A)  
Variable/ 
RPL554  
100g 
RPL554  
300g 
RPL554 1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
Overall 
  Category 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
 
Age (years) 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
Sex, n (%) 
  Male 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Female 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
Childbearing potential, n (%) * 
 
 
 
 
 
 
 
  Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
Primary race, n (%) 
 
 
 
 
 
 
 
  American Indian or Alaska 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Native Asian 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Black or African American 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Native Hawaiian or Other 
Pacific 
  Islander 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  White 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
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Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 104 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.1.4.1  
Demographic Characteristics  
(All Randomized Analysis Set in Part A)  
Variable/ 
RPL554  
100g 
RPL554  
300g 
RPL554 1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
Overall 
  Category 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
 
  Other 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
Ethnicity, n (%) 
 
 
 
 
 
 
 
  Hispanic or Latino 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  African American/African  
  Heritage 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Asian-Central/South Asian  
  Heritage 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Asian-East Asian Heritage 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Asian-Southeast Asian Heritage 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  White-White/Caucasian/European 
  Heritage 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Not reported 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
Weight (kg) 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height (cm) 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
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Clinical Study Report
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Version 1.0; 17 May 2021
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CONFIDENTIAL
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Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.1.4.1  
Demographic Characteristics  
(All Randomized Analysis Set in Part A)  
Variable/ 
RPL554  
100g 
RPL554  
300g 
RPL554 1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
Overall 
  Category 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
BMI (kg/m2) 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
  
  
  
  
  
  
  
  
BMI: Body Mass Index. SD: Standard deviation. n = number of patients. N = Number of patients in the analysis set. % = percentage of 
patients calculated relative to the total number of patients in the analysis set. * % = Percentage for childbearing potential 
calculated relative to the total number of female patients in the analysis set. Age (years) = As calculated relative to informed 
consent date. BMI (kg/m2) = weight (kg)/ height (m)2. 
 
Source: Listing 16.2.4.1 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes: 
Print all statistics and categories even if they are empty, except for the row of missings which will only be shown if 
present and is not shown in the shell here. 
 
 
 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 106 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.1.4.2 Demographic Characteristics (Safety Analysis Set in Part A) 
DM002: This output uses shell DM001 [Table 14.1.4.1]  
 
Programming Notes: 
Print if the number of patients in the SAF analysis set is different to the RND analysis set. 
 
 
 
 
 
Table 14.1.4.3 Demographic Characteristics (Full Analysis Set in Part A) 
DM003: This output uses shell DM001 [Table 14.1.4.1]  
 
Programming Notes: 
Print if the number of patients in the SAF analysis set is different to the RND analysis set. 
 
 
 
 
 
Table 14.1.4.4 Demographic Characteristics (Pharmacokinetics Analysis Set in Part A) 
DM004: This output uses shell DM001 [Table 14.1.4.1]  
 
Programming Notes: 
Print if the number of patients in the SAF analysis set is different to the RND analysis set. 
Do not present Placebo treatment group as Placebo is not included for Pharmacokinetics analysis set. 
 
 
 

 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 107 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.1.5.1 Screening Disease Characteristics (All Randomized Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.1.5.1  
Screening Disease Characteristics  
(All Randomized Analysis Set in Part A)  
Variable/ 
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
Overall 
  Statistics 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
  
Pre-bronchodilator FEV1 
(L) 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
Pre-bronchodilator FEV1 
(% of predicted normal) 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
Post-bronchodilator FEV1 
(L) 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 108 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.1.5.1  
Screening Disease Characteristics  
(All Randomized Analysis Set in Part A)  
Variable/ 
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
Overall 
  Statistics 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
Post-bronchodilator FEV1 
(% of predicted normal) 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
FEV1 reversibility (mL) 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
FEV1 reversibility (%) 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 109 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.1.5.1  
Screening Disease Characteristics  
(All Randomized Analysis Set in Part A)  
Variable/ 
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
Overall 
  Statistics 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
  
Pre-bronchodilator FVC 
(L) 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
Post-bronchodilator FVC 
(L) 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
Pre-bronchodilator 
FEV1/FVC 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
Post-bronchodilator 
FEV1/FVC 
 
 
 
 
 
 
 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 110 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.1.5.1  
Screening Disease Characteristics  
(All Randomized Analysis Set in Part A)  
Variable/ 
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
Overall 
  Statistics 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
  
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
Reversibility assessment 
performed with four 
puffs of albuterol, n 
(%) 
 
 
 
 
 
 
 
  Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
Met protocol 
requirements of 
reversibility test [a], 
n (%) 
 
 
 
 
 
 
 
  Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  No  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  
  
  
  
  
  
  
  
FEV1: Forced expired volume in 1 second. FVC: Forced vital capacity. SD: Standard deviation. n = number of patients. N = Number of 
patients in the analysis set. % = percentage of patients calculated relative to the total number of patients in the analysis set. Pre-
, post-bronchodilator and reversibility values are the results of the screening reversibility test. 
[a] Patients meet the protocol requirements of the reversibility test by demonstatating >=150 mL increase from pre-bronchodilator FEV1. 
 
Source: Listing 16.2.4.2 
 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 111 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.1.5.1  
Screening Disease Characteristics  
(All Randomized Analysis Set in Part A)  
Variable/ 
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
Overall 
  Statistics 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
 
 
Table 14.1.5.2 Screening Disease Characteristics (Safety Analysis Set in Part A) 
DM006: This output uses shell DM005 [Table 14.1.5.1]  
 
Programming Notes: 
Print if the number of patients in the SAF analysis set is different to the RND analysis set. 
 
 
 
 
 
 
Table 14.1.5.3 Screening Disease Characteristics (Full Analysis Set in Part A) 
DM007: This output uses shell DM005 [Table 14.1.5.1]  
 
Programming Notes: 
Print if the number of patients in the SAF analysis set is different to the RND analysis set. 
 
 
 
 
 
 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 112 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
 
Table 14.1.5.4 Screening Disease Characteristics (Pharmacokinetics Analysis Set in Part A) 
DM008: This output uses shell DM005 [Table 14.1.5.1]  
 
Programming Notes: 
Print if the number of patients in the SAF analysis set is different to the RND analysis set. 
Do not present Placebo treatment group as Placebo is not included for Pharmacokinetics analysis set. 
 
 
 

 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 113 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.1.6 COPD and Smoking History (All Randomized Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.1.6  
COPD and Smoking History  
(All Randomized Analysis Set in Part A)  
Variable/ 
RPL554  
100g 
RPL554  
300g 
RPL554 1000g 
RPL554 3000g 
RPL554 6000g 
Placebo 
Overall 
  Category 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
 
Duration of COPD 
(years) (time since 
diagnosis) 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
Patient known to have 
Chronic Bronchitis, n 
(%)  
 
 
 
 
 
 
 
  Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Patient known to have 
Emphysema, n (%)*  
 
 
 
 
 
 
 
  Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
Smoking status, n (%) 
 
 
 
 
 
 
 
  Current Smokers 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Ex-smokers 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Number of packs per 
day 
 
 
 
 
 
 
 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 114 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.1.6  
COPD and Smoking History  
(All Randomized Analysis Set in Part A)  
Variable/ 
RPL554  
100g 
RPL554  
300g 
RPL554 1000g 
RPL554 3000g 
RPL554 6000g 
Placebo 
Overall 
  Category 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
  SD 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
xx.xxxx 
  Median 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
  Min, Max 
xx.xx, xx.xx 
xx.xx, xx.xx 
xx.xx, xx.xx 
xx.xx, xx.xx 
xx.xx, xx.xx 
xx.xx, xx.xx 
xx.xx, xx.xx 
 
Number of years 
smoking 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  SD 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
  Median 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Min, Max 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
Smoking exposure 
(pack-years) 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
  
  
  
  
  
  
  
  
COPD: Chronic obstructive pulmonary disease. SD: Standard deviation. n = number of patients. N = Number of patients in the analysis 
set. % = percentage of patients calculated relative to the total number of patients in the analysis set. Number of packs per day = 
average consumption during their smoking duration. Smoking exposure (pack-years) = number of packs per day x number of years smoking, 
for patients with a smoking history or a current smoker. Duration of COPD (years) (time since diagnosis) = Randomization date – first 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 115 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.1.6  
COPD and Smoking History  
(All Randomized Analysis Set in Part A)  
Variable/ 
RPL554  
100g 
RPL554  
300g 
RPL554 1000g 
RPL554 3000g 
RPL554 6000g 
Placebo 
Overall 
  Category 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
 
COPD diagnosis date. * Patients known to have emphysema will potentially overlap with patients known to have chronic bronchitis.   
 
Source: Listing 16.2.4.3 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 116 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
14.2 Efficacy 
Secondary Efficacy 
Table 14.2.1 FEV1 by Treatment and Timepoint Pre- and Post- Single Dose (Full Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.2.1  
FEV1 by Treatment and Timepoint Pre- and Post- Single Dose  
(Full Analysis Set in Part A) 
  
  
  
  
  
  
  
Statistics 
  
  
Timepoint 
Treatment group 
Category 
n 
Mean 
SD 
Minimum 
Median 
Maximum 
 
1-hour pre-
dose 
RPL554 100g (N=xx) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
RPL554 300g (N=xx) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
RPL554 1000g (N=xx) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
RPL554 3000ђg (N=xx) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
RPL554 6000ђg (N=xx) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
Placebo (N=xx) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
Immediately 
pre-dose 
RPL554 100g (N=xx) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
… 
… 
… 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
5 minutes 
post-dose 
RPL554 100g (N=xx) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
Pre-dose 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
Change from  
Pre-dose 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
… 
…  
… 
 … 
… 
… 
…  
…  
…  
SD: Standard deviation. FEV1: Forced expired volume in 1 second. n = Number of patients who have an assessment available pre-dose and 
the relevant post-dose assessment timepoint (Pre-dose and Change from Pre-dose). N = Number of patients in the analysis set. Pre-dose 
FEV1 is defined as the average of the FEV1 pre-dose assessments collected on Day 1 (within 60 and 5 minutes). Change from Pre-dose: 
Post-dose assessment – Pre-dose. 
 
Source: Listing 16.2.6.1 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
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	
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 117 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.2.1  
FEV1 by Treatment and Timepoint Pre- and Post- Single Dose  
(Full Analysis Set in Part A) 
  
  
  
  
  
  
  
Statistics 
  
  
Timepoint 
Treatment group 
Category 
n 
Mean 
SD 
Minimum 
Median 
Maximum 
 
Programming Notes: 
Display for the following days and timepoints, relative to dosing: 1 hour pre-dose and immediately pre-dose, 5 (± 2), 15 (± 5) and 30 
minutes (± 10) and 1, 1.5, 2, 4, 8, 11 and 12 hours (the latter assessments all ± 15 minutes). 
 
 
 
 
Table 14.2.2 Change from Baseline FEV1 to Average FEV1 (over 4 hours) After Single Dose (Full Analysis Set in Part A) 
EFF006: This output uses shell EFF004 [Table 14.2.4] 
ANCOVA: Analysis of covariance. CFB: Change from Baseline. CI: Confidence interval. FEV1: Forced expiratory volume in 1 second. 
GeoMean: Geometric mean. GeoMean Ratio: Geometric mean ratio to baseline. SD: Standard deviation. N = Number of patients in the 
analysis set. Baseline: average of the FEV1 pre-dose assessments collected on Day 1 (within 60 and 5 minutes). Change from Baseline: 
Ratio of (Post-dose assessment – Pre-dose), as each assessment will be log-transformed prior to analysis. [a] number of patients with 
valid values at baseline and timepoints. [b] ANCOVA model is used to model the change from baseline using baseline FEV1 as a continuous 
fixed effect and planned treatment as categorical fixed effects. [c] number of patients with at least one on treatment value who 
contributed to the model estimation. * Indicates a significant p-value (<0.05). 
 
Source: Listing 16.2.6.2 
Programming Notes 
Replace footnotes in original shell with those listed above 
 
 
 
 
 
 
 
 
 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 118 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
 
Table 14.2.3 Change from Baseline FEV1 to Average FEV1 (over 12 hours) After Single Dose (Full Analysis Set in Part A) 
EFF007: This output uses shell EFF004 [Table 14.2.4] 
ANCOVA: Analysis of covariance. CFB: Change from Baseline. CI: Confidence interval. FEV1: Forced expiratory volume in 1 second. 
GeoMean: Geometric mean. GeoMean Ratio: Geometric mean ratio to baseline. SD: Standard deviation. N = Number of patients in the 
analysis set. Baseline: average of the FEV1 pre-dose assessments collected on Day 1 (within 60 and 5 minutes). Change from Baseline: 
Ratio of (Post-dose assessment – Pre-dose), as each assessment will be log-transformed prior to analysis. [a] number of patients with 
valid values at baseline and timepoints. [b] ANCOVA model is used to model the change from baseline using baseline FEV1 as a continuous 
fixed effect and planned treatment as categorical fixed effects. [c] number of patients with at least one on treatment value who 
contributed to the model estimation. * Indicates a significant p-value (<0.05). 
 
Source: Listing 16.2.6.2 
Programming Notes 
Replace footnotes in original shell with those listed above 
 
 
 
 
 
 
Table 14.2.3a Change from Baseline FEV1 to Average FEV1 (over 12 hours) After Single Dose – Sensitivity Analysis (Full Analysis Set in 
Part A) 
 

 
EFF007: This output uses shell EFF004 [Table 14.2.4] 
ANCOVA: Analysis of covariance. CFB: Change from Baseline. CI: Confidence interval. FEV1: Forced expiratory volume in 1 second. 
GeoMean: Geometric mean. GeoMean Ratio: Geometric mean ratio to baseline. SD: Standard deviation. N = Number of patients in the 
analysis set. Baseline: average of the FEV1 pre-dose assessments collected on Day 1 (within 60 and 5 minutes). Change from Baseline: 
Ratio of (Post-dose assessment – Pre-dose), as each assessment will be log-transformed prior to analysis. [a] number of patients with 
valid values at baseline and timepoints. [b] ANCOVA model is used to model the change from baseline using baseline FEV1 as a continuous 
fixed effect and planned treatment as categorical fixed effects. [c] number of patients with at least one on treatment value who 
contributed to the model estimation. * Indicates a significant p-value (<0.05). 
 
Source: Listing 16.2.6.2 
 
Programming Notes 
Replace footnotes in original shell with those listed above 
Only include if at least 1 subject has taken rescue medication less than 6 hours prior to spirometry (ANL02FL=”Y”) 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 119 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.2.4 Change from Baseline FEV1 to Peak FEV1 (over 4 hours) After Single Dose (Full Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.2.4  
Change from Baseline FEV1 to Peak FEV1 (over 4 hours) After Single Dose  
(Full Analysis Set in Part A) 
  
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
  
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
Baseline FEV1 (L) 
 
 
 
 
 
 
  n [a] 
xx 
xx 
Xx 
xx 
xx 
xx 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
Peak FEV1 (L) 
 
 
 
 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
CFB FEV1  
 
 
 
 
 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
Estimates from ANCOVA [b] 
 
 
 
 
 
 
    n [c] 
Xx 
xx 
xx 
xx 
xx 
xx 
    GeoMean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    95% CI for GeoMean  
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
 
 
 
 
 
 
  Comparisons Against Placebo 
 
 
 
 
 
 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 120 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.2.4  
Change from Baseline FEV1 to Peak FEV1 (over 4 hours) After Single Dose  
(Full Analysis Set in Part A) 
  
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
  
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
    Treatment Effect - ANCOVA 
 
 
 
 
 
 
    GeoMean Ratio 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
    95% CI for GeoMean Ratio 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
    p-value 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxxx 
 
 
 
 
 
 
 
 
  Comparisons Against RPL554 doses 
 
 
 
 
 
 
    Treatment Effect - ANCOVA 
 
Comparison 
Against 
RPL554 100g 
Comparison 
Against 
RPL554 300g 
Comparison 
Against  
RPL554 1000g 
Comparison 
Against  
RPL554 3000ђg 
 
    GeoMean Ratio 
 
xx.x 
xx.x 
xx.x 
xx.x 
 
    95% CI for GeoMean Ratio 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
    p-value 
 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxxx 
 
  
  
  
  
  
  
  
ANCOVA: Analysis of covariance. CFB: Change from Baseline. CI: Confidence interval. FEV1: Forced expiratory volume in 1 second. 
GeoMean: Geometric mean. GeoMean Ratio: Geometric mean ratio to baseline. SD: Standard deviation. N = Number of patients in the 
analysis set. Baseline: average of the FEV1 pre-dose assessments collected on Day 1 (within 60 and 5 minutes). Change from Baseline: 
Ratio of (Post-dose assessment – Pre-dose), as each assessment will be log-transformed prior to analysis. [a] number of patients with 
valid values at baseline and timepoints. [b] ANCOVA model is used to model the change from baseline using baseline FEV1 as a continuous 
fixed effect and planned treatment as categorical fixed effects. [c] number of patients with at least one on treatment value who 
contributed to the model estimation. * Indicates a significant p-value (<0.05). 
 
Source: Listing 16.2.6.2 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 121 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
14.3 Safety 
Adverse Event 
Table 14.3.1 Treatment-emergent Adverse Events Summary (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.3.1  
Treatment-emergent Adverse Events Summary  
(Safety Analysis Set in Part A)  
  
RPL554 
RPL554 
RPL554 
RPL554 
RPL554 
  
  
 
100g 
300g 
1000g 
3000g 
6000g 
Placebo 
Overall 
Variable/ 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
  Category 
n (%) E 
n (%) E 
n (%) E 
n (%) E 
n (%) E 
n (%) E 
n (%) E 
  
  
  
  
  
  
  
  
Any TEAE 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
Any TEAE related to 
study medication 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
Any TEAE leading to 
studydiscontinuation 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
Any TEAEs classified by 
maximum severity  
  Severe 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
  Moderate 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
  Mild 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
Any serious TEAE 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
Any serious TEAE related 
to study medication 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
Any serious TEAE leading 
to studydiscontinuation 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
Any serious TEAEs 
classified by maximum 
severity  
  Severe 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
  Moderate 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
  Mild 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 122 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.3.1  
Treatment-emergent Adverse Events Summary  
(Safety Analysis Set in Part A)  
  
RPL554 
RPL554 
RPL554 
RPL554 
RPL554 
  
  
 
100g 
300g 
1000g 
3000g 
6000g 
Placebo 
Overall 
Variable/ 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
N=xx 
  Category 
n (%) E 
n (%) E 
n (%) E 
n (%) E 
n (%) E 
n (%) E 
n (%) E 
  
  
  
  
  
  
  
  
Any TEAE leading to 
death 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
  
  
  
  
  
  
  
  
TEAE: Treatment-emergent adverse event. n = Number of patients with at least one TEAE in each category. E = Number of mentions 
(events) in each category. N = Number of patients in the analysis set. % = percentage of patients calculated relative to the total 
number of patients in the analysis set. TEAE = All AEs that started or worsened in severity on or after the single dose of study 
medication, based on the investigator assessment of severity. TEAEs with a missing relationship to study medication were regarded as 
related to study medication. TEAEs starting after the single dose of study medication with a missing severity were classified as 
severe. 
 
Source: Listing 16.2.7.1 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 

 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 123 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.3.2 Treatment-emergent Adverse Events by System Organ Class and Preferred Term (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.3.2  
Treatment-emergent Adverse Events by System Organ Class and Preferred Term  
(Safety Analysis Set in Part A)  
System Organ Class 
RPL554  
100g 
RPL554  
300g 
RPL554 1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
  Preferred Term [a] 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
Patients with at least one TEAE 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
 
 
 
 
 
 
  System Organ Class #1 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
    Preferred Term #1 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
    Preferred Term #2 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
  System Organ Class #2 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
    Preferred Term #1 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
    Preferred Term #2 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
… 
 
 
 
 
 
 
PT: Preferred term. SOC: System organ class. TEAE: Treatment-emergent adverse event. n = number of patients with at least one TEAE in 
each category. E = Number of mentions (events) in each category. N = Number of patients in the analysis set. % = percentage of 
patients calculated relative to the total number of patients in the analysis set. TEAE = All AEs that started or worsened in severity 
on or after the first dose of study medication, based on the investigator assessment of severity. Each patient is counted once for 
each applicable specific AE, and a patient with multiple AEs within a SOC is counted once for that SOC. [a] SOCs and PTs are coded 
using the MedDRA (Version 21.0). 
 
Source: Listing 16.2.7.1 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
Programming Notes: 
SOCs and PTs within each SOC are sorted in descending order of percentage in the highest dose-level group. 
 
 
 
 
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	
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 124 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.3.3 Treatment-emergent Adverse Events Related to Study Medication by System Organ Class and Preferred Term (Safety Analysis 
Set in Part A) 
AE003: This output uses shell AE002 [Table 14.3.2] 
PT: Preferred term. SOC: System organ class. TEAE: Treatment-emergent adverse event related to study medication. n = number of 
patients with at least one related TEAE in each category. E = Number of mentions (events) in each category. N = Number of patients in 
the analysis set. % = percentage of patients calculated relative to the total number of patients in the analysis set. TEAE = All AEs 
that started or worsened in severity on or after the first dose of study medication, based on the investigator assessment of related 
or not. Each patient is counted once for each applicable specific AE, and a patient with multiple AEs within a SOC is counted once for 
that SOC. [a] SOCs and PTs are coded using the MedDRA (Version 21.0).  
 
Source: Listing 16.2.7.1 
 
Programming Notes: 
Replace footnotes in original shell with those listed above 
 
 

 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 125 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.3.4 Treatment-emergent Adverse Events by System Organ Class, Preferred Term and Maximum Severity (Safety Analysis Set in Part 
A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.3.4  
Treatment-emergent Adverse Events by System Organ Class, Preferred Term and Maximum Severity  
(Safety Analysis Set in Part A)  
System Organ Class (%) 
Maximum 
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
  Preferred Term, n (%) [a] 
Severity 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
  
Patients with at least  
one TEAE, n (%) 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
System Organ Class #1 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Preferred Term #1 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Preferred Term #2 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
System Organ Class #1 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
… 
… 
… 
… 
… 
… 
… 
… 
PT: Preferred term. SOC: System organ class. TEAE: Treatment-emergent adverse event. n = number of patients with at least one TEAE in 
each category. N = Number of patients in the analysis set. % = percentage of patients calculated relative to the total number of 
patients in the analysis set. TEAE = All AEs that started or worsened in severity on or after the first dose of study medication, 
based on the investigator assessment of severity. Each patient is counted once for each applicable specific TEAE at the maximum 
severity and a patient with multiple TEAEs within a SOC is counted once for that SOC at the maximum severity. [a] SOCs and PTs are 
coded using MedDRA (Version 21.0). SOCs and PTs within each SOC are sorted in descending order of percentage of severe AEs (then 

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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 126 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.3.4  
Treatment-emergent Adverse Events by System Organ Class, Preferred Term and Maximum Severity 
(Safety Analysis Set in Part A)  
System Organ Class (%) 
Maximum 
RPL554  
100g
RPL554  
300g
RPL554  
1000g
RPL554  
3000g
RPL554  
6000g
Placebo 
  Preferred Term, n (%) [a] 
Severity 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
moderate and mild AEs). TEAEs starting after the first dose of study medication with a missing severity will be classified as severe. 
Source: Listing 16.2.7.1 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
Table 14.3.5 Treatment-emergent Adverse Events Leading to Discontinuation of Study by System Organ Class and Preferred Term (Safety 
Analysis Set in Part A) 
AE005: This output uses shell AE004 [Table 14.3.2] 
Programming Notes 
Use the same template of table 14.3.2, selecting only the TEAEs leading to discontinuation of study and update “Any TEAE” to “Any TEAE 
leading to discontinuation of study”.  
Update source footnote to “Source: Listing 16.2.7.2”. 

	
	
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 127 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.3.6 Serious treatment-emergent Adverse Events by System Organ Class and Preferred Term (Safety Analysis Set in Part A) 
AE006: This output uses shell AE002 [Table 14.3.2] 
 
Programming Notes 
Replace footnotes in original shell updating “Patients with at least one TEAE” to “Patients with at least one serious TEAE”. 
Update source footnote to “Source: Listing 16.2.7.4”. 
 
 
 
 
 
Table 14.3.7 Serious treatment-emergent Adverse Events Related to Study Medication by System Organ Class and Preferred Term (Safety 
Analysis Set in Part A) 
AE007: This output uses shell AE003 [Table 14.3.3] 
 
Programming Notes 
Use the same template of Table 14.3.3, selecting only the serious TEAEs and update “Patients with at least one TEAE” to “Patients with 
at least one serious TEAE”. 
Update source footnote to “Source: Listing 16.2.7.4”. 
 
 
 
 
 
Table 14.3.8 Serious treatment-emergent Adverse Events by System Organ Class, Preferred Term and Maximum Severity (Safety Analysis Set 
in Part A) 
AE008: This output uses shell AE004 [Table 14.3.4] 
 
Programming Notes 
Use the same template of Table 14.3.4, selecting only the serious TEAEs and update “Patients with at least one TEAE” to “Patients with 
at least one serious TEAE”. 
Update source footnote to “Source: Listing 16.2.7.4”. 
 
 
 
 
 

	
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
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 128 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.3.9 Serious treatment-emergent Adverse Events Leading to Discontinuation of Sutdy by System Organ Class and Preferred Term 
(Safety Analysis Set in Part A) 
AE009: This output uses shell AE005 [Table 14.3.5] 
 
Programming Notes 
Use the same template of Table 14.3.5, selecting only the serious TEAEs and update “Any TEAE leading to discontinuation of study” to 
“Any serious TEAE leading to discontinuation of study”. 
Update source footnote to “Source: Listing 16.2.7.4”. 
 
 
 
 
 
Table 14.3.10 Treatment-emergent Adverse Events with Outcome of Death by System Organ Class and Preferred Term (Safety Analysis Set in 
Part A) 
AE010: This output uses shell AE002 [Table 14.3.2] 
 
Programming Notes 
Replace footnotes in original shell updating “Patients with at least one TEAE” to “Patients with a TEAE with outcome of death”. 
Update source footnote to “Source: Listing 16.2.7.3”. 
 
 
 
 
 
 
 
 
 
 
 
 
 

	
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 129 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Laboratory 
Table 14.3.11 Hematology Laboratroy Data at Screening (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.3.11  
Hematology Laboratory Data at Screening  
(Safety Analysis Set in Part A) 
Laboratory Test (unit) 
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
  Statistics 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
Test #1 (unit) 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
Test #2 (unit) 
… 
… 
… 
… 
… 
… 
  
  
  
  
  
  
  
SD: Standard deviation. n = Number of patients with a screening value. N = Number of patients in the analysis set.  
 
Source: Listing 16.2.8.1 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes: 
At Screening, blood samples will be taken and tested at the laboratory for the following hematology laboratory tests: Hemoglobin, 
hematocrit, total white cell count, leukocyte differential count and platelet count. Present in alphabetical order. 
 
 
 
 
 
 
 
 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 130 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
 
Table 14.3.12 Biochemistry Laboratroy Data at Screening (Safety Analysis Set in Part A) 
LB002: This output uses shell LB001 [Table 14.3.11] 
 
Programming Notes 
Repeat 14.3.11 for Biochemistry (includes creatinine, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine 
transaminase, gamma-glutamyl transferase, lactate dehydrogenase, creatine kinase, thyroid stimulating hormone, triiodothyronine and 
thyroxine, glucose, potassium, sodium, and calcium. Present in alphabetical order. 
Update source footnote to “Source: Listing 16.2.8.2”. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 131 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.3.13 Urinalysis Laboratroy Data at Screening (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.3.13  
Urinalysis Laboratory Data at Screening  
(Safety Analysis Set in Part A) 
Laboratory Test 
(unit) 
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
  Category 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
Test #1 (unit) 
 
 
 
 
 
 
  Negative 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Trace 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  1+ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  2+ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  3+ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  4+ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Total 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Test #2 (unit) 
… 
… 
… 
… 
… 
… 
  
  
  
  
  
  
  
n = Number of patients with a Screening value. N = Number of patients in the analysis set. % = Percentage of patients in each category 
relative to the total number of patients in the analysis set, with assessments at Screening. 
 
Source: Listing 16.2.8.3 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes: 
At Screening, samples will be taken and tested at the laboratory for the following Urinalyis laboratory tests: Leukocytes esterase, 
blood, ketones, bilirubin, urobilinogen, protein and glucose. If urinalysis on Dipstick is positive for leucocytes and/or 
blood/hemoglobin, a microscopic examination including erythrocytes, leucocytes, bacteria, casts, epithelial cells and crystals). 
Present in alphabetical order. 
 

 
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	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 132 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.3.14 Viral Serology Laboratroy Data at Screening (Safety Analysis Set in Part A) 
LB008: This output uses shell LB001 [Table 14.3.11] 
 
Programming Notes 
Repeat 14.3.13 for Viral Serology (includes [to confirm post-menopausal status where appropriate] follicle-stimulating hormone 
[FSH]).. Present in alphabetical order.  
 
Update source footnote to “Source: Listing 16.2.8.4”. 
 
 

 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 133 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.3.15 Hematology Laboratroy Data at Screening – Normal Reference Ranges (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.3.15  
Hematology Laboratory Data at Screening - Normal Reference Ranges  
(Safety Analysis Set in Part A)  
Laboratory Test/ 
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
  Reference Range 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
 
Test #1 (unit) 
 
 
 
 
 
 
  Low 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  High 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Total 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Test #2 (unit) 
… 
… 
… 
… 
… 
… 
  
  
  
  
  
  
  
LLN: Lower limit of normal. ULN: Upper limit of normal reference range. n = Number of patients with a Screening value. N = Number of 
patients in the analysis set. % = Percentage of patients in each category relative to the total number of patients in the analysis 
set, with assessments at Screening. Reference range classification: Low: < LLN. Normal: >= LLN to <= ULN. High: > ULN. 
 
Source: Listing 16.2.8.1 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes: 
At Screening, blood samples will be taken and tested at the laboratory for the following laboratory tests: Hemoglobin, hematocrit, 
total white cell count, leukocyte differential count and platelet count. Present in alphabetical order. 
 
 
 
 
 
 
 
 
 
 
 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 134 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.3.16 Biochemistry Laboratroy Data at Screening – Normal Reference Ranges (Safety Analysis Set in Part A) 
LB004: This output uses shell LB003 [Table 14.3.15] 
 
Programming Notes 
Repeat Table 14.3.15 for Biochemistry. Table should present these parameters only: Creatinine, total bilirubin, alkaline phosphatase, 
aspartate aminotransferase, alanine transaminase, gamma-glutamyl transferase, lactate dehydrogenase, creatine kinase, thyroid 
stimulating hormone, triiodothyronine and thyroxine, glucose, potassium, sodium, and. Present in alphabetical order. 
Update source footnote to “Source: Listing 16.2.8.2”. 
 
 
 
 
 
Table 14.3.17 Urinalysis Laboratroy Data at Screening – Normal Reference Ranges (Safety Analysis Set in Part A) 
LB005: This output uses shell LB003 [Table 14.3.15] 
 
Programming Notes 
Repeat Table 14.3.15 for Urinalysis, and update category to ‘Negative’ if the results are ‘Normal’ or ‘Negative’, to ‘Trace’ if the 
results are ‘Trace’ and ‘Positive’ if the results are equal to ‘1+’, ‘2+’, ‘3+’,’ or ‘4+’.  
Table should present these parameters only: Leukocytes esterase, occult blood, ketones, bilirubin, urobilinogen, protein and glucose. 
If urinalysis on Dipstick is positive for leucocytes and/or blood/hemoglobin, a microscopic examination including erythrocytes, 
leucocytes, bacteria, casts, epithelial cells and crystals. Present in alphabetical order. 
Update source footnote to “Source: Listing 16.2.8.3”. 
 
 
 
 
 
Table 14.3.18 Viral Serology Laboratroy Data at Screening (Safety Analysis Set in Part A) 
LB009: This output uses shell LB003 [Table 14.3.15] 
 
Programming Notes 
Repeat 14.3.13 for Viral Serology (includes human immunodeficiency virus, hepatitis B and hepatitis C serology). Present in 
alphabetical order. Note: Patients who received a hepatitis B vaccination and are positive for hepatitis B surface antibody, but are 
negative for both hepatitis B surface antigen and hepatitis B core antibody, do not need to be excluded from the study. 
Update source footnote to “Source: Listing 16.2.8.4”. 
 
 

 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 135 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.3.19 Hematology Laboratroy Data at Screening – Markedly Abnormal Values (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.3.19  
Biochemistry Laboratory Data - Markedly Abnormal Values  
(Safety Analysis Set in Part A) 
  
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
Laboratory Test, n (%) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
Alanine Aminotransferase (ALT) 
 
 
 
 
 
 
  > 3 x ULN 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Alkaline Phosphatase (ALP) 
 
 
 
 
 
 
  > 3 x ULN  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Aspartate Aminotransferase (AST) 
 
 
 
 
 
 
  > 3 x ULN 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Creatinine 
 
 
 
 
 
 
  > 221 mol/L 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Gamma Glutamyl Transferase (GGT) 
 
 
 
 
 
 
  > 3 x ULN 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Bilirubin (TBL) 
 
 
 
 
 
 
  > 3 x ULN 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  
  
  
  
  
  
  
ULN: Upper limit of normal reference range. n = Number of patients with at least one markedly abnormal value. N = Number of patients 
in the analysis set. % = percentage of patients with at least one markedly abnormal value relative to the total number of patients in 
the analysis set. 
 
Source: Listing 16.2.8.2 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 

 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 136 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
ECG 
Table 14.3.20 12-Lead Electrocardiogram Data by Timepoint (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.3.20  
12-Lead Electrocardiogram Data by Timepoint  
(Safety Analysis Set in Part A)  
Parameter (Unit) 
  
  
  
  
  
  
  Timepoint 
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
    Statistics 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
 
  
  
  
  
  
  
Parameter #1 (unit) 
 
 
 
 
 
 
  Pre-dose 
 
 
 
 
 
 
    n 
xx 
xx 
xx 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    Min, Max 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
1-hour post-dose  
 
 
 
 
 
 
  Observed 
 
 
 
 
 
 
n [a] 
xx 
xx 
xx 
xx 
xx 
xx 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
  Change from Pre-dose 
 
 
 
 
 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
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	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 137 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.3.20  
12-Lead Electrocardiogram Data by Timepoint  
(Safety Analysis Set in Part A)  
Parameter (Unit) 
  
  
  
  
  
  
  Timepoint 
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
    Statistics 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
 
  
  
  
  
  
  
Min, Max 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
Parameter #2 (unit) 
 
 
 
 
 
 
… 
 
 
 
 
 
 
SD: Standard deviation. n = Number of patients who have an assessment available. N = Number of patients in the analysis set. Change 
from Pre-dose: (Post-dose assessment – Pre-dose assessment). 
 
Source: Listing 16.2.9.2 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes: 
ECG quantitative assessments include: QTcF Interval (msec), QRS Interval (msec), PR Interval (msec), RR (msec), Heart rate (bpm). 
Present in alphabetical order. Display for the following timepoints: Pre-dose, 1, 1.5, 2, 4 and 8 hours (all ± 10 minutes) 
 

 
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	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 138 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.3.21 12-Lead Electrocardiogram – Shifts from Pre-Dose ECG Assessment by Timepoint (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.3.21  
12-Lead Electrocardiograms – Shifts from Pre-Dose ECG Assessment by Timepoint  
Safety Analysis Set  
  
  
  
  
Category at Timepoint 
  
  
 
 
 
  
  
  
  
Timepoint 
 
Pre-dose 
Normal 
Abnormal NCS 
Abnormal CS 
Total 
  Treatment group 
N 
Category 
n (%) 
n (%) 
n (%) 
n (%) 
  
  
  
  
  
  
  
1-hour post-dose 
 
 
 
 
 
 
  RPL554 100g 
xxx   
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Abnormal NCS 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Abnormal CS 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
  RPL554 300g 
xxx   
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Abnormal NCS 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Abnormal CS 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
… 
… 
… 
… 
… 
… 
… 
NCS: Not clinically significant; CS: Clinically significant. n = Number of patients in each category with a pre-dose and post-dose 
assessment. N = Number of patients in the analysis set. % = Percentage of patients in each category relative to the total number of 
patients in the analysis set, with assessments pre-dose and at the relevant timepoint. 
 
Source: Listing 16.2.9.1 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes: 
ECG quantitative assessments include: QTcF Interval (msec), QRS Interval (msec), PR Interval (msec), RR (msec), Heart rate (bpm). 
Display for timepoints: 1, 1.5, 2, 4 and 8 hours (all ± 10 minutes). 
 
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	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 139 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.3.22 Change from Baseline Heart Rate to peak Heart Rate (over 4 hours) After Single Dose (Safety Analysis Set in Part A) 
This output uses shell Table 14.2.4 
ANCOVA: Analysis of covariance. CFB: Change from Baseline. CI: Confidence interval. LSMean: Least square mean. LSMean Diff: Least 
square mean difference. SD: Standard deviation. N = number of patients in the analysis set. Baseline: Pre-dose heart rate. Change 
from Baseline: Post-dose assessment – Pre-dose. [a] number of patients with valid values at baseline and timepoints. [b] ANCOVA 
model is used to model the change from baseline heart rate using baseline heart rate as a continuous fixed effect and actual 
treatment as categorical fixed effects. [c] number of patients with at least one on treatment value who contributed to the model 
estimation. * Indicates a significant p-value (<0.05). 
 
Source: Listing 16.2.9.4 
 
Programming Notes 
Replace footnotes in original shell with those listed above 
 
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	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 140 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Vital Signs 
Table 14.3.23 Vital Sign Data – Change from Pre- to Post- dose by Timepoint (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.3.23  
Vital Sign Data - Change from Pre- to Post- dose by Timepoint  
(Safety Analysis Set in Part A)  
Parameter (Unit) 
  
  
  
  
  
  
  Timepoint 
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
    Statistics 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
Systolic Blood Pressure (mmHg) 
 
 
 
 
 
 
  Pre-dose 
 
 
 
 
 
 
    n 
xx 
xx 
xx 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    Min, Max 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
  1-hour post-dose  
 
 
 
 
 
 
    Observed 
 
 
 
 
 
 
    n 
xx 
xx 
xx 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    Min, Max 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
    Change from Pre-dose 
 
 
 
 
 
 
    Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 141 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.3.23  
Vital Sign Data - Change from Pre- to Post- dose by Timepoint  
(Safety Analysis Set in Part A)  
Parameter (Unit) 
  
  
  
  
  
  
  Timepoint 
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
    Statistics 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
    Min, Max 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
  2-hours post-dose 
 
 
 
 
 
 
… 
 
 
 
 
 
 
SD: Standard deviation. n = Number of patients who have an assessment available. N = Number of patients in the analysis set. Change 
from Pre-dose: (Post-dose assessment – Pre-dose assessment). 
 
Source: Listing 16.2.9.3 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
Programming Notes: 
Vital signs assessments include: Systolic blood pressure, diastolic blood pressure and pulse rate. Present in alphabetical order. 
Display for the following timepoints: Pre-dose, 1, 1.5, 2, 4, 8, 12 and 24 hours (all ± 10 minutes). 
 

 
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	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 142 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.3.24 Vital Sign Data – Markedly Abnormal Values (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.3.24  
Vital Sign Data - Markedly Abnormal Values  
Safety Analysis Set  
  
RPL554 
100g 
RPL554 300g 
RPL554 1000g 
RPL554 3000g 
RPL554 6000g 
Placebo 
Vital Sign Parameter 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
Systolic Blood Pressure (mmHg), n (%) 
 
 
 
 
 
 
  n [a] 
xx  
xx  
xx  
xx  
xx  
xx  
  Value <=90 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  A decrease from baseline of >=40 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Value >=180 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  An increase from baseline of >=40 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Diastolic Blood Pressure (mmHg), n (%) 
 
 
 
 
 
 
  n [a] 
xx  
xx  
xx  
xx  
xx  
xx  
  Value <=50 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  A decrease from baseline of >=20 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Value >=105 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  An increase from baseline of >=20 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Pulse Rate (bpm), n (%) 
 
 
 
 
 
 
  n [a] 
xx  
xx  
xx  
xx  
xx  
xx  
  Value <=50 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  A decrease from baseline of >=30 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Value >=110 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  An increase from baseline of >=30 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 143 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.3.24  
Vital Sign Data - Markedly Abnormal Values  
Safety Analysis Set  
  
RPL554 
100g 
RPL554 300g 
RPL554 1000g 
RPL554 3000g 
RPL554 6000g 
Placebo 
Vital Sign Parameter 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
bpm: beats per minute. mmHg: millimeters mercury. [a] n = Number of patients with a baseline value and post-baseline value. Baseline 
and post-baseline value would be needed for criteria relating to an increase/decrease from baeline. N = Number of patients in the 
analysis set. % = percentages are based on n. 
 
Source: Listing 16.2.9.3 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
 
 
 
 

 
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	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 144 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Table 14.3.25 Change from Baseline Pulse Rate to Peak Pulse Rate (over 4 hours) After Single Dose (Safety Analysis Set in Part A) 
This output uses shell Table 14.2.4 
ANCOVA: Analysis of covariance. CFB: Change from Baseline. CI: Confidence interval. LSMean: Least square mean. LSMean Difference: Leat 
square mean difference. SD: Standard deviation. N = number of patients in the analysis set. Baseline: Pre-dose pulse rate. Change from 
Baseline: Post-dose assessment – Pre-dose. [a] number of patients with valid values at baseline and timepoints. [b] ANCOVA model is 
used to model the change from baseline pulse rate using baseline pulse rate as a continuous fixed effect and actual treatment as 
categorical fixed effects. [c] number of patients with at least one on treatment value who contributed to the model estimation. * 
Indicates a significant p-value (<0.05). 
 
Source: Listing 16.2.9.4 
 
 
Programming Notes: 
Replace footnotes in original shell with those listed above 
 

 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 145 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Physical Examination 
Table 14.3.26 Physical Examination Data by Timepoint (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Table 14.3.26  
Physical Examination Data by Timepoint  
(Safety Analysis Set in Part A)  
Physical Examination: <Full/Brief> 
Assessment 
  
  
  
  
  
  
  Timepoint 
RPL554  
100g 
RPL554  
300g 
RPL554  
1000g 
RPL554  
3000g 
RPL554  
6000g 
Placebo 
    Category 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
  
  
  
  
  
  
  
Abdomen (liver and spleen) 
 
 
 
 
 
 
  Pre-dose 
 
 
 
 
 
 
    Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Abnormal NCS 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Abnormal CS 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Cardiovascular system 
 
 
 
 
 
 
  Pre-dose 
 
 
 
 
 
 
… 
 
 
 
 
 
 
CS = Clinically significant. NCS = Not clinically significant. n = Number of patients who have an assessment available at the relevant 
timepoint. N = Total number of patients in the analysis set.  
 
Source: Listing 16.2.9.5 and 16.2.9.6 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes: 
• Full Physical Examination assessments include: Abdomen [liver and spleen], Cardiovascular system, Extremities, Lymph nodes, 
Neurological system, Nose, Throat, Respiratory system, Skin, Thyroid gland. Present in alphabetical order. 
• Brief Physical Examination assessments include: Abdomen (liver and spleen), Cardiovascular system, Respiratory system, Skin. Present 
in alphabetical order. 
• Display for the following timepoints: Full Physical Examination: Screening and Brief Physical Examination: Pre-dose. 
 
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	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 146 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Figures 
Figure 14.2.1 Geometric Mean of ratios of Average FEV1 (over 4 hours)to pre-dose FEV1 by Treatment (Full Analysis Set in Part A) 
EFF09: This output uses shell EFF008 [Figure 14.2.3] 
 
Programming Notes 
Use template of figure 14.2.3, adjusting for Average FEV1 (over 4 hours).  
 
 
 
 
 
Figure 14.2.2 Geometric Mean of ratios of Average FEV1 (over 12 hours) to pre-dose FEV1 by Treatment (Full Analysis Set in Part A) 
EFF10: This output uses shell EFF008 [Figure 14.2.3] 
 
Programming Notes 
Use template of figure 14.2.3, adjusting for Average FEV1 (over 12 hours).  
 
 

 
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	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 147 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Figure 14.2.3 Geometric Mean of ratios to Peak FEV1 (over 4 hours) to pre-dose FEV1 by Treatment (Full Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Figure 14.2.3  
Geometric Mean of ratios of Peak FEV1 (over 4 hours) to pre-dose FEV1 by Treatment  
(Full Analysis Set in Part A)  
  
  
  
  
  
  
 
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FEV1: Forced expiratory volumn in 1 second. Pre-dose FEV1: Average of pre-dose FEV1 assessed immediately pre-dose (within 5 minutes) 
and 1 hour pre-dose (within 5 minutes). Bottom and top whiskers: 95% lower confidence limit and 95% upper confidence limit. Bar: 
Geometric means of the ratio to pre-dose. ANCOVA model is used to model the change from pre-dose FEV1 using pre-dose FEV1 as a 
continuous fixed effect and planned treatment as categorical fixed effects. 
Source: Listing 16.2.6.2 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes: 
Above is an example. Display for all treatment groups in Part A in ascending order (RPL554 100g, RPL554 300g, RPL554 1000g, RPL554 
3000g and RPL554 6000g) and then placebo. For each treatment group present the LSMean and SEM (standard error of the mean).   
 
 
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	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 148 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Figure 14.2.4 Mean Change from pre-dose FEV1 during spirometry over Time by Treatment (Full Analysis Set in Part A) 
Verona Pharma                                                                                                              Page X of Y 
Protocol: RPL5554-MD-201                                                                                                        Part A 
RPL554 pressurised Metered Dose Inhaler 
 
Figure 14.2.4 
Mean Change from pre-dose FEV1 during spirometry over Time by Treatment 
(Full Analysis Set in Part A) 
 
 
 
 
Means are calculated on the observed data. 
Pre-dose: the highest FEV1 result collected immediately pre-dose (within 5 minutes). 
Source: Listing 16.2.6.1 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes: 
 
Above is an example. Display for all treatment groups and placebo. For each treatment group present the Mean change from baseline. 
Display for the following time points on Day 1: 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 8 hours, 11 hours 
and 12 hours. On the x-axis present actual time scale (in spacing of timepoints).   

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 149 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Figure 14.2.5 Change from Pre-dose FEV1 over Time by Treatment by Subject (Full Analysis Set in Part A) 
EFF09: This output uses shell EFF009 [Figure 14.2.4] 
 
Programming Notes 
Use template of figure 14.2.4. 
Update to have 1 page per treatment group with “Planned Treatment:” displayed above the figure on the left. 
Present each patient for that treatment. Do no include a legend so that unblinding does not occur on a subject-level. 
Update y-axis title to “Change from pre-dose FEV1 (L)”. 
Include the following footnote: “Pre-dose: the average of the FEV1 pre-dose assessments collected on Day 1 (within 60 and 5 minutes).” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 150 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Figure 14.3.1 Mean Change from Pre-dose Heart Rate to Peak Heart Rate (over 4 hours) by Treatment (Safety Analysis Set in Part A) 
This output uses shell Figure 14.2.1 
 
Pre-dose heart rate: The heart rate value assessed immediately before administration. Bottom and top whiskers: 95% lower confidence 
and 95% upper confidence limit. Bar: Results on orginal scale. ANCOVA model is used to model the change from pre-dose heart rate using 
pre-dose heart rate as a continuous fixed effect, and actual treatment as categorical fixed effects. 
 
Programming Notes 
Use template of figure 14.2.1, adjusting for ECG assessment = heart rate.  
Update source footnote to “Source: Listing 16.2.9.4”. 
Replace footnotes in original shell with those listed above 
 
 
 
 
 
 
Figure 14.3.2 Mean Change from Pre-dose in Heart Rate over Time by Treatment (Safety Analysis Set in Part A) 
 
This output uses shell Figure 14.2.4 
 
Means are calculated on the observed data. 
Pre-dose: the pre-dose assessment collected of day 1. 
 
Programming Notes 
Display for all treatment groups and placebo. For each treatment group present the Mean change from baseline. 
Display for the following time points on Day 1: 1 hour, 2 hours, 4 hours and 8 hours.   
Update source footnote to “Source: Listing 16.2.9.2”. 
Replace footnotes in original shell with those listed above 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
 
 
 
 
 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 151 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Figure 14.3.3 Mean Change from Pre-dose Pulse Rate to Peak Pulse Rate (over 4 hours) by Treatment (Safety Analysis Set in Part A) 
This output uses shell Figure 14.2.1 
 
Pre-dose pulse rate: The pulse rate value assessed immediately before administration. Bottom and top whiskers: 95% lower confidence 
and 95% upper confidence limit. Bar: Results on orginal scale. ANCOVA model is used to model the change from pre-dose pulse rate using 
pre-dose pulse rate as a continuous fixed effect, and actual treatment as categorical fixed effects. 
 
Programming Notes: 
Use template of figure 14.2.1, adjusting for vital sign assessment = pulse rate.  
Update source footnote to “Source: Listing 16.2.9.4”. 
Replace footnotes in original shell with those listed above 
  
 
 
 
 
Figure 14.3.4 Mean Change from Pre-dose in Pulse Rate over Time by Treatment (Safety Analysis Set in Part A) 
 
This output uses shell Figure 14.2.4 
 
Means are calculated on the observed data. 
Pre-dose: the pre-dose assessment collected on day 1. 
 
Programming Notes: 
Display for all treatment groups and placebo. For each treatment group present the Mean change from baseline. 
Display for the following time points on Day 1: 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, Day 2: 24 hours.  
Update source footnote to “Source: Listing 16.2.9.3”.  
Replace footnotes in original shell with those listed above 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 

 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 152 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listings 
Listing 16.2.1.1 Completed/Discontinued Patients (All Randomized Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.1.1  
Completed/Discontinued Patients  
(All Randomized Analysis Set in Part A)  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID  
Informed 
consent 
date/Study 
day 
Randomization 
date/Study day 
Completed Part 
A/Primary reason 
if not completed 
Part A 
Treatment 
discontinued 
Discontinued 
between Part A 
and Part B 
Date of 
completion/discontinuation/ 
Study day 
XXXXXXX 
DDMMMYYYY/xx 
DDMMMYYYY/xx 
No/XXXXXX 
xx 
xx 
DDMMMYYYY/xx 
  
  
  
  
  
 
  
Study day: Day relative to day of the single dose of study medication. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell) and within group by patient ID. 
 
 
 
 
 
 
 
 
 
 
 
 
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	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 153 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.2.1 Protocol Deviations (All Randomized Analysis Set in Part A) 
Verona Pharma 
 
 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.2.1  
Protocol Deviations  
(All Randomized Analysis Set in Part A)  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID  
Age/Sex/Race 
Deviation date/Study Day 
Protocol 
deviation 
Type of 
deviation 
Severity 
XXXXXXXXXXXXXX 
XX/X/XXXXXXX 
DDMMMYYYY/xx 
XXXXXXXXXXX 
XXXXXXXXXXX 
XXXXXXXXXXX 
  
  
  
  
  
  
As: Native Asian. Bl: Black or African American. F: Female. Ia: American Indian or Alaskan. M: Male. Ot: Other. PI: Native Hawaiian or 
Pacific Islanders. Un: Unknown. W: White. Age (years): As calculated relative to informed consent date. Study day: Day relative to day 
of the single dose of study medication. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell) and within group by patient ID and then the deviation date. 

 
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	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 154 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.3.1 Patients Excluded from Analysis Sets (All Randomized Analysis Set in Part A) 
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.3.1  
Patient Excluded from Analysis Sets  
(All Randomized Analysis Set in Part A)  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Age/Sex/Race 
Affected analysis set 
XXXXXXX 
47/M/W 
PK 
XXXXXXX 
67/M/Bl 
SAF 
… 
 
 
As: Native Asian. Bl: Black or African American. eCRF: Electronic case report form. F: Female. Ia: American Indian or Alaskan. M: 
Male. Ot: Other. PI: Native Hawaiian or Pacific Islanders. Un: Unknown. W: White. Age (years): As calculated relative to informed 
consent date. All measurements listed above are measured at Screening on the Demography eCRF.  
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell) and within group by patient ID. 
Print "No patient excluded from any analysis set" if the listing has no observations. 
 

 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 155 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.4.1 Demographic Characteristics (All Randomized Analysis Set in Part A) 
Verona Pharma 
 
 
 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.4.1  
Demographic Characteristics  
(All Randomized Analysis Set in Part A)  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Country 
Age/Sex/Race 
Ethnicity 
Weight 
(kg) 
Height 
(cm) 
BMI 
(kg/m2) 
Re-
screened 
patient 
Childbearing 
potential 
XXXXXXXXX  
USA 
62/F/W 
White-
White/Caucasian/European 
Heritage 
XX 
XXX 
XX.X 
X 
X 
XXXXXXXXX  
USA 
67/M/W 
White-
White/Caucasian/European 
Heritage 
XX 
XXX 
XX.X 
X 
NA 
  
  
  
  
  
  
  
  
  
  
As: Native Asian. Bl: Black or African American. BMI: Body mass index. eCRF: Electronic case report form. F: Female. Ia: American 
Indian or Alaska. M: Male. NA: Not applicable. Ot: Other. Pi: Native Hawaiian or Pacific Islanders. Un: Unknown. W: White. Age 
(years): As calculated relative to informed consent date. BMI (kg/m2) = Weight (kg) / Height (m)2. All measurements listed above are 
measured at Screening on the Demography eCRF. 
 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes: 
Order by treatment group (as per shell) and within group by patient ID. 
 

 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 156 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.4.2 Screening Disease Characteristics (All Randomized Analysis Set in Part A) 
Verona Pharma 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
 
 
 
 
 
 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
 
 
  
  
Listing 16.2.4.2  
Screening Disease Characteristics  
(All Randomized Analysis Set in Part A)  
  
  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient 
ID 
Age/Sex/Race 
Bronchodilator FEV1 
 
Bronchodilator 
FVC (L) 
 
Bronchodilator 
FEV1/FVC 
 
Reversibility 
FEV1 
Assessment 
performed 
with four 
puffs of 
albuterol 
Met 
reversibility 
test criteria? 
Pre 
(L) 
Post 
(L) 
Pre 
(%) 
Post 
(%) 
 
Pre 
Post 
 
Pre 
Post 
 
mL 
% 
XXXX 
XX/X/XXX 
XX 
XX 
XX 
XX 
XX 
XX 
 
XX 
XX 
 
XX 
XX 
XXX 
XXX 
  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
 
As: Native Asian. Bl: Black or African American. eCRF: Electronic case report form. F: Female. FEV1: Forced expired volume in 1 second. FVC: 
Forced vital capacity. Ia: American Indian or Alaskan. Ot: Other. PI: Native Hawaiian or Pacific Islanders. Un: Unknown. W: White. Age 
(years): As calculated relative to informed consent date. Pre-, post-bronchodilator and reversibility values are the results of the 
screening reversibility test.  
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell) and within group by patient ID. 
 

 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 157 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.4.3 COPD and Smoking History (All Randomized Analysis Set in Part A) 
Verona Pharma 
 
 
 
 
 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
 
 
 
 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.4.3  
COPD and Smoking History  
(All Randomized Analysis Set in Part A)  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
  
  
  
  
  
  
Smoking History 
Patient ID 
Date of COPD  
first 
diagnosed 
Duration of COPD 
(years)  
(time since 
diagnosis) 
Date of most 
recent  
exacerbation/S
tudy day 
Bronchiti
s?/ 
Emphysema
? 
Smoking 
category 
Number of 
packs  
per day 
Number of 
years  
smoking 
Smoking exposure  
(pack-years) 
XXXXXXX 
DDMMMYYYY 
xx.x 
DDMMMYYYY/xx 
Yes/Yes 
Current 
XX 
XX 
XX 
  
  
  
  
  
  
  
  
  
COPD: Chronic Obstructive Pulmonary Disease. Smoking exposure (pack-years) = Number of packs per day * Number of years smoking, for 
patients with a smoking history or a current smoker. Study day: Day relative to day of the first dose of study medication. Duration of 
COPD (years) (time since diagnosis) = Randomization date – date COPD first diagnosed. 
 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes: 
Order by treatment group (as per shell) and within group by patient ID. 
 

 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 158 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.4.4 Medical History (All Randomized Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.4.4  
Medical History  
(All Randomized Analysis Set in Part A) 
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Medical history diagnosis 
SOC/PT 
Start date/ 
Study day 
End date/ 
Study day 
XXXXXXXXX  
XXXXXXXXXXXXXXXX 
XXXXXXXXXXXX/ 
XXXXXXXXXXXXXX 
DDMMMYYYY/xx 
DDMMMYYYY/xx 
  
  
  
  
  
MedDRA: Medical Dictionary for Regulatory Activities. PT: Preferred Term. SOC: System Organ Class. Medical history: Coded using MedDRA 
(Version 21.0). Study day: Day relative to day of the single dose of study medication. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes: 
Order by treatment group (as per shell) and within group by patient ID. 
 

 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 159 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.4.5 Surgical Procedure History (All Randomized Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.4.5  
Surgical Procedure History  
(All Randomized Analysis Set in Part A)  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Reported name of 
procedure 
Purpose of procedure 
Start date of 
procedure/  
Study day 
End date of 
procedure/  
Study day 
XXXXXXXXX  
XXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXX 
DDMMMYYYY/xx 
DDMMMYYYY/xx 
  
  
  
  
  
  
Surgical procedure history: Coded using MedDRA (Version 21.0). Study day: Day relative to day of the single dose of study medication. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes: 
Order by treatment group (as per shell) and within group by patient ID. 
 
 
 
 
 
 
 
 
 
 
 
 
 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 160 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.4.6 Prior and Concomitant Medications (All Randomized Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.4.6  
Prior and Concomitant Medications  
(All Randomized Analysis Set in Part A) 
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
  
Patient ID 
Start date  
(Study day)/ 
End date  
(Study day) 
Prior?[a]/ 
Concomitant?[b] 
System organ class/ 
Preferred term/ 
Reported term 
Indication 
Dose 
(Unit) 
Frequency 
Route 
XXXXX 
DDMMMYYYY 
(xx)/ 
DDMMMYYYY (xx) 
Prior 
xxxxxxxxxxxxxxxxxxx/ 
xxxxxxxxxxxxxxxxxxx/ 
xxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxx 
(xx) 
xx 
xxx 
 
DDMMMYYYY 
(xx)/ 
ongoing 
Prior/Concomitant 
xxxxxxxxxxxxxxxxxxx/ 
xxxxxxxxxxxxxxxxxxx/ 
xxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxx 
(xx) 
xx 
xxx 
 
DDMMMYYYY 
(xx)/ 
ongoing 
Concomitant 
xxxxxxxxxxxxxxxxxxx/ 
xxxxxxxxxxxxxxxxxxx/ 
xxxxxxxxxxxxxxxxx 
xxxxxxx 
xxxx 
(xx) 
xx 
xxx 
  
  
  
  
  
  
  
  
[a] Medications which started and stopped in the 3 months prior to the single dose of study medication [b] Medication with onset date 
on or after the single dose of study medication and ended on or after the single dose of study medication or were ongoing at the end 
of Part A. A patient can report more than one concomitant medication with the same preferred term. Study day: Day relative to day of 
the single dose of study medication. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell) and within group by patient ID. 

 

	
	

Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 161 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.5.1 Drug Exposure and Accountability (All Randomized Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.5.1  
Drug Exposure and Accountability  
(All Randomized Analysis Set in Part A)  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Dosing date/ 
Study day 
Start time 
of inhalations 
Date of Part A completion/ 
discontinuation/Study day 
XXXXXXXXX 
DDMMMYYYY/xx 
HH:MM 
DDMMMYYYY/xx 
  
  
  
  
Study day: Day relative to day of the single dose of study medication. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell) and within group by patient ID. 
 

 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 162 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.6.1 Spirometry: FEV1 Results (Full Analysis Set in Part A) 
Verona Pharma 
 
 
 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
 
 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.6.1  
Spirometry: FEV1 Results  
(Full Analysis Set in Part A)  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Timepoint 
Assessment 
performed/ 
Date and 
time/ 
Study day 
Refrained 
from  
smoking 
Capable of 
withdrawing from  
long acting 
bronchodilators  
FEV1 measurement 
(L) 
Predicted FEV1 (%) 
XXXXX 
XXXXXX 
XX/DDMMYYY 
HH:MM/xx 
XX 
XX 
X.XXX  
XX.X 
 
XXXXXX 
 
 
 
 
 
 
… 
 
 
 
 
 
FEV1: Forced expiratory volume in 1 second. FEV1 pre-dose assessment (-5 minutes) collected at visit of interest. Study day: Day 
relative to day of the first dose of study medication. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
The assessment timepoints can be Pre PFT, Post PFT, Pre PFT -60 min, Immediately Predose, Post PFT 5min, 15min, 30min, 1h, 1.5h, 2h, 
4h, 8h, 11h, 12h and EOS. The minutes from dosing is the difference between the Date/Time of assessments (from dataset 
CDM.T_SSM/CDM.R_SSM) and the Date/Time of Dosing (from dataset CDM.EX). Order by treatment group (as per shell) and within group by 
patient ID. 
 

 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 163 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.6.2 Spirometry: FEV1 Derived Measurements (Full Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.6.2  
Spirometry: FEV1 Derived Measurements  
(Full Analysis Set in Part A) 
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Assessment performed/ 
Date/ 
Study day 
Peak 
FEV1 (over 4 hours) 
Average 
FEV1 (over 4 
hours) 
Average 
FEV1 (over 12 
hours) 
XXXXX 
XX/DDMMYYY/xx 
X.XXX 
X.XXX 
X.XXX 
… 
… 
… 
… 
… 
AUC: Area under the curve. FEV1: Forced expiratory volume in 1 second. FEV1 pre-dose assessment (-5 minutes) collected at visit of 
interest. Peak FEV1 = Maximum post-dose value among the values collected up to timepoint of interest hours. Average FEV1 AUC: AUC of 
the FEV1 values divided by the length of the time (in hours) interval of interest (per visit). Study day: Day relative to day of the 
single dose of study medication. * when a subject has taken rescue medication less than 8 or 6 hours (for protocol version 1 or 2 
respectively) prior to study medication. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
The assessment timepoints can be Pre PFT, Post PFT, Pre PFT -60 min, Immediately Pre-dose, Post PFT 5min, 15min, 30min, 1h, 1.5h, 2h, 
4h, 8h, 11h, 12h and EOS. The minutes from dosing is the difference between the Date/Time of assessments (from dataset CDM.SPIRO) and 
the Date/Time of Dosing (from dataset CDM.EX) Order by treatment group (as per shell) and within group by patient ID. 
In the “Average FEV1 (over 12 hours)” * any results where a subject has taken rescue medication less than 8 or 6 hours (for protocol 
version 1 or 2 respectively) prior to study medication. 
 
 
 
 
 
 
 
 
 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 164 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.6.3 Rescue Medications Taken at Site (All Randomized Analysis Set in Part A) 
Verona Pharma 
 
 
 
 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
 
 
 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.6.3  
Rescue Medications Taken at Site  
(All Randomized Analysis Set in Part A) 
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Medication 
name 
Date/time of administration/ 
Study day 
Number of Albuterol or Salbuterol puffs taken/ 
Number of Ipratropium puffs taken 
XXXX/XXXX 
XXXXXXXXX 
DDMMMYYYY/ 
HH:MM/xx 
XX/YY 
 
 
 
 
Rescue medications = Short acting bronchodilators used to relieve i.e., rescue symptoms immediately. Study day: Day relative to day of 
the single dose of study medication. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell) and within group by patient ID and visit. 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 165 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.6.4 Rescue Medication Taken between Visits (All Randomized Analysis Set in Part A) 
Verona Pharma 
 
 
 
  
Page X of Y 
Protocol: RPL554-MD-201 
 
 
 
  
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.6.4  
Rescue Medications Taken between Visits  
(All Randomized Analysis Set in Part A) 
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Inhaler 
number 
Rescue 
medication 
canister 
dispensed?/ 
collected? 
(Y/N) 
Date and time 
canister 
dispensed/collected Reason canister not dispensed/collected 
Dispensed rescue 
medication weight 
(g)/ 
Collected weight 
(g) 
 
xx 
X/X 
DDMMMYYYY/HH:MM/ 
DDMMMYYYY/HH:MM 
XXXXXXX/ 
XXXXXXX 
XX.X/ 
XX.X 
 
 
 
 
 
 
Rescue medications = Short acting bronchodilators used to relieve i.e., rescue symptoms immediately.  
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell) and within group by patient ID and visit. 

 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 166 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.7.1 All Adverse Events (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.7.1  
All Adverse Events  
(Safety Analysis Set in Part A) 
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient 
ID 
Study day 
of first 
treatment 
SOC/PT/Reported 
term [a] 
Start/End 
date 
or ongoing 
(Study 
day) [b] 
Sev  
[c] 
Rel  
[d] 
Act  
[e] 
Ser  
[f] 
Out  
[g] 
Chronicit
y 
[h] 
Treatmen
t 
given 
Disconti
- 
nued 
from  
study 
Blind  
broken 
XXXXX 
XX 
XXXXXX/XXXXX/XXXXX 
DDMMMYYYYY 
MI 
Y 
NC 
N 
Rslv 
XX/X/X 
Yes 
Yes 
Yes 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
PT: Preferred term. SOC: System organ class.  
 
[a] An asterisk “*” indicates a non-treatment-emergent adverse event. 
 
[b] Study day: Day relative to day of the single dose of study medication. 
 
[c] Severity: MI=Mild, MO=Moderate, SE=Severe.  
 
[d] Related to study drug. 
 
[e] Action taken with respect to study drug: NC = Dose not changed, DI = Drug Interrupted DW = Drug withdrawn, OT = Other, NA = Not 
Applicable. 
 
[f] Serious AE.  
 
[g] Outcome: Fatal = Fatal, NRslv = Not recovered/not resolved, Rslv = Recovered/Resolved, RslvS = Recovered/Resolved with sequelae, 
Recovering/Resolving = RslvG, Unk = Unknown. 
 
[h] S = Single Occasion, I = Intermittent, P = Persistent. 
SOCs and PTs are coded using the MedDRA (Version 21.0). 
 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell) and within treatment by patient ID, adverse event start date and adverse event end date (in 
that order). 
 
 
 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 167 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.7.2 Treatment-emergent Adverse Events Leading to Study Discontinuation (Safety Analysis Set in Part A) 
L017: This output uses shell L016 [Listing 16.2.7.1] 
 
 
 
 
 
 
 
 
 
Listing 16.2.7.3 Treatment-emergent Adverce Events Leading to Death (Safety Analysis Set in Part A) 
L018: This output uses shell L016 [Listing 16.2.7.1] 
 
 
 
 
 
 
 
 
Listing 16.2.7.4 Serious Treatment-emergent Adverse Events (Safety Analysis Set in Part A) 
L019: This output uses shell L016 [Listing 16.2.7.1] 
 
 
 
 
 
 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 168 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.7.5 Serious Treatment-emergent Adverse Events - Details (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.7.5  
Serious Treatment-emergent Adverse Events – Details  
(Safety Analysis Set in Part A)  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
SOC/PT/ 
Reported Term 
SAE details 
Answer 
XXXXXXXXXXX 
XXXXXXX/XXXXXXX/XXXXXX 
Date Investigator became aware of SAE  
DDMMMYYYY 
 
 
Death  
XXXXX 
 
 
Life-threatening  
XXXXX 
 
 
Initial or prolonged hospitalization  
XXXXX 
 
 
Date of admission (DD MMM YYYY)  
DDMMMYYYY 
 
 
Date of discharge (DD MMM YYYY)  
DDMMMYYYY 
 
 
Persistent or significant disability/incapacity  
XXXXX 
 
 
Congenital anomaly/birth defect  
XXXXX 
 
 
Occurred with overdose  
XXXXX 
 
 
Other medically important event  
XXXXX 
 
 
Was the SAE caused by other medication? (e.g. Concomitant medication, 
background medication, rescue medication) 
XXXXX 
 
 
If Yes, Please Specify  
XXXXX 
 
 
Was the SAE caused by study procedure(s)?  
XXXXX 
 
 
If Yes, Please Specify  
XXXXX 
 
 
Describe treatment for event including medications (1)  
XXXXX 
 
 
Describe treatment for event including medications (2) 
XXXXX 
 
 
Describe treatment for event including medications (3) 
XXXXX 
 
 
List all diagnostic tests that were done to confirm event (1)  
XXXXX 
 
 
List all diagnostic tests that were done to confirm event (2)  
XXXXX 
 
 
List all diagnostic tests that were done to confirm event (3)  
XXXXX 
 
 
Description of SAE/narrative  
XXXXX 
 
 
Additional information 
XXXXX 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 169 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.7.5  
Serious Treatment-emergent Adverse Events – Details  
(Safety Analysis Set in Part A)  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
SOC/PT/ 
Reported Term 
SAE details 
Answer 
  
  
  
  
PT: Preferred Term. SAE: Serious Adverse Event. SOC: System Organ Class. SOCs and PTs are coded using the MedDRA (Version 21.0). 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell) and within group by patient ID. 
 

 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 170 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.8.1 Hematology (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.8.1  
Hematology  
(Safety Analysis Set in Part A)  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Parameter 
Reference 
Range 
(Lower-
Upper) 
Timepoint 
Date/Time of  
assessment/ 
Study day 
Value (unit) 
L/H [a] 
Change  
from  
Baseline 
XXXXXXXXXXX 
Hemoglobin 
XX.X – XX.X 
Scr 
DDMMMYYYY/HH:MM/ 
xx 
XX (unit) 
XX.X 
  
  
  
  
  
  
  
Scr: Screening. [a] L = Below low normal range. H = Above high normal range. * = Markedly abnormal values. Study day: Day relative to 
day of the single dose of study medication. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Add a symbol ‘*’ next to the value to identify markedly abnormal values.  
Order by treatment group (as per shell), hematology parameter (in alphabetical order) and by patient ID. 
 
 
 
 
Listing 16.2.8.2 Biochemistry (Safety Analysis Set in Part A) 
L022: This output uses shell L021 [Listing 16.2.8.1] 
Scr: Screening. [a] L = Below lower limit of reference range. H = Above upper limit of reference range. Study day: Day relative to day 
of the single dose of study medication. 
* = Markedly abnormal value (refer to section 16.2.1 of the statistical analysis plan for the markedly abnormal criteria). 
Programming Notes 
Replace footnotes with those above. 
 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 171 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.8.3 Urinalysis (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.8.3  
Urinalysis  
(Safety Analysis Set in Part A) 
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Parameter 
Timepoint 
Date/Time of assessment/ 
Study day 
Result [a] 
XXXXXXXXXXX 
Bilirubin 
Screening 
DDMMMYYYY/HH:MM/xx 
NEGATIVE (N) 
 
 
… 
DDMMMYYYY/HH:MM/xx 
TRACE (T) 
 
 
… 
DDMMMYYYY/HH:MM/xx 
1+ (P) 
  
  
  
  
  
Scr: Screening. [a] Category assigned and used in the shift table: N = Normal or ‘Negative’; T = ‘Trace’ P = ‘1+’,‘2+’,‘3+’,’ or ‘4+’. 
The flag appears only for the following parameters: Leucocyte Esterase, Bilirubin, Glucose, Ketones, Occult blood, Protein and 
Urobilinogen. Study day: Day relative to day of the single dose of study medication. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell), urinalysis parameter (in alphabetical order) and by patient ID. 
 
 
 
 
Listing 16.2.8.4 Viral Serology (Safety Analysis Set in Part A) 
L022: This output uses shell L021 [Listing 16.2.8.3] 
Programming Notes 
Replace footnotes with those related to Viral Serology 
 

 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 172 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.9.1 Electrocardiogram Local Reading Overall Evaluation (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.9.1  
Electrocardiogram Local Reading Overall Evaluation  
(Safety Analysis Set in Part A)  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Day/Timepoint 
Date/Time of 
assessment/Study day 
Overall ECG 
Evaluation 
Abnormal 
Significant 
XXXXXXXXXXXX 
XXXX/XXXX 
DDMMMYYYY/HH:MM/xx 
Normal 
Y 
  
  
  
  
  
ECG: Electrocardiogram. Study day: Day relative to day of the single dose of study medication. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell), within group by patient ID and then by timepoint. 
 

 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 173 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.9.2 12-Lead ECG (Safety Analysis Set in Part A) 
Verona Pharma 
 
 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.9.2  
12-lead ECG  
(Safety Analysis Set in Part A)  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Day/Timepoint 
Date/Time of 
assessment/Study day 
ECG parameter (unit) 
Result 
Baseline 
CFB 
XXXXXXXXXXXXX 
XXXXX 
DDMMMYYY/HH:MM/xx 
HR (bpm) 
XX.X 
XX.X 
XX.X 
 
 
 
RR interval (msec) 
XX.X 
XX.X 
XX.X 
 
 
 
PR interval (msec) 
XX.X 
XX.X 
XX.X 
 
 
 
QRS duration (msec) 
XX.X 
XX.X 
XX.X 
 
 
 
QT interval (msec) 
XX.X 
XX.X 
XX.X 
 
 
 
Bazett's QTc (msec) 
XX.X 
XX.X 
XX.X 
 
 
 
Fridericia's QTc (msec) 
XX.X 
XX.X 
XX.X 
 
XXXXX 
DDMMMYYY/HH:MM/xx 
… 
… 
… 
… 
  
  
  
  
  
  
  
bpm: beats per minute. CFB: Change from baseline. ECG: Electrocardiogram. HR: Heart rate. QTcB: QT interval using Bazett’s correction 
formula. msec: milliseconds. QTcF: QT interval using Fridericia’s correction formula. Study day: Day relative to day of the single 
dose of study medication. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell), within group by patient ID and then by timepoint. 
 

 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 174 of 291


Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.9.3 Vital Signs (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.9.3  
Vital Signs  
(Safety Analysis Set in Part A)  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Day/Timepoint 
Date/Time of 
assessment/Study 
day 
Vital sign 
parameter (unit) 
Result 
Baseline 
CFB 
Markedly 
abnormal 
XXXXXXXXXXX 
XXXXX 
DDMMMYYYY/HH:MM/xx 
SBP (mmHg) 
XX.X L 
XX.X 
XX.X 
Y 
 
 
 
DBP (mmHg) 
XX.X 
XX.X 
XX.X 
 
 
 
 
Pulse (beats/min) 
XX.X 
XX.X 
XX.X H 
Y 
 
XXXXX 
DDMMMYYYY/HH:MM/xx 
… 
… 
… 
… 
… 
  
  
  
  
  
  
  
  
CFB: Change from baseline. Study day: Day relative to day of the single dose of study medication. Baseline: Defined as the assessment 
performed pre-dose. L and H represents marked decrease or increase from baseline. 
 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell), within group by patient ID, and then timepoint. 
 
 
 
 
 
 
 
 
 
 
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Version 1.0; 17 May 2021
Verona Pharma plc
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Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.9.4 Derived Safety Measurements (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.9.4  
Derived Safety Measurements  
(Safety Analysis Set in Part A) 
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Date/ 
Study day 
Peak 
Heart Rate (bpm) (over 4 hours) 
Peak 
Pulse Rate (bpm) (over 4 hours) 
XXXXX 
DDMMMYYYY/xx 
X.XXX 
X.XXX 
… 
… 
… 
… 
Peak = Maximum post-dose value among the values collected up to timepoint of interest hours. Study day: Day relative to day of the 
single dose of study medication.  
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell), within group by patient ID, and then date/time. 
 
 
 
 
 
 
 
 
 
 
 
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Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.9.5 Brief Physical Examination (Safety Analysis Set in Part A) 
 

 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.9.5  
Brief Physical Examination 
(Safety Analysis Set in Part A) 
Treatment group: <RPL554 150g/RPL554 500g/RPL554 1500g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Date/Time of 
examination/Study day 
Body system 
Result 
If Abnormal, clinical significant, Specify 
XXXXXXXXXXX 
DDMMMYYYY/HH:MM/xx 
XXXXXXXXXXXXXX 
XXXXXXXXXXXXXX 
  
  
  
  
Study day: Day relative to day of the single dose of study medication. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell), within group by patient ID and then alphabetically by body system. 
Only include patients with at least one markedly abnormal clinically significant finding. 
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Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.9.6 Full Physical Examination (Safety Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.9.6  
Full Physical Examination  
(Safety Analysis Set in Part A)  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Date/Time of 
examination/Study day 
Body system 
Result 
If Abnormal, clinical significant, Specify 
XXXXXXXXXXX 
DDMMMYYYY/HH:MM/xx 
XXXXXXXXXXXXXX 
XXXXXXXXXXXXXX 
  
  
  
  
  
CFB: Change from baseline. Study day: Day relative to day of the single dose of study medication. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell), within group by patient ID and then alphabetically by body system. 
Only include patients with at least one markedly abnormal clinically significant finding. 
 

 
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Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.9.7 Chest X-ray (All Randomized Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.9.7  
Chest X-ray  
(All Randomized Analysis Set in Part A)  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Chest X-ray  
performed 
Date of X-ray/ 
Study day 
Result of X-ray/ 
Specification (eCRF) 
XXXXXXXXX 
New 
DDMMMYYYY/xx 
Abnormal clinically 
significant/please specify 
XXXXXXXXX 
Historical 
DDMMMYYYY/xx 
Consistent with COPD 
  
  
  
  
eCRF: Electronic case report form. Study day: Day relative to day of the single dose of study medication. Chest X-ray is assessed at 
Screening. Patient performs either a new X-ray ("New") or if an X-ray was performed in the last 12 months, this is acceptable 
("Historical"). 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell) and within group by patient ID. Specification (eCRF) refers to result “Abnormal clinically 
significant” where free text could be required to be concatenated. 
 
 
 
 
 
 
 
 
 
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Version 1.0; 17 May 2021
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CONFIDENTIAL
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Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.9.8 Inhalation Training (All Randomized Analysis Set in Part A) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.9.8  
Inhalation Training  
(All Randomized Analysis Set in Part A) 
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Timepoint 
Inhalation training 
given? 
Date of inhalation training/ 
Study day 
XXXXXXX 
XXXX/XXXX 
XXXXXXX 
DDMMMYYYY/xx 
  
  
  
  
Study day: Day relative to day of the single dose of study medication. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell) and within group by patient ID. 
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Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.9.9 Pregnancy Serum and Urine Test at Screening (All Randomized Analysis Set in Part A) 
Verona Pharma 
 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.9.9 
Pregnancy Serum and Urine Test at Screening  
(All Randomized Analysis Set in Part A) 
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Serum pregnancy test 
performed/Date of test/Study 
day 
Serum pregnancy test 
result  
Urine pregnancy test 
performed/Date of 
test/Study day 
Urine 
pregnancy 
test result  
  
  
  
  
  
XXXXXXX 
XX/DDMMMYYYY/xx 
XXXXXXX 
XX/DDMMMYYYY/xx 
XXXXXXX 
 
 
 
 
 
Study day: Day relative to day of the single dose of study medication. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell) and within group by patient ID. 
Consider only female patients. 
Multiple pregnancy risk factors and multiple relevant family history will be presented as one result per row, as these are not 
presented separately in Pregnancy report eCRF. 
 
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Version 1.0; 17 May 2021
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Document: Z:\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 – Part A 
 
Version: 2.0 
Author: Nicholas Roubinis/Jennifer Allsopp 
Date: 13JAN2021 
Listing 16.2.9.10 Pregnancy Report at Screening (All Randomized Analysis Set in Part A) 
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part A  
RPL554 pressurised Metered Dose Inhaler 
Listing 16.2.9.10  
Pregnancy Report at Screening  
(All Randomized Analysis Set in Part A)  
Treatment group: <RPL554 100g/RPL554 300g/RPL554 1000g/RPL554 3000g/RPL554 6000g/Placebo> 
Patient ID 
Pregnancy report item 
Results 
XXXXXXXXXXXXX 
Date of last menstrual period/Study day 
DDMMMYYYY/xx 
 
Date of expected delivery/Study day 
DDMMMYYYY/xx 
 
Overall number of previous pregnancies 
XX 
 
Number of normal deliveries 
XX 
 
Number of spontaneous miscarriages 
XX 
 
Number of other previous pregnancies 
XX 
 
Relevant pregnancy risk factors 
XXXXXXXXX 
 
Relevant family history 
XXXXXXXXX 
 
  
  
  
Study day: Day relative to day of the single dose of study medication. 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
Programming Notes 
Order by treatment group (as per shell) and within group by patient ID. 
Consider only female patients. 
Multiple pregnancy risk factors and multiple relevant family history will be presented as one result per row, as these are not 
presented separately in Pregnancy report eCRF. 
 
 
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Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
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RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
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Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
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Clinical Study Report
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Version 1.0; 17 May 2021
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CONFIDENTIAL
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Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
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Tables............................................................................................................................... 8 
14.1 Demographic Data .............................................................................................................. 8 
Table 14.1.7 Patient Disposition by Treatment Sequence (Part A Completers) ....................................................... 8 
Table 14.1.8 Patient Disposition by Treatment Group (All Randomized Analysis Set in Part B) ..................................... 10 
Table 14.1.9 Analysis Set by Treatment Sequence (All Randomized Analysis Sets in Part B) ........................................ 12 
Table 14.1.10 Analysis Set by Treatment Group (All Randomized Analysis Sets in Part B) .......................................... 13 
Table 14.1.11 Major/Critical Protocol Deviations (All Randomized Analysis Sets in Part B) ....................................... 14 
Table 14.1.12 Demographic Characteristics (All Randomized Analysis Sets in Part B) .............................................. 15 
Table 14.1.13 Screening Disease Characteristics (All Randomized Analysis Sets in Part B) ........................................ 19 
Table 14.1.14 COPD and Smoking History (All Randomized Analysis Sets in Part B) ................................................. 23 
Table 14.1.15 Drug Exposure and Accountability (Safety Analysis Sets in Part B) ................................................. 25 
14.2 Efficacy ..................................................................................................................... 26 
Primary Efficacy .................................................................................................................. 26 
Table 14.2.5 FEV1 by Treatment and Timepoint (Full Analyis Set in Part B) ........................................................ 26 
Table 14.2.6 Change from Baseline FEV1 to Peak FEV1 (over 4 hours) on Day 7 (Full Analysis Set in Part B) ........................ 28 
Table 14.2.6a Change from Baseline FEV1 to Peak FEV1 (over 4 hours) on Day 7 – Sensitivity Analysis (Completers Analysis Set in Part 
B) .............................................................................................................................. 30 
Secondary Efficacy ................................................................................................................ 31 
Table 14.2.7 Average FEV1 by Day and Treatment Group (Full Analysis Set in Part B) ............................................... 31 
Table 14.2.8 Change from Baseline FEV1 to Average FEV1 (over 4 hours) on Day 7 (Full Analysis Set in Part B) ..................... 32 
Table 14.2.9 Change from Baseline FEV1 to Average FEV1 (over 12 hours) on Day 7 (Full Analysis Set in Part B) .................... 33 
Table 14.2.9a Change from Baseline FEV1 to Average FEV1 (over 12 hours) on Day 7 – Sensitivity Analysis (Full Analysis Set in Part 
B) .............................................................................................................................. 33 
Table 14.2.10 Change from Baseline FEV1 to Morning Trough FEV1 on Day 7 (Full Analysis Set in Part B) ............................ 34 
Table 14.2.11 Change from Baseline FEV1 to Peak FEV1 (over 4 hours) on Day 1 (Full Analysis Set in Part B) ....................... 35 
Table 14.2.12 Change from Baseline FEV1 to Average FEV1 (over 4 hours) on Day 1 (Full Analysis Set in Part B) .................... 35 
Table 14.2.13 Change from Baseline FEV1 to Average FEV1 (over 12 hours) on Day 1 (Full Analysis Set in Part B) ................... 35 
Table 14.2.14 Time to Onset of Action (>10% Increase in FEV1) on Day 1 (Full Analysis Set in Part B) ............................. 36 
Table 14.2.15 Rescue Medication Use (Full Analysis Set in Part B) ............................................................... 38 
Exploratory Efficacy .............................................................................................................. 39 
Table 14.2.16 Dyspnea Scale by Day and Timepoint (Full Analysis Set in Part B) .................................................. 39 
Table 14.2.17 Comparison of Change from Baseline Dyspnea Score by Day and Timepoint (Full Analysis Set in Part B) ............... 41 
14.3 Safety ....................................................................................................................... 44 
Adverse Event ..................................................................................................................... 44 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.3.27 Treatment-emergent Adverse Events Summary (Safety Analysis Set in Part B) ......................................... 44 
Table 14.3.28 Treatment-emergent Adverse Events by System Organ Class and Preferred Term (Safety Analysis Set in Part B) ........ 46 
Table 14.3.29 Treatment-emergent Adverse Events Related to Study Medication by System Organ Class and Preferred Term (Safety 
Analysis Set in Part B) ......................................................................................................... 48 
Table 14.3.30 Treatment-emergent Adverse Events by System Organ Class and Preferred Term and Maximum Severity (Safety Analysis Set 
in Part B) ...................................................................................................................... 49 
Table 14.3.31 Treatment-emergent Adverse Events Leading to Discontinuation of Study by System Organ Class and Preferred Term 
(Safety Analysis Set in Part B) ................................................................................................. 51 
Table 14.3.32 Serious Treatment-emergent Adverse Events by System Organ Class and Preferred Term (Safety Analysis Set in Part B) 51 
Table 14.3.33 Serious Treatment-emergent Adverse Events Related to Study Medication by System Organ Class and Preferred Term 
(Safety Analysis Set in Part B) ................................................................................................. 51 
Table 14.3.34 Serious Treatment-emergent Adverse Events by System Organ Class, and Preferred Term and Maximum Severity (Safety 
Analysis Set in Part B) ......................................................................................................... 52 
Table 14.3.35 Serious Treatment-emergent Adverse Events Leading to Discontinaution of Study by System Organ Class and Preferred 
Term (Safety Analysis Set in Part B) ............................................................................................ 52 
Table 14.3.36 Treatment-emergent Adverse Events with Outcome of Death by System Organ Class and Preferred Term (Safety Analysis Set 
in Part B) ...................................................................................................................... 52 
Laboratory ........................................................................................................................ 53 
Table 14.3.37 Hematology Laboratory Data by Day (Safety Analysis Set in Part B) ................................................. 53 
Table 14.3.38 Biochemistry Laboratory Data by Day (Safety Analysis Set in Part B) ............................................... 55 
Table 14.3.39 Urinalysis Laboratory Data by Day (Safety Analysis Set in Part B) ................................................. 55 
Table 14.3.40 Hematology Laboratory Data – Shifts from Baseline in Normal Reference Ranges by Day (Safety Analysis Set in Part B) 56 
Table 14.3.41 Biochemistry Laboratory Data – Shifts from Baseline in Normal Reference Ranges by Day (Safety Analysis Set in Part B)
 ................................................................................................................................ 58 
Table 14.3.42 Urinalysis Laboratory Data – Shifts from Baseline in Normal Reference Ranges by Day (Safety Analysis Set in Part B) 58 
Table 14.3.43 Biochemistry Laboratory Data – Markedly Abnormal Values (Safety Analysis Set in Part B) ........................... 59 
ECG ............................................................................................................................... 60 
Table 14.3.44 12-Lead Electrocardiogram Data by Day and Timepoint (Safety Analysis Set in Part B) ............................... 60 
Table 14.3.45 12-Lead Electrocardiogram – Shifts from Baseline by Day and Timepoint (Safety Analysis Set in Part B) ............. 62 
Vital Signs ....................................................................................................................... 63 
Table 14.3.46 Vital Sign Data – Change from Baseline to Post-dose by Day and Timepoint (Safety Analysis Set in Part B) .......... 63 
Table 14.3.47 Vital Sign Data – Number and Percentage of Markedly Abnormal Values (Safety Analysis Set in Part B) ............... 65 
Table 14.3.48 Change from Baseline Pulse Rate to Peak Pulse Rate (over 4 hours) (Safety Analysis Set in Part B) ................. 67 
Physical Examination .............................................................................................................. 68 
Table 14.3.49 Physical Examination Data by Treatment Period and Timepoint (Safety Analysis Set in Part B) ....................... 68 
Table 14.3.50 Physical Examinations – Shifts from Baseline by Treatment Period and Timepoint (Safety Analysis Set in Part B) .... 70 
Figures............................................................................................................................. 72 
Figure 14.2.6 Geometric Mean of ratios of Peak FEV1 (over 4 hours) to pre-dose FEV1 by Treatment (Full Analysis Set in Part B) ... 72 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Figure 14.2.7 Mean Change from pre-dose FEV1 to Peak FEV1 (over 4 hours) by Treatment (Full Analysis Set in Part B) .............. 73 
Figure 14.2.8 Mean Change from Pre-dose FEV1 during spirometry over Time by Treatment and Day (Full Analysis Set in Part B) ...... 74 
Figure 14.2.9 Kaplan-Meier plot of Time to Onset of Action (>10% Increase in FEV1) on Day 1 (Full Analysis Set in Part B) ........ 75 
Figure 14.3.5 Mean Change from Pre-dose Pulse Rate to Peak Pulse Rate (over 4 hours) by Treatment (Safety Analysis Set in Part B) 76 
Figure 14.3.6 Mean Change from Pre-dose in Pulse Rate over Time by Treatment and Day (Safety Analysis Set in Part B) ............ 76 
Listings............................................................................................................................ 77 
Listing 16.2.1.2 Completed/Discontinued Patients (All Randomized Analysis Set in Part B) ........................................ 77 
Listing 16.2.2.2 Protocol Deviations (All Randomized Analysis Set in Part B) .................................................... 78 
Listing 16.2.3.2 Patient Included in Analysis Sets (All Randomized Analysis Set in Part B) ...................................... 79 
Listing 16.2.4.7 Demographic Characteristics (All Randomized Analysis Set in Part B) ............................................ 80 
Listing 16.2.4.8 Screening Disease Characteristics (All Randomized Analysis Set in Part B) ...................................... 81 
Listing 16.2.4.9 COPD and Smoking History (All Randomized Analysis Set in Part B) ............................................... 82 
Listing 16.2.4.10 Medical History (All Randomized Analysis Set in Part B) ....................................................... 83 
Listing 16.2.4.11 Surgical Procedure History (All Randomized Analysis Set in Part B) ............................................ 84 
Listing 16.2.4.12 Prior and Concomitant Medications (All Randomized Analysis Set in Part B) ..................................... 85 
Listing 16.2.4.13 Prior COPD Medications (All Randomized Analysis Set in Part B) ................................................ 86 
Listing 16.2.5.2 Drug Exposure and Accountability (All Randomized Analysis Set in Part B) ....................................... 87 
Listing 16.2.6.5 Spirometry: FEV1 Results (Full Analysis Set in Part B) .......................................................... 88 
Listing 16.2.6.6 Spirometry: FEV1 Derived Measurements (Full Analysis Set in Part B) ............................................. 89 
Listing 16.2.6.7 Spirometry: FEV1 Time to First Occurrence of Onset of Action (Full Analysis Set in Part B) ...................... 90 
Listing 16.2.6.8 Dyspnea Scale Score (Full Analysis Set in Part B) .............................................................. 91 
Listing 16.2.6.9 Rescue Medications (All Randomized Analysis Set in Part B) ..................................................... 92 
Listing 16.2.6.10 Rescue Medications Canister Dispensed, Weight and Collection Information (All Randomized Analysis Set in Part B)
 ................................................................................................................................ 93 
Listing 16.2.7.6 List of All Adverse Events (Safety Analysis Set in Part B) ..................................................... 94 
Listing 16.2.7.7 Treatment-emergent Adverse Events Leading to Study Discontinutation (Safety Analysis Set in Part B) ............ 95 
Listing 16.2.7.8 Treatment-emergent Adverse Events Leading to Death (Safety Analysis Set in Part B) ............................. 95 
Listing 16.2.7.9 Serious Treatment-emergent Adverse Events (Safety Analysis Set in Part B) ...................................... 95 
Listing 16.2.7.10 Serious Treatment-emergent Adverse Events - Details (Safety Analysis Set in Part B) ........................... 96 
Listing 16.2.8.5 Hematology (Safety Analysis Set in Part B) ..................................................................... 98 
Listing 16.2.8.6 Biochemistry (Safety Analysis Set in Part B) ................................................................... 98 
Listing 16.2.8.7 Urinalysis (Safety Analysis Set in Part B) ..................................................................... 99 
Listing 16.2.9.11 Electrocardiogram Local Reading Overall Evaluation (Safety Analysis Set in Part B) ........................... 100 
Listing 16.2.9.12 12-lead ECG (Safety Analysis Set in Part B) .................................................................. 101 
Listing 16.2.9.13 Vital Signs (Safety Analysis Set in Part B) .................................................................. 102 
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Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.9.14 Vital Signs – Patients with at Least One Markedly Abnormal Finding (Safety Analysis Set in Part B) ........... 103 
Listing 16.2.9.15 Derived Safety Measurements (Safety Analysis Set in Part B) .................................................. 104 
Listing 16.2.9.16 Brief Physical Examination (Safety Analysis Set in Part B) ................................................... 105 
Listing 16.2.9.17 Full Physical Examination (Safety Analysis Set in Part B) .................................................... 106 
Listing 16.2.9.18 Inhalation Training (All Randomized Analysis Set in Part B) .................................................. 107 
Listing 16.2.9.19 Pregnancy Urine Test Results (All Randomized Analysis Set in Part B) ......................................... 108 
Listing 16.2.9.20 Pregnancy Report Results (All Randomized Analysis Set in Part B) ............................................. 109 
 
 
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Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Tables 
14.1 Demographic Data 
Table 14.1.7 Patient Disposition by Treatment Sequence (Part A Completers) 
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Table 14.1.7 
Patient Disposition by Treatment Sequence 
(Part A Completers)  
 
  
Seq 1 
Seq 2 
Seq 3 
Seq 4 
Overall 
Description, n (%) 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
 
 
 
 
 
 
Number of patients conmpleted Part A 
 
 
 
 
xx  
Number of patients to withdrew between Part A and Part B 
 
 
 
 
xx 
Number of patients randomized (n) 
xx  
xx  
xx  
xx  
xx  
Number of patients treated in: 
 
 
 
 
 
  Treatment Period 1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Treatment Period 2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Treatment Period 3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Treatment Period 4 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Number of patients who completed the study 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Number of patients who discontinued the study in: 
 
 
 
 
 
  Treatment Period 1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Treatment Period 2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Treatment Period 3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Treatment Period 4 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Overall 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Primary reason for early study discontinuation 
 
 
 
 
 
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Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Table 14.1.7 
Patient Disposition by Treatment Sequence 
(Part A Completers)  
 
  
Seq 1 
Seq 2 
Seq 3 
Seq 4 
Overall 
Description, n (%) 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
 
 
 
 
 
 
  Adverse event 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Death 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Lost to follow-up 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Pregnancy 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Protocol violation 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Physician decision 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Study terminated by sponsor 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Withdrawal by patient 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Other 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
n = Number of patients. N = Number of patients randomized in Part B. % = Percentage of patients calculated relative to the total 
number of patients in the analysis Set.  
Patients who completed the study excludes patients who withdrew from the study and patients who did not complete all treatment 
periods i.e. a patient who receives a first and last dose intake plus 1 day for all 4 treatment periods per schedule of events. 
Percentages for early discontinuation reasons is calculated based on the number of patients who had early discontinuation data. 
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Source: Listing 16.2.1.2 
 
Output ID: DS001  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
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Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.1.8 Patient Disposition by Treatment Group (All Randomized Analysis Set in Part B) 
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Table 14.1.8 
Patient Disposition by Treatment Group 
(All Randomized Analysis Set in Part B) 
 
  
RPL554 300μg 
RPL554 
1000μg 
RPL554 
3000μg 
Placebo 
Overall 
Description, n (%) 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
 
 
 
 
 
 
Number of patients treated 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Number of patients who completed the study 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Number of patients who discontinued the study 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Primary reason for early study discontinuation 
 
 
 
 
 
  Adverse event 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Death 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Lost to follow-up 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Pregnancy 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Protocol violation 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Physician decision 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Study terminated by sponsor 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Withdrawal by patient 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Other 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
N = Number of patients in the analysis set. % = Percentage of patients calculated relative to the total number of patients in the 
analysis Set.  
Patients who completed the study excludes patients who withdrew from the study and patients who did not complete all treatment 
periods i.e. a patient who receives a first and last dose intake plus 1 day for all 4 treatment periods per schedule of events. 
Percentages for early discontinuation reasons is calculated based on the number of patients who had early discontinuation data. 
 
Source: Listing 16.2.1.2 
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Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Table 14.1.8 
Patient Disposition by Treatment Group 
(All Randomized Analysis Set in Part B) 
 
  
RPL554 300μg 
RPL554 
1000μg 
RPL554 
3000μg 
Placebo 
Overall 
Description, n (%) 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
 
 
 
 
 
 
 
Output ID: DS002 
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Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.1.9 Analysis Set by Treatment Sequence (All Randomized Analysis Sets in Part B) 
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Table 14.1.9 
Analysis Sets by Treatment Sequence  
(All Randomized Analysis Set in Part B) 
 
  
Seq 1 
Seq 2 
Seq 3 
Seq 4 
Overall 
Analysis set, n (%) 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
 
 
 
 
 
 
Randomized Analysis Set 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Safety Analysis Set 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Full Analysis Set 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Completers Analysis Set 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Pharmacokinetics Analysis Set 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
n = Number of patients. N = Number of patients in the analysis set. % = Percentage of patients calculated relative to the total 
number of patients in All Randomized Analysis Set in Part B. 
All Randomized Analysis Set: Randomized patients. 
Safety Analysis Set: Randomized patients who received at least one dose of study medication. 
Full Analysis Set: Patients included in the Safety Analysis Set with sufficient data to compute the pharmacodynamic parameters on at 
least two treatment periods. 
Completers Analysis Set: Patients included in the Safety Analysis Set who complete all treatment periods i.e. a patient who receives 
a first and last dose intake plus 1 day for all 4 treatment periods per schedule of events.  
Pharmacokinetics Analysis Set: Patients included in the All Randomized Analysis Set who have a blood sampling performed after at 
least one dose of study medication and pharmacokinetic parameter data.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Source: Listing 16.2.3.2 
 
Output ID: DS003  
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Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.1.10 Analysis Set by Treatment Group (All Randomized Analysis Sets in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Table 14.1.10 
Analysis Sets by Treatment Group  
(All Randomized Analysis Set in Part B) 
 
  
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
Overall 
Analysis set, n (%) 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
 
 
 
 
 
 
Randomized Analysis Set 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Safety Analysis Set 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Full Analysis Set 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Completers Analysis Set 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Pharmacokinetics Analysis Set 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
n = Number of patients. N = Number of patients randomized. % = Percentage of patients calculated relative to the total number of 
patients in All Randomized Analysis Set in Part B.  
All Randomized Analysis Set: Randomized patients.  
Safety Analysis Set: Randomized patients who received at least one dose of study medication.  
Full Analysis Set: Patients included in the Safety Analysis Set with sufficient data to compute the pharmacodynamic parameters on at 
least two treatment periods.  
Completers Analysis Set: Patients included in the Safety Analysis Set who complete all treatment periods i.e. a patient who receives 
a first and last dose intake plus 1 day for all 4 treatment periods per schedule of events.  
Pharmacokinetics Analysis Set: Patients included in the All Randomized Analysis Set who have a blood sampling performed after at 
least one dose of study medication and pharmacokinetic parameter data. 
 
Source: Listing 16.2.3.2 
 
Output ID: DS004  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
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Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.1.11 Major/Critical Protocol Deviations (All Randomized Analysis Sets in Part B) 
 
 

 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
Table 14.1.11 
Major/Critical Protocol Deviations  
(All Randomized Analysis Set in Part B)  
 
 
 
 
 
 
 
Severity/ 
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
Overall 
  Deviation type 
 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  
 
 
 
 
 
 
Patients with at least one critical/major  
protocol deviation, n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Critical 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Type 1 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Type 2 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  … 
 
 
 
 
 
 
Major 
 
 
 
 
 
 
  …  
  
  
  
  
  
  
CTMS: Clinical trial management system. n = Number of patients. N = Number of patients in the analysis set. % = Percentage of 
patients calculated relative to the total number of patients in the analysis set. Protocol deviations were obtained from CTMS. 
 
Source: Listing 16.2.2.2 
 
Programming Notes 
Deviation types are sorted in descending order of frequency of the Overall column. A patient may have multiple critical/major 
protocol deviations within and is counted once at each level of summarization.   
 
Output ID: DV001  
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Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.1.12 Demographic Characteristics (All Randomized Analysis Sets in Part B)  
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Table 14.1.12 
Demographic Characteristics  
(All Randomized Analysis Set in Part B)   
 
Characteristic / 
RND 
SAF 
 
FAS 
 
CAS 
 
PK 
  Statistics 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
 
 
 
 
 
 
Age (years) 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
Sex, n (%) 
 
 
 
 
 
  Male 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Female 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Childbearing potential, n (%) * 
 
 
 
 
 
  Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Primary race, n (%) 
 
 
 
 
 
  American Indian or Alaska 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Native Asian 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Black or African American 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Native Hawaiian or Other Pacific Islander 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  White 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
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Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Table 14.1.12 
Demographic Characteristics  
(All Randomized Analysis Set in Part B)   
 
Characteristic / 
RND 
SAF 
 
FAS 
 
CAS 
 
PK 
  Statistics 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
 
 
 
 
 
 
  Other 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Ethnicity, n (%) 
 
 
 
 
 
  Hispanic or Latino 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  African American/African Heritage 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Asian-Central/South Asian Heritage 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Asian-East Asian Heritage 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Asian-Southeast Asian Heritage 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  White/Caucasian/European Heritage 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Not reported 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Weight (kg) 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
Height (cm) 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Table 14.1.12 
Demographic Characteristics  
(All Randomized Analysis Set in Part B)   
 
Characteristic / 
RND 
SAF 
 
FAS 
 
CAS 
 
PK 
  Statistics 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
 
 
 
 
 
 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
BMI (kg/m2) 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
  Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
  
  
 
  
 
 
 
BMI: Body Mass Index. SD: Standard deviation.  
n = Number of patients. N = Number of patients in the analysis set. % = Percentage of patients calculated relative to the total number of 
patients in the analysis set. * % = Percentage for childbearing potential calculated relative to the total number of female patients in the 
analysis set.  
All Randomised Analysis Set in Part B (RND): Randomized patients in Part B.  
Safety Analysis Set (SAF): Randomized patients who received at least one dose of study medication.  
Full Analysis Set (FAS): Patients included in the Safety Analysis Set with sufficient data to compute the pharmacodynamic parameters on at 
least two treatment periods.  
Completers Analysis Set (CAS): Patients included in the Safety Analysis Set who complete all treatment periods i.e. a patient who receives a 
first and last dose intake plus 1 day for all 4 treatment periods per schedule of events.  
Pharmacokinetics Analysis Set (PK): Patients included in the All Randomized Analysis Set who have a blood sampling performed after at least 
one dose of study medication and pharmacokinetic parameter data.  
 
Source: Listing 16.2.4.7 
 
Programming Notes 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Table 14.1.12 
Demographic Characteristics  
(All Randomized Analysis Set in Part B)   
 
Characteristic / 
RND 
SAF 
 
FAS 
 
CAS 
 
PK 
  Statistics 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
 
 
 
 
 
 
Print all statistics and categories even if they are empty, except for the row of missings which will only be shown if 
present and is not shown in the shell here. This will not be relevant for ethnicity as there is a category noted as not reported. Therefore, 
no reason why missing should occur. 
 
 
 
 
 
 
 
 
Output ID: DM001  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 

 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.1.13 Screening Disease Characteristics (All Randomized Analysis Sets in Part B)  
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part B 
RPL554 pressurised Metered Dose Inhaler 
  
Table 14.1.13 
Screening Disease Characteristics  
(All Randomized Analysis Set in Part B) 
 
 
 
 
 
 
 
Characteristic / 
 
RND 
SAF 
FAS 
CAS 
PK 
  Statistics 
 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  
 
 
  
  
  
  
Pre-bronchodilator FEV1 (L) 
  
 
 
 
 
  n 
 
xx 
xx 
xx 
xx 
xx 
  Mean  
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
  
 
 
 
 
Post-bronchodilator FEV1 (L) 
 
 
 
 
 
 
  n 
 
xx 
xx 
xx 
xx 
xx 
  Mean  
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
  
 
 
 
 
FEV1 reversibility (mL) 
  
 
 
 
 
  n 
 
xx 
xx 
xx 
xx 
xx 
  Mean  
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
  
 
 
 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part B 
RPL554 pressurised Metered Dose Inhaler 
  
Table 14.1.13 
Screening Disease Characteristics  
(All Randomized Analysis Set in Part B) 
 
 
 
 
 
 
 
Characteristic / 
 
RND 
SAF 
FAS 
CAS 
PK 
  Statistics 
 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  
 
 
  
  
  
  
FEV1 reversibility (%) 
  
 
 
 
 
  n 
 
xx 
xx 
xx 
xx 
xx 
  Mean  
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
  
 
 
 
 
Pre-bronchodilator FVC (L) 
  
 
 
 
 
  n 
 
xx 
xx 
xx 
xx 
xx 
  Mean  
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
  
 
 
 
 
Post-bronchodilator FVC (L) 
  
 
 
 
 
  n 
 
xx 
xx 
xx 
xx 
xx 
  Mean  
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
  
 
 
 
 
Pre-bronchodilator FEV1/FVC 
  
 
 
 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part B 
RPL554 pressurised Metered Dose Inhaler 
  
Table 14.1.13 
Screening Disease Characteristics  
(All Randomized Analysis Set in Part B) 
 
 
 
 
 
 
 
Characteristic / 
 
RND 
SAF 
FAS 
CAS 
PK 
  Statistics 
 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  
 
 
  
  
  
  
  n 
 
xx 
xx 
xx 
xx 
xx 
  Mean  
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
  
 
 
 
 
Post-bronchodilator FEV1/FVC 
  
 
 
 
 
  n 
 
xx 
xx 
xx 
xx 
xx 
  Mean  
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
  
 
 
 
 
Post-bronchodilator FEV1 (% of predicted 
normal) 
  
 
 
 
 
  n 
 
xx 
xx 
xx 
xx 
xx 
  Mean  
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
  
 
 
 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part B 
RPL554 pressurised Metered Dose Inhaler 
  
Table 14.1.13 
Screening Disease Characteristics  
(All Randomized Analysis Set in Part B) 
 
 
 
 
 
 
 
Characteristic / 
 
RND 
SAF 
FAS 
CAS 
PK 
  Statistics 
 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  
 
 
  
  
  
  
 
Reversibility assessment performed with four 
puffs of albuterol, n (%) 
  
 
 
 
 
  Yes 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  No 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  
 
 
 
 
Met protocol requirements of reversibility 
test [a], n (%) 
  
 
 
 
 
  Yes 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  No  
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  
  
 
  
  
  
  
FEV1: Forced expired volume in 1 second. FVC: Forced vital capacity. SD: Standard deviation.  
n = Number of patients. N = Number of patients in the analysis set. % = Percentage of patients calculated relative to the total 
number of patients in the analysis set.  
Pre-, post-bronchodilator and reversibility values are the results of the screening reversibility test. 
[a] Patients meet the protocol requirements of the reversibility test by demonstrating >=150 mL increase from pre-bronchodilator 
FEV1.   
All Randomised Analysis Set in Part B (RND): Randomized patients in Part B.  
Safety Analysis Set (SAF): Randomized patients who received at least one dose of study medication.  
Full Analysis Set (FAS): Patients included in the Safety Analysis Set with sufficient data to compute the pharmacodynamic parameters 
on at least two treatment periods.  
Completers Analysis Set (CAS): Patients included in the Safety Analysis Set who complete all treatment periods i.e. a patient who 
receives a first and last dose intake plus 1 day for all 4 treatment periods per schedule of events.  
Pharmacokinetics Analysis Set (PK): Patients included in the All Randomized Analysis Set who have a blood sampling performed after 
at least one dose of study medication and pharmacokinetic parameter data. 
 
Source: Listing 16.2.4.8 
 
 
Output ID: DM005 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
 
Table 14.1.14 COPD and Smoking History (All Randomized Analysis Sets in Part B)  
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part B 
RPL554 pressurised Metered Dose Inhaler 
 
Table 14.1.14 
COPD and Smoking History  
(All Randomized Analysis Set in Part B) 
 
Variable/ 
 
RND 
SAF 
FAS 
CAS 
PK 
  Category 
 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
 
 
 
 
 
 
 
Duration of COPD (years) (time since diagnosis) 
 
 
 
 
 
 
  n 
 
xx 
xx 
xx 
xx 
xx 
  Mean  
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
Patient known to have Chronic Bronchitis, n (%)   
 
 
 
 
 
  Yes 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  No 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Patient known to have Emphysema, n (%)  
 
 
 
 
 
 
  Yes 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  No 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
  
 
 
 
 
Smoking status, n (%) 
 
 
 
 
 
 
  Current Smokers 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Ex-smokers 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Smoking exposure (pack-years) 
 
 
 
 
 
 
  n 
 
xx 
xx 
xx 
xx 
xx 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part B 
RPL554 pressurised Metered Dose Inhaler 
 
Table 14.1.14 
COPD and Smoking History  
(All Randomized Analysis Set in Part B) 
 
Variable/ 
 
RND 
SAF 
FAS 
CAS 
PK 
  Category 
 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
 
 
 
 
 
 
 
  Mean  
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
  
   
  
  
  
  
COPD: Chronic obstructive pulmonary disease. SD: Standard deviation.  
n = Number of patients. N = Number of patients in the analysis set. % = Percentage of patients calculated relative to the total 
number of patients in the analysis set.  
Smoking exposure (pack-years) = Number of packs per day x Number of years smoking, for patients with a smoking history or a current 
smoker.  
Duration of COPD (years) (time since diagnosis) = (Randomization date – first COPD diagnosis date) / 365.25.  
All Randomised Analysis Set in Part B (RND): Randomized patients in Part B.  
Safety Analysis Set (SAF): Randomized patients who received at least one dose of study medication.  
Full Analysis Set (FAS): Patients included in the Safety Analysis Set with sufficient data to compute the pharmacodynamic 
parameters on at least two treatment periods.  
Completers Analysis Set (CAS): Patients included in the Safety Analysis Set who complete all treatment periods i.e. a patient who 
receives a first and last dose intake plus 1 day for all 4 treatment periods per schedule of events.  
Pharmacokinetics Analysis Set (PK): Patients included in the All Randomized Analysis Set who have a blood sampling performed after 
at least one dose of study medication and pharmacokinetic parameter data. 
 
Source: Listing 16.2.4.9 
 
  
 
 
 
Output ID: MH001 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.1.15 Drug Exposure and Accountability (Safety Analysis Sets in Part B)  
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Table 14.1.15 
Drug Exposure and Accountability  
(Safety Analysis Set in Part B) 
 
Variable/ 
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
Overall 
  Category 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  
 
 
 
 
 
 
Duration of exposure (days) [a] 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
  Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
Drug accountability (weight of pMDI used (g)) 
[b] 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
  Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
  Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
  
 
SD: Standard deviation. 
Study medication administration and accountability data are from the Drug Accountability eCRF page. 
[a] Duration of exposure per period (days) = (Date of last study medication administration – date of first study medication 
administration + 1).  
[b] Drug accountability (weight of pMDI used (g)) = Weight of pMDI dispensed - weight of pMDI returned, including those dispensed 
and taken on site.  
 
Source: Listing 16.2.5.2 
 
 
 
 
 
 
Output ID: DA001  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
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Version 1.0; 17 May 2021
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
14.2 Efficacy 
Primary Efficacy 
Table 14.2.5 FEV1 by Treatment and Timepoint (Full Analyis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
 
 
Table 14.2.5  
FEV1 by Treatment and Timepoint 
(Full Analysis Set in Part B) 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
Statistics 
  
  
Day 
Timepoint 
Treatment group 
Category 
n 
Mean 
SD 
Minimum 
Median 
Maximum 
  
  
  
  
  
  
  
  
  
  
Day 1 
1-hour pre-
dose 
RPL554 300μg (N=XX) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
RPL554 1000μg (N=XX) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
RPL554 3000μg (N=XX) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
Placebo (N=XX) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
 
Immediately 
pre-dose 
RPL554 300μg (N=XX) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
5 mins post-
dose 
RPL554 300μg (N=XX) 
Result  
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
 
Pre-dose 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
 
Change from Pre-dose 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
SD: Standard deviation. FEV1: Forced expiratory volume in 1 second.  
n = Number of patients who have an assessment available at the relevant post-dose assessment timepoint (Result). n = Number of 
patients who have an assessment available at Pre-dose and the relevant post-dose assessment timepoint (Pre-dose and Change from Pre-
dose). N = Number of patients in the analysis set.  
Pre-dose: highest FEV1 result collected immediately pre-dose (within 5 minutes). Change from Pre-dose: Post-dose assessment – 
Baseline.  
 
Source: Listing 16.2.6.5 
 
 
 
 
 
 
 
 
 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 

 
Programming Notes 
Display for the following days and timepoints, relative to dosing:  
Day 1 - 1 hour pre-dose and immediately pre-dose, 5 (± 2), 15 (± 5) and 30 minutes (± 10) and 1, 1.5, 2, 4, 8 and 12 hours (the 
latter assessments all ± 15 minutes). 
Day 7 - 1 hour pre-dose and immediately pre-dose, 30 minutes (± 10) and 1, 1.5, 2, 4, 8, 11 and 12 hours (the latter assessments all 
± 15 minutes). 
 
 
 
 
 
 
 
 
 
 
Output ID: EFF003  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
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Version 1.0; 17 May 2021
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.2.6 Change from Baseline FEV1 to Peak FEV1 (over 4 hours) on Day 7 (Full Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
Table 14.2.6  
Change from Baseline FEV1 to Peak FEV1 (over 4 hours) on Day 7  
(Full Analysis Set in Part B) 
 
 
 
 
 
 
  
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
Day 7 
 
N=XX 
N=XX 
N=XX 
N=XX 
  
 
  
  
  
  
Baseline FEV1 (L) 
 
 
 
 
 
  n [a] 
 
xx 
xx 
xx 
xx 
  Mean (SD) 
 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
  Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
Peak FEV1 (L) 
 
 
 
 
 
  Mean (SD) 
 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
  Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
Change from Baseline FEV1  
 
 
 
 
 
  Mean (SD) 
 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
  Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
  Min, Max 
 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
Estimates from ANCOVA [b] 
 
 
 
 
 
    n [c] 
 
xx 
xx 
xx 
xx 
    GeoMean  
 
xx.x 
xx.x 
xx.x 
xx.x 
    95% CI for GeoMean  
 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
 
 
 
 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
Table 14.2.6  
Change from Baseline FEV1 to Peak FEV1 (over 4 hours) on Day 7  
(Full Analysis Set in Part B) 
 
 
 
 
 
 
  
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
Day 7 
 
N=XX 
N=XX 
N=XX 
N=XX 
  
 
  
  
  
  
  Comparisons Against Placebo 
 
 
 
 
 
    Treatment Effect - ANCOVA [c] 
 
 
 
 
 
    GeoMean Ratio 
 
xx.x 
xx.x 
xx.x 
 
    95% CI for GeoMean Ratio 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
    p-value 
 
x.xxxx 
x.xxxx 
x.xxxx 
 
 
 
 
 
 
 
  Comparisons Against RPL554 doses 
 
 
 
 
 
    Treatment Effect - ANCOVA [c] 
 
 
Comparison Against 
RPL554 300μg 
Comparison Against 
RPL554 1000μg 
 
    GeoMean Ratio 
 
 
xx.x 
xx.x 
 
    95% CI for GeoMean Ratio 
 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
    p-value 
 
 
x.xxxx 
x.xxxx 
 
  
  
  
  
  
  
ANCOVA: Analysis of covariance. CI: Confidence interval. FEV1: Forced expiratory volume in 1 second. GeoMean: Geometric mean. GeoMean 
Ratio: Geometric mean ratio. SD: Standard deviation.  
N = Number of patients in the analysis set.  
Baseline: average of the FEV1 pre-dose assessments collected on Day 1 (within 60 and 5 minutes).  
[a] number of patients with valid values at baseline and peak.  
[b] ANCOVA model is used to model the change from baseline using baseline FEV1 as a continuous fixed effect and planned treatment and 
treatment period as categorical fixed effects.  
[c] number of patients with at least one on treatment value who contributed to the model estimation.  
* Indicates a significant adjusted p-value (<0.05). 
 
Source: Listing 16.2.6.6 
 
Output ID: EFF004  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
 
Table 14.2.6a Change from Baseline FEV1 to Peak FEV1 (over 4 hours) on Day 7 – Sensitivity Analysis (Completers Analysis Set in Part B) 
 


 
 
EFF005: This output uses shell EFF004 [Table 14.2.6] 
 
 
 
 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Secondary Efficacy 
Table 14.2.7 Average FEV1 by Day and Treatment Group (Full Analysis Set in Part B) 
 
EFF006: This output uses shell EFF003 [Table 14.2.5] 
 
AUC: Area under the curve. SD: Standard deviation.  
n = Number of patients who have an assessment available at the relevant post-dose assessment timepoint (Result). n = Number of 
patients who have an assessment available pre-dose and the relevant post-dose assessment timepoint (Pre-dose and Change from Pre-
dose). N = Number of patients in the analysis set.  
Pre-dose: average of the FEV1 pre-dose assessments (-60 minutes and -5 minutes). Change from Pre-dose: Post-dose assessment – Pre-
dose. AUC: If a patient misses’ the last two assessments in the time interval measured, or does not have any pre-dose assessments 
then the AUC is set to missing.  
 
Source: Listing 16.2.6.6 
 
 
Programming Notes 
Replace footnotes in original shell with tha listed above. 
Amend the presentation to AUC. 
To be presented for both AUC0-4h and AUC0-12h on Day 1 and Day 7, respectively.  
 
 

 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.2.8 Change from Baseline FEV1 to Average FEV1 (over 4 hours) on Day 7 (Full Analysis Set in Part B) 
 
EFF007: This output uses shell EFF004 [Table 14.2.6] 
 
ANCOVA: Analysis of covariance. AUC: Area under the curve. CI: Confidence interval. FEV1: Forced expiratory volume in 1  
second. GeoMean: Geometric mean. GeoMean Ratio: Geometric mean ratio. SD: Standard deviation.  
N = Number of patients in the analysis set.  
Baseline: average of the FEV1 pre-dose assessments collected on Day 1 (within 60 and 5 minutes). 
[a] number of patients with valid values at baseline and average.  
[b] ANCOVA model is used to model the change from baseline AUC0-t using baseline FEV1 as a continuous fixed effect and actual 
treatment and treatment period as categorical fixed effects.  
[c] number of patients with at least one on treatment value who contributed to the model estimation.  
* Indicates a significant adjusted p-value (<0.05).  
 
Source: Listing 16.2.6.6 
 
Programming Notes 
Replace footnotes in original shell with those listed above. 
 
 
 

 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.2.9 Change from Baseline FEV1 to Average FEV1 (over 12 hours) on Day 7 (Full Analysis Set in Part B) 
 
 
 
 
Table 14.2.9a Change from Baseline FEV1 to Average FEV1 (over 12 hours) on Day 7 – Sensitivity Analysis (Full Analysis Set in Part B) 
 
 
 
EFF008: This output uses shell EFF004 [Table 14.2.6] 
 
ANCOVA: Analysis of covariance. AUC: Area under the curve. CI: Confidence interval. FEV1: Forced expiratory volume in 1  
second. GeoMean: Geometric mean. GeoMean Ratio: Geometric mean ratio. SD: Standard deviation.  
N = Number of patients in the analysis set.  
Baseline: average of the FEV1 pre-dose assessments collected on Day 1 (within 60 and 5 minutes). 
[a] number of patients with valid values at baseline and average.  
[b] ANCOVA model is used to model the change from baseline AUC0-t using baseline FEV1 as a continuous fixed effect and actual 
treatment and treatment period as categorical fixed effects.  
[c] number of patients with at least one on treatment value who contributed to the model estimation.  
* Indicates a significant adjusted p-value (<0.05).  
 
Source: Listing 16.2.6.6 
Programming Notes 
Replace footnotes in original shell with those listed above 
 
 
EFF009: This output uses shell EFF004 [Table 14.2.6] 
 
ANCOVA: Analysis of covariance. AUC: Area under the curve. CI: Confidence interval. FEV1: Forced expiratory volume in 1  
second. GeoMean: Geometric mean. GeoMean Ratio: Geometric mean ratio. SD: Standard deviation.  
N = Number of patients in the analysis set.  
Baseline: average of the FEV1 pre-dose assessments collected on Day 1 (within 60 and 5 minutes). 
Includes subjects who took rescue medication less than 6 hours prior to spirometry. 
[a] number of patients with valid values at baseline and average.  
[b] ANCOVA model is used to model the change from baseline AUC0-t using baseline FEV1 as a continuous fixed effect and actual 
treatment and treatment period as categorical fixed effects.  
[c] number of patients with at least one on treatment value who contributed to the model estimation.  
* Indicates a significant adjusted p-value (<0.05).  
 
Source: Listing 16.2.6.6 
 
Programming Notes 
Replace footnotes in original shell with those listed above 
Only include if at least 1 subject has taken rescue medication less than 6 hours prior to spirometry (ANL02FL=”Y”) 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.2.10 Change from Baseline FEV1 to Morning Trough FEV1 on Day 7 (Full Analysis Set in Part B) 
 
 
 

 
 
 
 
 
 
 
 
EFF0010: This output uses shell EFF004 [Table 14.2.6] 
 
 
 
 
 
 
 
ANCOVA: Analysis of covariance. CI: Confidence interval. FEV1: Forced expiratory volume in 1 second. GeoMean: Geometric mean. GeoMean 
Ratio: Geometric mean ratio. SD: Standard deviation.  
N = Number of patients in the analysis set.  
Baseline: average of the FEV1 pre-dose assessments collected on Day 1 (within 60 and 5 minutes). 
Morning trough FEV1 is the average of the FEV1 pre-dose assessments (-60 minutes and -5 minutes) on Day 7.  
[a] number of patients with valid values at baseline and morning trough.  
[b] ANCOVA model is used to model the change from baseline in morning trough FEV1 using baseline FEV1 as a continuous fixed effect, 
actual treatment and treatment period as categorical fixed effects.  
[c] number of patients with at least one on treatment value who contributed to the model estimation.  
* Indicates a significant p-value (<0.05).  
 
Source: Listing 16.2.6.6 
 
 
 
 
 
 
 
Programming Notes 
Replace footnotes in original shell with those listed above 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.2.11 Change from Baseline FEV1 to Peak FEV1 (over 4 hours) on Day 1 (Full Analysis Set in Part B) 
 
 
 
 
 
Table 14.2.12 Change from Baseline FEV1 to Average FEV1 (over 4 hours) on Day 1 (Full Analysis Set in Part B) 
 
 
EFF12: This output uses shell EFF006 [Table 14.2.8] 
 
 
Programming Notes 
Footnotes should be the same as Table 14.2.8 
 
 
 
 
 
 
Table 14.2.13 Change from Baseline FEV1 to Average FEV1 (over 12 hours) on Day 1 (Full Analysis Set in Part B) 
 
EFF13: This output uses shell EFF007 [Table 14.2.9] 
 
Programming Notes 
Footnotes should be the same as Table 14.2.9 
 

 
 
EFF11: This output uses shell EFF004 [Table 14.2.6] 
 
Programming Notes 
Footnotes should be the same as Table 14.2.6 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.2.14 Time to Onset of Action (>10% Increase in FEV1) on Day 1 (Full Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Table 14.2.14  
Time to Onset of Action (>10% Increase in FEV1) on Day 1  
(Full Analysis Set in Part B) 
 
  
  
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Parameter 
Statistics 
 
N=XX 
N=XX 
N=XX 
  
  
 
  
  
  
Number of patients with onset of action 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
  
 
 
Number of patients censored 
n (%) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Time to onset of action (mins) 
P25 
 
x.x 
x.x 
x.x 
 
Median (Min, Max) 
 
x.x (x.x, x.x) 
x.x (x.x, x.x) 
x.x (x.x, x.x) 
 
P75 
 
x.x 
x.x 
x.x 
 
 
 
 
 
 
 
Hodges-Lehmann Median difference 
to RPL554 3000μg 
 
x.x 
x.x 
 
 
p-value 
 
x.xxxx 
x.xxxx 
 
 
 
 
 
 
 
n = Number of patients with onset of action. % = Percentage of patients calculated relative to the total number of patients in the 
analysis set.  
Time to onset of action (mins): Time of onset of action (defined as >10% increase in FEV1 from pre-first dose) = Time of onset of 
action (or censoring time) – time of end of inhalation (mins).  
P25, Median and P75: Patients not experiencing onset of action are censored at 120 mins or at time of premature discontinuation 
(if withdrawn before 120 minutes).  
p-value is based on a Gehan-Wilcoxon test between treatment groups and highest dose (RPL554 3000μg). 
 
Source: Listing 16.2.6.7 
 
 
 
 
 
 
 
 
Programming Notes 
Only present if the number of onset of action cases are sufficient to calculate the statistics presented (≥ 10% of patients with 
onset of action). 
The pre-dose value is inserted at time 0. 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Table 14.2.14  
Time to Onset of Action (>10% Increase in FEV1) on Day 1  
(Full Analysis Set in Part B) 
 
  
  
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Parameter 
Statistics 
 
N=XX 
N=XX 
N=XX 
  
  
 
  
  
  
 
Output ID: EFF14  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.2.15 Rescue Medication Use (Full Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
 
 
Table 14.2.15 
Rescue Medication Use 
(Full Analysis Set in Part B) 
 
 
 
 
 
 
 
 
 
 
  
  
Statistics 
Treatment group 
Category 
n 
Mean 
SD 
Minimum 
Median 
Maximum 
 
 
 
 
 
 
 
 
RPL554 300μg (N=XX) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
RPL554 1000μg (N=XX) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
RPL554 3000μg (N=XX) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
Placebo (N=XX) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
SD: Standard deviation. n = Number of patients who have an assessment available at the relevant post-dose assessment timepoint 
(Result). N = Number of patients in the analysis set. The average number of puffs of rescue medication taken per day between days 1 
and 7 (inclusive) for each treatment period was collected in the patient diaries.  
 
Source: Listing 16.2.6.9 
 
Programming Notes 
Use information from the patient diarys (number of puffs). 
For each treatment period calculate the average of the 7 days. 
If less than 4 days have results between days 1 and 7 then no result will be presented for that treatment period. 
 
Output ID: EFF15  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
 
 
 
 
 
 
 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
 
Exploratory Efficacy 
Table 14.2.16 Dyspnea Scale by Day and Timepoint (Full Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
 
 
Table 14.2.16  
Dyspnea Scale by Day and Timepoint  
(Full Analysis Set in Part B) 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
Statistics 
Day 
Timepoint 
Treatment group 
Category 
n 
Mean 
SD 
Minimum 
Median 
Maximum 
Day 1 
Pre-dose 
RPL554 300μg (N=XX) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
RPL554 1000μg (N=XX) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
RPL554 3000μg (N=XX) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
Placebo (N=XX) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
 
30 mins post-dose 
RPL554 300μg (N=XX) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
 
Baseline 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
 
CFB 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
 
 
RPL554 1000μg (N=XX) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
1 hour post-dose 
RPL554 300μg (N=XX) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
CFB: Change from Baseline. SD: Standard deviation.  
n = Number of patients who have an assessment available at the relevant post-dose assessment timepoint (Result). n = Number of 
patients who have an assessment available at Baseline and the relevant post-dose assessment timepoint (Baseline and Change from 
Baseline). N = Number of patients in the analysis set.  
Baseline dyspnea score is defined as the value of dyspnea assessed prior to dosing on day 1 of treatment period 1.  
Change from Baseline: Post-dose assessment – Baseline.  
 
Source: Listing 16.2.6.8 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
 
 
Table 14.2.16  
Dyspnea Scale by Day and Timepoint  
(Full Analysis Set in Part B) 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
Statistics 
Day 
Timepoint 
Treatment group 
Category 
n 
Mean 
SD 
Minimum 
Median 
Maximum 
Day 1 
Pre-dose 
RPL554 300μg (N=XX) 
Result 
xx 
xx.x 
xx.xx 
xx.xx 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
 
Programming Notes 
Display for the following day and timepoints, relative to dosing:  
Day 1 – 30 minutes and 1, 1.5, 2, 4, 8 and 12 hours post-dose 
Day 7 - 30 minutes and 1, 1.5, 2, 4, 8, 11 and 12 hours post-dose 
Output ID: EFF16  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.2.17 Comparison of Change from Baseline Dyspnea Score by Day and Timepoint (Full Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
  
 
 
 
Table 14.2.17 
Comparisons of Change from Baseline Dyspnea Score by Day and Timepoint  
(Full Analysis Set in Part B) 
 
 
 
  
 
 
 
  
  
  
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
Day 
Timepoint 
Statistic 
 
N=XX 
N=XX 
N=XX 
N=XX 
Day 1 
Pre-dose 
Baseline Dyspnea Score 
 
 
 
 
 
 
 
 
    n [a] 
 
xx 
xx 
xx 
xx 
 
 
 
    Mean (SD) 
 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
    Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
    Min, Max 
 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
Day 7 
Pre-dose 
Dyspnea Score 
 
 
 
 
 
 
 
 
    n 
 
xx 
xx 
xx 
xx 
 
 
 
    Mean (SD) 
 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
    Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
    Min, Max 
 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
CFB Dyspnea Score 
 
 
 
 
 
 
 
 
    Mean (SD) 
 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
    Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
    Min, Max 
 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
Estimates from ANCOVA [b] 
 
 
 
 
 
 
 
 
    n [c] 
 
xx 
xx 
xx 
xx 
 
 
 
    LSMean  
 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
    95% CI for LSMean  
 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
  
 
 
 
Table 14.2.17 
Comparisons of Change from Baseline Dyspnea Score by Day and Timepoint  
(Full Analysis Set in Part B) 
 
 
 
  
 
 
 
  
  
  
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
Day 
Timepoint 
Statistic 
 
N=XX 
N=XX 
N=XX 
N=XX 
 
 
  Comparisons Against Placebo 
 
 
 
 
 
 
 
 
    Treatment Effect - ANCOVA [c] 
 
 
 
 
 
 
 
 
    LSMean Diff 
 
xx.x 
xx.x 
xx.x 
 
 
 
 
    95% CI for LSMean Diff 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
 
 
 
    p-value 
 
x.xxxx 
x.xxxx 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Comparisons Against RPL554 doses 
 
 
 
 
 
 
 
 
    Treatment Effect - ANCOVA [c] 
 
 
Comparison 
Against RPL554 
300μg 
Comparison 
Against RPL554 
1000μg 
 
 
 
 
    LSMean Diff 
 
 
xx.x 
xx.x 
 
 
 
 
    95% CI for LSMean Diff 
 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
 
 
 
    p-value 
 
 
x.xxxx 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
30 mins  
post-dose 
… 
 
… 
… 
.. 
… 
 
  
  
  
    
  
  
  
 
ANCOVA: Analysis of covariance. CFB: Change from Baseline. CI: Confidence interval. LSMean: Least square mean. LSMean Diff: Least 
squares mean difference. SD: Standard deviation.  
N = Number of patients in the analysis set. n = Number of patients who have an assessment available pre-dose and the relevant post-
baseline timepoint. Baseline: Day 1 pre-dose Dyspnea Score.  
[a] number of patients with valid values at baseline and post-baseline.  
[b] ANCOVA model is used to model the change from baseline using baseline Dyspnea Score as a continuous fixed effect and planned 
treatment and treatment period as categorical fixed effects.  
[c] number of patients with at least one on treatment value who contributed to the model estimation.  
* Indicates a significant adjusted p-value (<0.05).  
 
Source: Listing 16.2.6.8 
 
 
 
 
  
 
 
 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
  
 
 
 
Table 14.2.17 
Comparisons of Change from Baseline Dyspnea Score by Day and Timepoint  
(Full Analysis Set in Part B) 
 
 
 
  
 
 
 
  
  
  
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
Day 
Timepoint 
Statistic 
 
N=XX 
N=XX 
N=XX 
N=XX 
Programming Notes 
Display for the following day and timepoints, relative to dosing:  
Day 1 – Pre-dose (Baseline), 30 minutes and 1, 1.5, 2, 4, 8 and 12 hours post-dose 
Day 7 – Pre-dose, 30 minutes and 1, 1.5, 2, 4, 8, 11 and 12 hours post-dose 
 
 
 
  
 
 
 
 
Output ID: EFF17  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
14.3 Safety 
Adverse Event 
Table 14.3.27 Treatment-emergent Adverse Events Summary (Safety Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Table 14.3.27  
Treatment-emergent Adverse Events Summary  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
  
RPL554 
RPL554 
RPL554 
  
  
 
300μg 
1000μg 
3000μg 
Placebo 
Overall 
Variable/ 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  Category 
n (%) E 
n (%) E 
n (%) E 
n (%) E 
n (%) E 
  
  
  
  
  
  
Any TEAE 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
Any TEAE related to study medication 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
Any TEAE leading to study discontinuation 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
Any TEAEs classified by maximum severity, n (%) 
 
 
 
 
 
  Mild 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
  Moderate 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
  Severe 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Any TEAE leading to death 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
Any serious TEAE 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
Any serious TEAE related to study medication 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
Any serious TEAE leading to study discontinuation 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
Any serious TEAEs classified by maximum severity, n (%) 
 
 
 
 
 
  Mild 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
  Moderate 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
  Severe 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Table 14.3.27  
Treatment-emergent Adverse Events Summary  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
  
RPL554 
RPL554 
RPL554 
  
  
 
300μg 
1000μg 
3000μg 
Placebo 
Overall 
Variable/ 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  Category 
n (%) E 
n (%) E 
n (%) E 
n (%) E 
n (%) E 
  
  
  
  
  
  
  
  
  
  
  
  
  
TEAE: Treatment-emergent adverse event.  
n = Number of patients with at least one TEAE in each category. E = Number of mentions (events) in each category. N = Number of 
patients in the analysis set. % = Percentage of patients calculated relative to the total number of patients in the analysis set.  
TEAE = All AEs that started or worsened in severity on or after the first dose of study medication, based on the investigator 
assessment of severity.  
TEAEs with a missing relationship to study medication will be regarded as related to study medication.  
TEAEs starting after the first dose of study medication with a missing severity will be classified as severe.  
Overall group TEAEs are independent of treatment group. Overall = Presented for all patients in the Safety Analysis Set. 
 
Source: Listing 16.2.7.6 
 
Output ID: AE001  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.3.28 Treatment-emergent Adverse Events by System Organ Class and Preferred Term (Safety Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
Table 14.3.28  
Treatment-emergent Adverse Events by System Organ Class and Preferred Term  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
 
System Organ Class (%) 
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
Overall 
  Preferred Term (%) [a] 
 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  
 
  
  
  
  
  
Patients with at least one TEAE, n (%) E 
 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
xx (xx.x) xx 
 
 
 
 
 
 
 
  System Organ Class #1 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Preferred Term #1 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Preferred Term #2 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
  System Organ Class #2 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Preferred Term #1 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Preferred Term #2 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
… 
 
 
 
 
 
 
PT: Preferred term. SOC: System organ class. TEAE: Treatment-emergent adverse event.  
n = Number of patients with at least one TEAE in each category. E = Number of mentions (events) in each category. N = Number of 
patients in the analysis set. % = Percentage of patients calculated relative to the total number of patients in the analysis set.  
TEAE = All AEs that started or worsened in severity on or after the first dose of study medication, based on the investigator 
assessment of severity.  
Each patient is counted once for each applicable specific AE, and a patient with multiple AEs within an SOC is counted once for that 
SOC.  
[a] SOCs and PTs are coded using the MedDRA (Version 21.0). 
 
Source: Listing 16.2.7.6 
 
Programming Notes 
SOCs and PTs within each SOC are sorted in descending order of percentage in the Overall group. 
 
Output ID: AE002  
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
Table 14.3.28  
Treatment-emergent Adverse Events by System Organ Class and Preferred Term  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
 
System Organ Class (%) 
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
Overall 
  Preferred Term (%) [a] 
 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  
 
  
  
  
  
  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
 

 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.3.29 Treatment-emergent Adverse Events Related to Study Medication by System Organ Class and Preferred Term (Safety Analysis 
Set in Part B) 
 
 

 
 
AE003: This output uses shell AE002 [Table 14.3.28] 
 
PT: Preferred term. SOC: System organ class. TEAE: Treatment-emergent adverse event.  
n = Number of patients with at least one related TEAE in each category. E = Number of mentions (events) in each category. N = Number 
of patients in the analysis set. % = Percentage of patients calculated relative to the total number of patients in the analysis set. 
TEAE = All AEs that started or worsened in severity on or after the first dose of study medication, based on the investigator 
assessment of related or not.  
Each patient is counted once for each applicable specific AE, and a patient with multiple AEs within an SOC is counted once for that 
SOC.  
[a] SOCs and PTs are coded using the MedDRA (Version 21.0).  
 
Source: Listing 16.2.7.6 
Programming Notes: 
Replace footnotes in original shell with those listed above 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.3.30 Treatment-emergent Adverse Events by System Organ Class and Preferred Term and Maximum Severity (Safety Analysis Set in 
Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
Table 14.3.30 
Treatment-emergent Adverse Events by System Organ Class, Preferred Term and Maximum Severity  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
 
 
System Organ Class (%) 
Maximum 
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
Overall 
  Preferred Term, n (%) [a] 
Severity 
 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  
  
 
  
  
  
  
  
Patients with at least one TEAE, n (%) 
Severe 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Mild 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
System Organ Class #1 
Severe 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Mild 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Preferred Term #1 
Severe 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Mild 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Preferred Term #2 
Severe 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Mild 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
System Organ Class #2 
Severe 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Mild 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
… 
… 
 
… 
… 
… 
… 
… 
PT: Preferred term. SOC: System organ class. TEAE: Treatment-emergent adverse event.  
n = Number of patients with at least one TEAE in each category. N = Number of patients in the analysis set. % = Percentage of 
patients calculated relative to the total number of patients in the analysis set.  
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
Table 14.3.30 
Treatment-emergent Adverse Events by System Organ Class, Preferred Term and Maximum Severity  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
 
 
System Organ Class (%) 
Maximum 
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
Overall 
  Preferred Term, n (%) [a] 
Severity 
 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  
  
 
  
  
  
  
  
TEAE = All AEs that started or worsened in severity on or after the first dose of study medication, based on the investigator 
assessment of severity.  
Each patient is counted once for each applicable specific TEAE at the maximum severity and a patient with multiple TEAEs within an 
SOC is counted once for that SOC at the maximum severity.  
[a] SOCs and PTs are coded using MedDRA (Version 21.0).  
TEAEs starting after the first dose of study medication with a missing severity will be classified as missing.  
Overall = Presented for all patients in the Safety Analysis Set. 
 
Source: Listing 16.2.7.6 
 
Programming Note 
SOCs and PTs within each SOC are sorted in descending order of percentage in the Overall group.> 
 
 
Output ID: AE004  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
 
 

 
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Version 1.0; 17 May 2021
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.3.31 Treatment-emergent Adverse Events Leading to Discontinuation of Study by System Organ Class and Preferred Term (Safety 
Analysis Set in Part B) 
 
AE005: This output uses shell AE004 [Table 14.3.28] 
 
 
 
 
 
 
 
Programming Notes 
Use the same template of table 14.3.28, selecting only the TEAEs leading to discontinuation of study medications and update “Any 
TEAE” to “Any TEAE leading to discontinuation of study”.  
Update source footnote to “Source: Listing 16.2.7.7”. 
 
 
 
 
Table 14.3.32 Serious Treatment-emergent Adverse Events by System Organ Class and Preferred Term (Safety Analysis Set in Part B) 
 
AE006: This output uses shell AE002 [Table 14.3.28] 
 
      
Programming Notes 
Replace footnotes in original shell updating “Patients with at least one TEAE” to “Patients with at least one serious TEAE”. 
Update source footnote from to “Source: Listing 16.2.7.9”. 
 
 
 
 
Table 14.3.33 Serious Treatment-emergent Adverse Events Related to Study Medication by System Organ Class and Preferred Term (Safety 
Analysis Set in Part B) 
 
AE007: This output uses shell AE003 [Table 14.3.28] 
 
  
 
  
 
Programming Notes 
Use the same template of Table 14.3.28, selecting only the serious TEAEs and update “Patients with at least one TEAE” to “Patients 
with at least one serious TEAE”. 
Update source footnote from to “Source: Listing 16.2.7.9”. 
 
 
 
 
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Version 1.0; 17 May 2021
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.3.34 Serious Treatment-emergent Adverse Events by System Organ Class, and Preferred Term and Maximum Severity (Safety 
Analysis Set in Part B) 
 
AE008: This output uses shell AE004 [Table 14.3.30] 
 
  
 
   
Programming Notes 
Use the same template of Table 14.3.28, selecting only the serious TEAEs and update “Patients with at least one TEAE” to “Patients 
with at least one serious TEAE”. 
Update source footnote to “Source: Listing 16.2.7.9”. 
 
 
 
Table 14.3.35 Serious Treatment-emergent Adverse Events Leading to Discontinaution of Study by System Organ Class and Preferred Term 
(Safety Analysis Set in Part B) 
 
AE009: This output uses shell AE005 [Table 14.3.28] 
 
 
 
 
 
 
 
Programming Notes 
Use the same template of Table 14.3.29, selecting only the serious TEAEs and update “Any TEAE leading to discontinuation of study” 
to “Any serious TEAE leading to discontinuation of study”. Also update “n = Number of patients with at least one related TEAE in 
each category.” to “n = Number of patients with at least one serious TEAE leading to discontinuation of study.”. 
Update source footnote to “Source: Listing 16.2.7.9”. 
 
 
 
Table 14.3.36 Treatment-emergent Adverse Events with Outcome of Death by System Organ Class and Preferred Term (Safety Analysis Set in 
Part B) 
 
AE010: This output uses shell AE002 [Table 14.3.28] 
 
      
Programming Notes 
Replace footnotes in original shell updating “Patients with at least one TEAE” to “Patients with a TEAE with outcome of death”. 
Update source footnote to “Source: Listing 16.2.7.8”. 
 

 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Laboratory 
Table 14.3.37 Hematology Laboratory Data by Day (Safety Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
Table 14.3.37  
Hematology Laboratory Data by Day  
(Safety Analysis Set in Part B)  
 
 
 
 
 
 
 
Laboratory Test 
RPL554 
RPL554 
RPL554 
  
  
  Time Point 
300μg 
1000μg 
3000μg 
Placebo 
Overall 
    Statistics 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  
  
  
 
  
  
Test #1 (unit) 
 
 
 
 
 
  Baseline 
 
 
 
 
 
    n 
xx 
xx 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    Min, Max 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
  Day 7 
 
 
 
 
 
    Observed 
 
 
 
 
 
      n  
xx 
xx 
xx 
xx 
 
      Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
      SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
      Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
      Min, Max 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
    Change from Baseline 
 
 
 
 
 
      Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
      SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
Table 14.3.37  
Hematology Laboratory Data by Day  
(Safety Analysis Set in Part B)  
 
 
 
 
 
 
 
Laboratory Test 
RPL554 
RPL554 
RPL554 
  
  
  Time Point 
300μg 
1000μg 
3000μg 
Placebo 
Overall 
    Statistics 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  
  
  
 
  
  
      Median 
xx.x 
xx.x 
xx.x 
xx.x 
 
      Min, Max 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
Test #2 (unit) 
… 
… 
… 
… 
 
  
  
  
  
  
  
SD: Standard deviation.  
n = Number of patients with a Baseline value and a post-baseline value. N = Number of patients in the analysis set.  
Change from Baseline: (Post-baseline assessment – Baseline).  
Baseline: Defined as the pre-dose assessment for each treatment period.  
Overall: Presented for all patients in the first treatment period in the Safety Analysis Set. Overall n = Number of Baseline values 
with an assessment available at Baseline and at least one post-dose assessment for treatment period 1. 
 
Source: Listing 16.2.8.5 
 
 
 
 
 
 
 
Programming Notes 
Blood samples will be taken and tested at the laboratory for the following hematology laboratory tests: Hemoglobin, hematocrit, 
total white cell count, leukocyte differential count and platelet count. Present in alphabetical order. 
 
 
 
 
 
 
 
 
Output ID: LB001  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
 
 

 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.3.38 Biochemistry Laboratory Data by Day (Safety Analysis Set in Part B) 
 
 
 
 
 
 
Table 14.3.39 Urinalysis Laboratory Data by Day (Safety Analysis Set in Part B) 
 
 
 
 
 
 
 
LB007: This output uses shell LB001 [Table 14.3.37] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Notes 
Repeat 14.3.37 for Urinalysis (includes Leukocytes esterase, occult blood, ketones, bilirubin, urobilinogen, protein and glucose. If 
urinalysis on Dipstick is positive for leucocytes and/or blood/hemoglobin, a microscopic examination including erythrocytes, 
leucocytes, bacteria, casts, epithelial cells and crystals). Present in alphabetical order. 
Update source footnote to “Source: Listing 16.2.8.7”. 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
LB002: This output uses shell LB001 [Table 14.3.37] 
Programming Notes 
Repeat 14.3.37 for Biochemistry (includes creatinine, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine 
transaminase, gamma-glutamyl transferase, lactate dehydrogenase, creatine kinase, thyroid stimulating hormone, triiodothyronine and 
thyroxine, glucose, potassium, sodium, calcium. Present in alphabetical order. 
Update source footnote to “Source: Listing 16.2.8.6”. 
Add footnote “A number of missing chemistry labs are due to a processing issues such as hemolyzed samples.”.  
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.3.40 Hematology Laboratory Data – Shifts from Baseline in Normal Reference Ranges by Day (Safety Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
Table 14.3.40  
Hematology Laboratory Data - Shifts from Baseline in Normal Reference Ranges by Day  
(Safety Analysis Set in Part B)  
 
 
 
 
 
 
 
 
 
  
  
Category at Time Point  
  
Laboratory Test 
 
 
  
  
  
 
  Day 
 
Baseline 
Low 
Normal 
High 
Total 
    Treatment 
N [a] 
Category 
n (%) 
n (%) 
n (%) 
n (%) 
  
  
  
  
  
  
  
Test #1 
 
 
 
 
 
 
  Day 7 
 
 
 
 
 
 
    RPL554 300μg 
xx 
Low 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
High 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
    RPL554 1000μg 
xx 
Low 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
High 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
    RPL554 3000μg 
xx 
    …  
    …  
    …  
    …  
    …  
    …  
 
    …  
    …  
    …  
    …  
    …  
 
 
    …  
    …  
    …  
    …  
    …  
 
 
    …  
    …  
    …  
    …  
    …  
  End of Study 
 
 
 
 
 
 
    Overall 
xx 
    …  
    …  
    …  
    …  
    …  
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
Table 14.3.40  
Hematology Laboratory Data - Shifts from Baseline in Normal Reference Ranges by Day  
(Safety Analysis Set in Part B)  
 
 
 
 
 
 
 
 
 
  
  
Category at Time Point  
  
Laboratory Test 
 
 
  
  
  
 
  Day 
 
Baseline 
Low 
Normal 
High 
Total 
    Treatment 
N [a] 
Category 
n (%) 
n (%) 
n (%) 
n (%) 
  
  
  
  
  
  
  
 
 
    …  
    …  
    …  
    …  
    …  
 
 
    …  
    …  
    …  
    …  
    …  
Test #2 
 
 
 
 
 
 
  …  
 
 
 
 
 
 
  
  
  
  
  
  
  
LLN: Lower limit of normal reference range. ULN: Upper limit of normal reference range.  
n = Number of patients. [a] N = Number of patients with a baseline value and a post-baseline value at the time point. Percentages 
are based on N.  
Reference range classification: Low: < LLN. Normal: >= LLN to <= ULN. High: > ULN.  
Baseline: Defined as the pre-dose assessment for each treatment period.  
End of Study: Defined as the last available assessment assigned to study. 
 
Source: Listing 16.2.8.5 
 
 
 
 
 
 
 
Programming Notes 
Blood samples will be taken and tested at the laboratory for the following laboratory tests: Hemoglobin, hematocrit, total white 
cell count, leukocyte differential count and platelet count. Present in alphabetical order. 
 
 
 
 
 
 
 
 
Output ID: LB003  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.3.41 Biochemistry Laboratory Data – Shifts from Baseline in Normal Reference Ranges by Day (Safety Analysis Set in Part B) 
 
LB004: This output uses shell LB003 [Table 14.3.40] 
Programming Notes 
Repeat Table 14.3.40 for Biochemistry. Table should present these parameters only: Creatinine, total bilirubin, alkaline 
phosphatase, aspartate aminotransferase, alanine transaminase, gamma-glutamyl transferase, lactate dehydrogenase, creatine kinase, 
thyroid stimulating hormone, triiodothyronine and thyroxine, glucose, potassium, sodium, and calcium. Present in alphabetical order. 
Update source footnote to “Source: Listing 16.2.8.6”. 
Add footnote “A number of missing chemistry labs are due to a processing issues such as hemolyzed samples.”. 
 
 
 
 
 
 
 
 
Table 14.3.42 Urinalysis Laboratory Data – Shifts from Baseline in Normal Reference Ranges by Day (Safety Analysis Set in Part B) 
 
LB005: This output uses shell LB003 [Table 14.3.40] 
Programming Notes 
Repeat Table 14.3.40 for Urinalysis, and update category to “Negative’ if the results are ‘Normal’ or ‘Negative’, to ‘Trace’ if the 
results are ‘Trace’ and ‘Positive’ if the results are equal to ‘1+’,’2+’,’3+’,’ or ‘4+’.  
Table should present these parameters only: Leukocytes esterase, occult blood, ketones, bilirubin, urobilinogen, protein and 
glucose. If urinalysis on Dipstick is positive for leucocytes and/or blood/hemoglobin, a microscopic examination including 
erythrocytes, leucocytes, bacteria, casts, epithelial cells and crystals. Present in alphabetical order. 
Update source footnote to “Source: Listing 16.2.8.7”. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.3.43 Biochemistry Laboratory Data – Markedly Abnormal Values (Safety Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
Table 14.3.43  
Biochemistry Laboratory Data - Markedly Abnormal Values  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
  
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
Laboratory Test, n (%) 
 
N=XX 
N=XX 
N=XX 
N=XX 
  
 
  
  
  
  
Alanine Aminotransferase (ALT) 
 
 
 
 
 
  > 3 x ULN 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Alkaline Phosphatase (ALP) 
 
 
 
 
 
  > 3 x ULN  
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Aspartate Aminotransferase (AST) 
 
 
 
 
 
  > 3 x ULN 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Creatinine 
 
 
 
 
 
  > 2.5 mg/dL 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Gamma Glutamyl Transferase (GGT) 
 
 
 
 
 
  > 3 x ULN 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Bilirubin (TBL) 
 
 
 
 
 
  > 3 x ULN 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  
  
  
  
  
  
ULN: Upper limit of normal reference range. n = Number of patients in each category with at least one markedly abnormal value. N = 
Number of patients in the analysis set. % = Percentage of patients with at least one markedly abnormal value relative to the total 
number of patients in each treatment group. 
 
Source: Listing 16.2.8.6 
 
Output ID: LB006  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
ECG 
Table 14.3.44 12-Lead Electrocardiogram Data by Day and Timepoint (Safety Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
Table 14.3.44  
12-Lead Electrocardiogram Data by Day and Timepoint  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
 
Parameter (Unit) 
    
  
  
  
  
  Day 
 
RPL554 
RPL554 
RPL554 
 
 
    Time Point 
 
300μg 
1000μg 
3000μg 
Placebo 
Overall 
      Statistics 
 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  
 
  
  
  
  
  
ECG Parameter #1 (unit) 
 
 
 
 
 
 
      Baseline 
 
 
 
 
 
 
        n 
 
xx 
xx 
xx 
xx 
xx 
        Mean 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
        SD 
 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
        Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
        Min, Max 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
  Day 7 
 
 
 
 
 
 
    Pre-dose 
 
 
 
 
 
 
      Observed 
 
 
 
 
 
 
        n 
 
xx 
xx 
xx 
xx 
 
        Mean 
 
xx.x 
xx.x 
xx.x 
xx.x 
 
        SD 
 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
        Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
 
        Min, Max 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
 
      Change from Baseline 
 
 
 
 
 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
Table 14.3.44  
12-Lead Electrocardiogram Data by Day and Timepoint  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
 
Parameter (Unit) 
    
  
  
  
  
  Day 
 
RPL554 
RPL554 
RPL554 
 
 
    Time Point 
 
300μg 
1000μg 
3000μg 
Placebo 
Overall 
      Statistics 
 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  
 
  
  
  
  
  
        Mean 
 
xx.x 
xx.x 
xx.x 
xx.x 
 
        SD 
 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
        Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
 
        Min, Max 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
 
ECG Parameter #2 (unit) 
 
 
 
 
 
 
… 
 
 
 
 
 
 
  
    
  
  
  
  
SD: Standard deviation.  
n = Number of patients with baseline value and a post-baseline value at the time point. N = Number of patients in the analysis set.  
Change from baseline: (Pre-dose assessment – baseline assessment).  
Baseline: Defined as the pre-dose assessment for each treatment period.  
Overall n = Number of patients with a Baseline value at treatment period 1, Day 1. 
 
Source: Listing 16.2.9.12 
 
 
 
 
 
 
 
Programming Notes 
ECG quantitative assessments include: QTcF Interval (msec), QRS Interval (msec), PR Interval (msec), RR (msec), Heart rate (bpm). 
Present in alphabetical order. Display for Pre-dose on Day 7. 
 
 
 
 
 
 
 
 
Output ID: EG001  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.3.45 12-Lead Electrocardiogram – Shifts from Baseline by Day and Timepoint (Safety Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
Table 14.3.45  
12-Lead Electrocardiograms – Shifts from Baseline by Day and Timepoint  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
 
  
  
  
Category at Timepoint 
 
Day 
 
 
  
  
  
  
  Time Point 
 
Baseline 
Normal 
Abnormal NCS 
Abnormal CS 
Total 
    Treatment 
N 
Category 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
Day 7 
 
 
 
 
 
 
  Pre-dose 
 
 
 
 
 
 
    RPL554 300μg 
xxx   
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Abnormal NCS 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Abnormal CS 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
    RPL554 1000μg 
xxx   
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
NCS = Not clinically significant; CS = Clinically significant.  
N = Number of patients with a baseline value and a post-baseline value at the time point. Percentages are based on N.  
Baseline: Defined as the pre-dose assessment for each treatment period.  
 
Source: Listing 16.2.9.11 
 
 
 
 
 
 
 
Programming Notes 
ECG quantitative assessment is Interpretation of results. Display for Pre-dose on Day 7. 
 
Output ID: EG002  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Vital Signs 
Table 14.3.46 Vital Sign Data – Change from Baseline to Post-dose by Day and Timepoint (Safety Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
Table 14.3.46  
Vital Sign Data – Change from Baseline to Post-dose by Day and Timepoint  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
 
Parameter (Unit) 
  
  
  
  
  
  
  Day 
 
 
 
 
 
 
    Time Point 
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
Overall 
      Statistics 
 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  
  
  
  
  
  
  
Systolic Blood Pressure (mmHg) 
 
 
 
 
 
 
      Baseline 
 
 
 
 
 
 
        n 
 
xx 
xx 
xx 
xx 
xx 
        Mean 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
        SD 
 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
        Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
        Min, Max 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
  Day 1 
 
 
 
 
 
 
    1-hour post-dose  
 
 
 
 
 
 
      Observed 
 
 
 
 
 
 
        n [a] 
 
xx 
xx 
xx 
xx 
 
        Mean 
 
xx.x 
xx.x 
xx.x 
xx.x 
 
        SD 
 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
        Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
 
        Min, Max 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
      Change from Baseline 
 
 
 
 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
Table 14.3.46  
Vital Sign Data – Change from Baseline to Post-dose by Day and Timepoint  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
 
Parameter (Unit) 
  
  
  
  
  
  
  Day 
 
 
 
 
 
 
    Time Point 
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
Overall 
      Statistics 
 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
  
  
  
  
  
  
  
        Mean 
 
xx.x 
xx.x 
xx.x 
xx.x 
 
        SD 
 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
        Median 
 
xx.x 
xx.x 
xx.x 
xx.x 
 
        Min, Max 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
 
    2-hour post-dose  
 
 
 
 
 
 
… 
 
 
 
 
 
 
SD: Standard deviation.  
[a] n = Number of patients who have an assessment available at the relevant post-dose assessment timepoint (Observed).  
n = Number of patients who have an assessment available at Baseline and the relevant post-dose assessment timepoint (Baseline).  
N = Number of patients in the analysis set.  
Change from baseline: (Pre-dose assessment – baseline assessment).  
Baseline: Defined as the pre-dose assessment for each parameter.  
Overall: Presented for all patients in the first treatment period in the Safety Analysis Set. Overall n = Number of Baseline values 
with an assessment available at Baseline and at least one post-dose assessment for treatment period 1, Day 1. 
 
Source: Listing 16.2.9.13 
 
 
Programming Notes 
Vital signs assessments include: Systolic blood pressure, diastolic blood pressure and pulse rate. Present in alphabetical order. 
Display for the following timepoints: Day 1 and Day 7: Pre-dose, 1, 2, 4, 8 and 12 hours (all ± 10 minutes). 
 
Output ID: VS001  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.3.47 Vital Sign Data – Number and Percentage of Markedly Abnormal Values (Safety Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
Table 14.3.47  
Vital Sign Data - Number and Percent of Markedly Abnormal Values  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
  
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
Vital Sign Parameter 
 
N=XX 
N=XX 
N=XX 
N=XX 
  
 
  
  
  
  
Systolic Blood Pressure (mmHg), n (%) 
 
 
 
 
 
  n [a] 
 
xx  
xx  
xx  
xx  
  Value <= 90 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  A decrease from baseline of >=40 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Value >= 180 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  An increase from baseline of >=40 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Diastolic Blood Pressure (mmHg), n (%) 
 
 
 
 
 
  n [a] 
 
xx  
xx  
xx  
xx  
  Value <= 50 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  A decrease from baseline of >=20 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Value >= 110 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  An increase from baseline of >=20 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Pulse Rate (bpm), n (%) 
 
 
 
 
 
  n [a] 
 
xx  
xx  
xx  
xx  
  Value <= 50 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  A decrease from baseline of >=30 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Value >= 110 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  An increase from baseline of >=30 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  
  
  
  
  
  
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
Table 14.3.47  
Vital Sign Data - Number and Percent of Markedly Abnormal Values  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
  
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
Vital Sign Parameter 
 
N=XX 
N=XX 
N=XX 
N=XX 
  
 
  
  
  
  
bpm: beats per minute. mmHg: millimeters mercury.  
[a] n = Number of patients with a baseline value and a post-baseline value.  
Baseline and post-baseline value would be needed for criteria relating to an increase/decrease from baseline.  
N = Number of patients in the analysis set. % = Percentages are based on n. 
 
Source: Listing 16.2.9.14 
 
Output ID: VS002  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.3.48 Change from Baseline Pulse Rate to Peak Pulse Rate (over 4 hours) (Safety Analysis Set in Part B) 
 
 
 
 
 
 
 
VS005: This output uses shell EFF004 [Table 14.2.6] 
 
 
 
 
 
 
 
Programming Notes 
Replace footnotes with: 
ANCOVA: Analysis of covariance. CI: Confidence interval. LSMean: Least square mean. LSMean Diff: Least squares mean difference. SD: 
Standard deviation.  
N = number of patients in the analysis set.  
Baseline: Pre-dose pulse rate on Day 1 of each treatment period.  
Change from Baseline: Post-dose assessment - Pre-dose.  
[a] Number of patients with valid values at baseline and timepoint.  
[b] ANCOVA model is used to model the change from baseline in pulse rate using baseline assessment as a continuous fixed effect, 
actual treatment and treatment period as categorical fixed effects.  
[c] Number of patients with at least one on treatment value who contributed to the model estimation.  
* Indicates a significant p-value (<0.05). 
 
Source: Listing 16.2.9.15 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Physical Examination 
Table 14.3.49 Physical Examination Data by Treatment Period and Timepoint (Safety Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
Table 14.3.49 
Physical Examination Data by Treatment Period and Timepoint  
(Safety Analysis Set in Part B) 
Physical Examination: Brief 
 
 
 
 
 
Assessment 
  
  
  
  
  
  Treatment Period 
 
 
 
 
 
    Time Point 
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
      Category 
 
N=XX 
N=XX 
N=XX 
N=XX 
  
 
  
  
  
  
Physical Examination Test #1 
 
 
 
 
 
  Treatment Period X - Day Y 
 
 
 
 
 
    Pre-dose 
 
 
 
 
 
      Normal 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      Abnormal NCS 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      Abnormal CS 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
… 
 
 
 
 
 
Physical Examination Test #2 
 
 
 
 
 
  Treatment Period X - Day Y 
 
 
 
 
 
    Pre-dose 
 
 
 
 
 
      Normal 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      Abnormal NCS 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
      Abnormal CS 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
… 
 
 
 
 
 
  
  
  
  
  
  
CS = Clinically significant. NCS = Not clinically significant. EOS: End of Study. 
n = Number of patients who have an assessment available at the relevant timepoint. N = Number of patients in the analysis set. % = 
Percentage of patients calculated relative to the total number of patients in the analysis set.  
Pre-dose: Defined as the assessment taken immediately prior to study medication.  
End of Study: Defined as the last available assessment assigned to study. 
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Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
Table 14.3.49 
Physical Examination Data by Treatment Period and Timepoint  
(Safety Analysis Set in Part B) 
Physical Examination: Brief 
 
 
 
 
 
Assessment 
  
  
  
  
  
  Treatment Period 
 
 
 
 
 
    Time Point 
 
RPL554 300μg 
RPL554 1000μg 
RPL554 3000μg 
Placebo 
      Category 
 
N=XX 
N=XX 
N=XX 
N=XX 
  
 
  
  
  
  
 
Source: Listing 16.2.9.16 and 16.2.9.17 
 
 
 
 
 
 
Programming Notes 
Full/Brief Physical Examination assessments include: For Full: Abdomen [liver and spleen], Cardiovascular system, Extremities, Lymph 
nodes, Neurological system, Nose, Throat, Respiratory system, Skin, Thyroid gland. For Brief: Abdomen (liver and spleen), 
Cardiovascular system, Respiratory system, Skin. Present in alphabetical order. 
 
For Full, display for treatment period/timepoints: EOS. 
For Brief, display for treatment period/timepoints: Treatment period 1 to 4 – Day 1/7 – pre-dose. 
 
 
 
 
 
 
 
Output ID: PE001  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Table 14.3.50 Physical Examinations – Shifts from Baseline by Treatment Period and Timepoint (Safety Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
Table 14.3.50 
Physical Examinations - Shifts from Baseline by Treatment Period and Timepoint  
(Safety Analysis Set in Part B) 
Physical Examination: Brief 
 
 
 
 
 
 
Assessment 
  
  
Category at Timepoint 
 
  Treatment Period 
 
 
  
  
  
  
    Time Point 
 
Baseline 
Normal 
Abnormal NCS 
Abnormal CS 
Total 
      Treatment 
N 
Category 
n (%) 
n (%) 
n (%) 
n (%) 
  
  
  
  
  
  
  
Physical Examination Parameter #1 
 
 
 
 
 
 
  Treatment Period X - Day Y 
 
 
 
 
 
 
    Pre-dose 
 
 
 
 
 
 
      RPL554 300μg 
xx 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Abnormal NCS 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Abnormal CS 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
      RPL554 1000μg 
xx 
Normal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Abnormal NCS 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Abnormal CS 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
…  
 
 
 
 
 
 
CS = Clinically significant. NCS = Not clinically significant. EOS: End of Study. 
n = Number of patients. N = Number of patients with a baseline value and a post-baseline value at the time point. Percentages are 
based on N.  
Baseline: Defined as the assessment taken immediately prior to study medication.  
End of Study: Defined as the last available assessment assigned to study. 
For full physical examination baseline is defined as the screening assessment. Baseline for brief physical examinations is Day 1 of 
each treatment period. Baseline for full physical examination is screening collected in Part A which is compared to the EOS visit 
from Part B. 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
Table 14.3.50 
Physical Examinations - Shifts from Baseline by Treatment Period and Timepoint  
(Safety Analysis Set in Part B) 
Physical Examination: Brief 
 
 
 
 
 
 
Assessment 
  
  
Category at Timepoint 
 
  Treatment Period 
 
 
  
  
  
  
    Time Point 
 
Baseline 
Normal 
Abnormal NCS 
Abnormal CS 
Total 
      Treatment 
N 
Category 
n (%) 
n (%) 
n (%) 
n (%) 
  
  
  
  
  
  
  
Source: Listing 16.2.9.16 and 16.2.9.17 
  
 
 
 
 
 
 
Full/Brief Physical Examination assessments include: For Full: Abdomen [liver and spleen], Cardiovascular system, Extremities, Lymph 
nodes, Neurological system, Nose, Throat, Respiratory system, Skin, Thyroid gland. For Brief: Abdomen (liver and spleen), 
Cardiovascular system, Respiratory system, Skin. Present in alphabetical order. 
 
For Full, display for treatment period/timepoints: EOS. 
For Brief, display for treatment period/timepoints: Treatment period 1 to 4 – Day 1/7 – pre-dose. 
 
Output ID: PE002  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Figures 
Figure 14.2.6 Geometric Mean of ratios of Peak FEV1 (over 4 hours) to pre-dose FEV1 by Treatment (Full Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
Figure 14.2.6  
Geometric Mean of ratios of Peak FEV1 (over 4 hours) to pre-dose FEV1 by Treatment  
(Full Analysis Set in Part B) 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
FEV1: Forced expiratory volume in 1 second. Pre-dose FEV1: The value of FEV1 assessed immediately before first administration on each 
Day 1.  
Bottom and top whiskers: 95% lower confidence limit and 95% upper confidence limit.  
Bar: Geometric means on the ratio to pre-dose. ANCOVA model is used to model the change from pre-dose FEV1 using pre-dose FEV1 as a 
continuous fixed effect, planned treatment and treatment period as categorical fixed effects.  
 
Source: Listing 16.2.6.6 
 
 
 
 
 
 
Programming Notes 
Above is an example. Display for all treatment groups in Part B in ascending order (RPL554 300μg, RPL554 1000μg and RPL554 3000μg) 
and then placebo. For each treatment group present the GeoMean and SEM (standard error of the mean).   
 
 
 
 
 
 
Output ID: EFF11  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Figure 14.2.7 Mean Change from pre-dose FEV1 to Peak FEV1 (over 4 hours) by Treatment (Full Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
Figure 14.2.7  
Mean Change from pre-dose FEV1 to Peak FEV1 (over 4 hours) Treatment  
(Full Analysis Set in Part B) 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
FEV1: Forced expiratory volume in 1 second. Pre-dose FEV1: The value of FEV1 assessed immediately before first administration on each 
Day 1.  
Bottom and top whiskers: 95% lower confidence limit and 95% upper confidence limit.  
Bar: LS Means change from pre-dose. ANCOVA model is used to model the change from pre-dose FEV1 using pre-dose FEV1 as a continuous 
fixed effect, planned treatment and treatment period as categorical fixed effects.  
 
Source: Listing 16.2.6.6 
 
 
 
 
 
 
Programming Notes 
Above is an example. Display for all treatment groups in Part B in ascending order (RPL554 300μg, RPL554 1000μg and RPL554 3000μg) 
and then placebo. For each treatment group present the LSMean and SEM (standard error of the mean).   
Update y-axis label to “LS Means change from pre-dose (mL)”. 
 
 
 
 
 
 
Output ID: EFF12  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Figure 14.2.8 Mean Change from Pre-dose FEV1 during spirometry over Time by Treatment and Day (Full Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
Figure 14.2.8  
Mean Change from Pre-dose FEV1 during Spirometry over Time by Treatment and Day  
(Full Analysis Set in Part B) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
Means are calculated on the observed data. 
Pre-dose: the highest FEV1 result collected immediately pre-dose (within 5 minutes) on day 1 for each treatment period. 
 
Source: Listing 16.2.6.5 
 
 
 
 
 
 
Programming Notes 
Insert a label below the figure for each of the treatment groups, each with a different colour and symbol. Display for all treatment 
groups in Part B in ascending order (RPL554 300μg, RPL554 1000μg and RPL554 3000μg) and then placebo. Also adjust x-axis for the 
correct timepoints.  
Repeat figure for Day 7. 
 
 
 
 
 
 
 
Output ID: EFF09  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Figure 14.2.9 Kaplan-Meier plot of Time to Onset of Action (>10% Increase in FEV1) on Day 1 (Full Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
Figure 14.2.9  
Kaplan-Meier plot of Time to Onset of Action (>10% Increase in FEV1) on Day 1  
(Full Analysis Set in Part B) 
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time to first onset of action (mins): Time of first onset of action (defined as >10% increase in FEV1 from pre-first dose) = Time of 
onset of action (or censoring time) – time of end of inhalation (mins).  
P25, Median and P75 time to onset of action: Estimated using Kaplan-Meier statistics.  
Censored: Patients not experiencing onset of action are censored at 120 mins or at time of premature discontinuation (if withdrawn 
before 120 minutes). 
 
Source: Listing 16.2.6.7 
 
 
 
 
 
 
Programming Notes 
Insert a label below the figure for each of the treatment groups, each with a different colour and symbols. 
 
 
 
 
 
 
Output ID: EFF10  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
 
Figure 14.3.5 Mean Change from Pre-dose Pulse Rate to Peak Pulse Rate (over 4 hours) by Treatment (Safety Analysis Set in Part B) 
 
 
 
 
 
 
 
Figure 14.3.6 Mean Change from Pre-dose in Pulse Rate over Time by Treatment and Day (Safety Analysis Set in Part B) 
 
 
 
 
 
 
VS004: This output uses shell EFF09 [Figure 14.2.6] 
 
 
 
 
 
 
Means are calculated on the observed data. 
Pre-dose: the pre-dose assessment collected on day 1 for each treatment period. 
Programming Notes 
Update source footnote to “Source: Listing 16.2.9.15”. 
Replace footnotes in original shell with those listed above 
 
 

 
 
 
 
 
 
 
VS003: This output uses shell EFF11 [Figure 14.2.6] 
 
 
 
 
 
 
Pre-dose pulse rate: The pulse rate value assessed immediately before administration on each Day 1. Bottom and top whiskers: 95% 
lower confidence and 95% upper confidence limit. Bar: Results on orginal scale. ANCOVA model is used to model the change from pre-
dose pulse rate using pre-dose pulse rate as a continuous fixed effect, and actual treatment as categorical fixed effects. 
 
 
 
 
 
 
Programming Notes 
Update source footnote to “Source: Listing 16.2.9.15”. 
Replace footnotes in original shell with those listed above 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listings 
Listing 16.2.1.2 Completed/Discontinued Patients (All Randomized Analysis Set in Part B) 
Verona Pharma 
 
 
 
 
 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
 
 
 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
  
 
 
Listing 16.2.1.2  
Completed/Discontinued Patients  
(All Randomized Analysis Set in Part B) 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
  
  
  
First date of treatment/Study day 
  
  
  
Patient 
ID  
Randomiz-
ation 
date/ 
Study day 
Was 
treatment 
unblinded by 
the site? If 
yes, provide 
date and 
reason 
TP 1 
TP 2 
TP 3 
TP 4 
Treatment 
period 
discontinued 
Completed study/ 
Date of 
completion/ 
discontinuation/ 
Study Day/Primary 
reason if not 
completed 
Reason not 
completed, Other 
(specify)/If AE, 
specification/If 
death, date of 
death 
XXXXXXX 
DDMMMYYYY/
xx 
XXX/DDMMMYYY
Y/XXXX 
DDMMMYYYY/
xx 
DDMMMYYYY/
xx 
DDMMMYYYY/
xx 
DDMMMYYYY/
xx 
XXXXXXXXX 
No/DDMMMYYYY/xx/ 
XXXXXX 
XXXXXXXXX/XXXXXXXX
/DDMMMYYYY 
  
  
  
  
  
  
  
  
  
  
TP: Treatment Period. Study day: Relative to first dose of study medication (i.e., Treatment period 1, Day 1).  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 3 = RPL554 
3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID. 
 
Output ID: L001  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.2.2 Protocol Deviations (All Randomized Analysis Set in Part B) 
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Listing 16.2.2.2  
Protocol Deviations  
(All Randomized Analysis Set in Part B) 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient ID  
Age/Sex/Race 
Treatment 
group 
Deviation date/ 
Relative Day 
Protocol 
deviation 
Type of 
deviation 
Severity 
  
XXXXXXXXXXXXXX 
XX/X/XXXXXXX 
XXXXXXXXX 
DDMMMYYYY/xx 
XXXXXXXXXXX 
XXXXXXXXXXX 
XXXXXXXXXXX 
  
  
  
  
  
  
  
  
As: Native Asian. Bl: Black or African American. CTMS: Clinical trial management system. eCRF: Electronic case report form. F: 
Female. Ia: American Indian or Alaskan. M: Male. Ot: Other. Pi: Native Hawaiian or Pacific islanders. Un: Unknown. W: White.  
Protocol deviations: Defined as deviation types reported in the CTMS log.  
Age (years): As reported in the eCRF.  
Relative day: Day relative to day of the first dose of study medication per treatment period (i.e., Treatment period X, Day 1).  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID and then the deviation date. 
 
Output ID: L003  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.3.2 Patient Included in Analysis Sets (All Randomized Analysis Set in Part B) 
Verona Pharma 
 
 
 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
 
 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
Listing 16.2.3.2 
Patient Included in Analysis Sets  
(All Randomized Analysis Set in Part B) 
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
  
Analysis Sets 
Patient ID 
Randomized 
Safety 
Full 
Completers 
Pharmacokinetic 
XXXXX 
Yes 
Yes 
Yes 
Yes 
Yes 
XXXXX 
Yes 
Yes 
Yes 
No 
Yes 
… 
 
 
 
 
 
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID. 
 
 
Output ID: L002  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.4.7 Demographic Characteristics (All Randomized Analysis Set in Part B) 
 

 
Verona Pharma 
 
 
 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.4.7  
Demographic Characteristics  
(All Randomized Analysis Set in Part B)  
 
 
 
 
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
  
  
  
  
Patient ID 
Country 
Age/Sex/Race 
Ethnicity 
Weight 
(kg) 
Height 
(cm) 
BMI 
(kg/m2) 
Re-
screened 
patient 
Childbearing 
potential 
XXXXXXXXX  
UK 
62/F/W 
XXXXXXXXX 
XX 
XXX 
XX.X 
X 
X 
XXXXXXXXX  
UK 
67/M/W 
XXXXXXXXX 
XX 
XXX 
XX.X 
X 
NA 
  
  
  
  
  
  
  
  
  
  
As: Native Asian. Bl: Black or African American. BMI: Body mass index. eCRF: Electronic case report form. F: Female. Ia: American 
Indian or Alaska. M: Male. NA: Not applicable. Ot: Other. Pi: Native Hawaiian or Pacific Islanders. Un: Unknown. W: White.  
Age (years): As calculated relative to informed consent date.  
BMI (kg/m2) = Weight (kg) / Height (m)2.  
All measurements listed above are measured at Screening on the Demography eCRF. 
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
 
Programming Notes: 
Order by treatment group (as per shell) and within group by patient ID. 
 
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
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Version 1.0; 17 May 2021
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.4.8 Screening Disease Characteristics (All Randomized Analysis Set in Part B) 
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.4.8  
Screening Disease Characteristics  
(All Randomized Analysis Set in Part B) 
 
 
 
 
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
  
  
Bronchodilator 
FEV1 (L) 
  
Bronchodilator 
FVC (L) 
  
  
  
 
Reversibility 
Patient 
ID 
Age/Sex
/Race 
Pre 
Post 
Predicted  
FEV1 (%) 
Pre 
Post 
Post-
bronchodi-
lator 
FEV1/FVC 
Assessment 
performed 
with four 
puffs of  
albuterol 
Met 
reversibility 
test criteria? 
% 
mL 
XXXX 
XX/X/XX
X 
XX 
XX 
  
XX 
XX 
XX 
XX 
XX 
X.X 
XXX 
  
  
  
  
  
  
  
  
  
 
 
 
As: Native Asian. Bl: Black or African American. F: Female. FEV1: Forced expired volume in 1 second. FVC: Forced vital capacity. Ia: 
American Indian or Alaska. M: Male. Ot: Other. Pi: Native Hawaiian or Pacific islanders. Un: Unknown. W: White.  
Pre-, post-bronchodilator and reversibility values are the results of the screening reversibility test.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID. 
 
Output ID: L005  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 

 
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.4.9 COPD and Smoking History (All Randomized Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
 
Listing 16.2.4.9 
COPD and Smoking History  
(All Randomized Analysis Set in Part B) 
 
 
 
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
  
  
  
  
  
  
Smoking History 
Patient 
ID 
Date COPD  
first  
diagnosed 
Duration of  
COPD (years)  
(time since 
diagnosis) 
Date of most 
recent  
exacerbation/ 
Study day 
Bronchitis/ 
Emphysema 
Smoking 
category 
Number of 
packs  
per day 
Number of 
years  
smoking 
Smoking exposure  
(pack-years) 
XXXXXXX 
DDMMMYYYY 
xx 
DDMMMYYYY/xx 
Yes/Yes 
Current 
Smokers 
XX 
XX 
XX 
  
  
  
  
  
  
  
  
  
COPD: Chronic Obstructive Pulmonary Disease.  
Smoking exposure (pack-years) = Number of packs per day * Number of years smoking, for patients with a smoking history or a current 
smoker.  
Study day: Relative to first dose of study medication (i.e., Treatment period 1, Day 1).  
Duration of COPD (years) (time since diagnosis) = (Randomization date – date COPD first diagnosed)/365.25.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID. 
 
Output ID: L006  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 

 
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Version 1.0; 17 May 2021
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.4.10 Medical History (All Randomized Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
Listing 16.2.4.10  
Medical History  
(All Randomized Analysis Set in Part B) 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient ID 
Medical history  
diagnosis 
SOC/PT 
Start date/ 
Study day 
End date/ 
Study day 
XXXXXXXXX  
XXXXXXXXXXXXXXXX 
XXXXXXXXXXXX/ 
XXXXXXXXXXXXXX 
DDMMMYYYY/xx 
DDMMMYYYY/xx 
  
  
  
  
  
MedDRA: Medical Dictionary for Regulatory Activities. PT: Preferred Term. SOC: System Organ Class.  
Medical history: Coded using MedDRA (Version 21.0).  
Study day: Relative to first dose of study medication (i.e., Treatment period 1, Day 1).  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID. 
 
Output ID: L007  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 

 
Clinical Study Report
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Version 1.0; 17 May 2021
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.4.11 Surgical Procedure History (All Randomized Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
Listing 16.2.4.11  
Surgical Procedure History  
(All Randomized Analysis Set in Part B)  
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient ID 
Reported name of procedure 
Purpose of procedure 
Start date of 
procedure/  
Study day 
End date of 
procedure/  
Study day 
XXXXXXXXX  
XXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXX 
DDMMMYYYY/xx 
DDMMMYYYY/xx 
  
  
  
  
  
  
Surgical procedure history: Coded using MedDRA (Version 21.0).  
Study day: Relative to first dose of study medication (i.e., Treatment period 1, Day 1).  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID. 
 
Output ID: L008  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 

 
Clinical Study Report
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Version 1.0; 17 May 2021
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CONFIDENTIAL
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Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.4.12 Prior and Concomitant Medications (All Randomized Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
 
Listing 16.2.4.12  
Prior and Concomitant Medications  
(All Randomized Analysis Set in Part B)  
 
 
 
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient ID 
Treatment 
group 
Treatment 
period 
Start date 
(Study day)/ 
End date 
(Study day) 
P?[a]/ 
C?[b] 
ATC Level 1/ 
Preferred term 
Indication 
Dose 
(Unit) 
Frequency/ 
Route 
XXXX/XXXX 
XXXXXXXXX 
XXXXXXXXX 
DDMMMYYYY (XX)/ 
DDMMMYYYY(XX) 
C 
XXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXX 
XXXXXX 
XX(XX) 
XXXXXXXX/ 
XXXXXXXX 
… 
 
 
 
 
 
 
 
 
 
ATC: Anatomical Therapeutic Chemical. C: Concomitant. P: Prior.  
[a] Medication taken between Part A and Part B of the study or prior to the start of study medication.  
[b] Medication taken between start and stop of study medication.  
Study day: Day relative to day of the first dose of study medication (i.e., Treatment period 1, Day 1).  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID 
'Prior' medications are medications which started and stopped in the time between Part A and Part B (prior to the study medication 
at TP1, Day 1) and have Started prior to start of study medication? = “Yes” on the Concomitant medications eCRF page.  
'Concomitant' medications are medications which:  
o Had an onset date on or after the study medication. 
o AND ended on or after the date of medication or were ongoing at the end of Part B. 
 
 
Output ID: L009  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
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Version 1.0; 17 May 2021
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– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.4.13 Prior COPD Medications (All Randomized Analysis Set in Part B) 

 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
 
Listing 16.2.4.13  
Prior COPD Medications  
(All Randomized Analysis Set in Part B)  
 
 
 
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient ID 
Start date 
(Study day)/ 
End date 
(Study day) 
ATC Level 1/ 
Preferred term 
Dose 
(Unit) 
Frequency/ 
Route 
XXXX 
DDMMMYYYY(XX)/ 
DDMMMYYYY(XX) 
XXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXX 
XX(XX) 
XXXXXXXX/ 
XXXXXXXX 
… 
 
 
 
 
 
 
 
ATC: Anatomical Therapeutic Chemical.  
Study day: Day relative to day of the first dose of study medication (i.e., Treatment period 1, Day 1).  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID 
'Prior' medications are medications which started and stopped in the time between Part A and Part B (prior to the study medication 
at TP1, Day 1) and have Started prior to start of study medication? = “Yes” on the Concomitant medications eCRF page.  
COPD medications are when Indication is “Other” and Other reason for medication is “COPD”. 
 
 
Output ID: L009  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
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Version 1.0; 17 May 2021
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Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.5.2 Drug Exposure and Accountability (All Randomized Analysis Set in Part B) 
Verona Pharma 
 
 
 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
Listing 16.2.5.2  
Drug Exposure and Accountability  
(All Randomized Analysis Set in Part B)  
 
 
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient ID 
Treatment 
group 
Treatment 
period/ 
Timepoint 
Start date and 
of study 
medication / 
Relative day 
Start time/ 
End time  
of inhalations 
Weight of  
pMDI dispensed 
(g) 
Weight of  
pMDI returned 
(g) 
Weight of  
pMDI used (g) 
XXXXXXXXX 
XXXXXXXXX XXXXXXXXX/ 
XXXXXXXXX 
DDMMMYYYY/xx 
HH:MM/HH:MM 
XX 
XX 
XX 
XXXXXXXXX 
XXXXXXXXX XXXXXXXXX/ 
XXXXXXXXX 
DDMMMYYYY/xx 
HH:MM/HH:MM 
XX 
XX 
XX 
  
  
  
  
  
 
 
  
Relative day: Relative to day of the first dose of study medication in each treatment period.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID and treatment period. 
 
Output ID: L010  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 

 
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RPL554-MD-201
Version 1.0; 17 May 2021
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Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.6.5 Spirometry: FEV1 Results (Full Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
  
 
 
 
Listing 16.2.6.5 
Spirometry: FEV1 Results  
(Full Analysis Set in Part B) 
 
 
 
 
 
  
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient 
ID 
Treatment 
group 
Treatment 
period/ 
Timepoint 
Date and 
time/ 
Relative 
day 
Refrained from  
smoking/Capable of 
withdrawing from long 
acting 
bronchodilators 
FEV1  
measurement  
(L) 
Predicted  
FEV1 (%) 
 
 
XXXXX 
XXXXX 
XXXXXX/ 
XXXXXX 
DDMMYYY 
HH:MM/xx 
XXXXXX/ 
XXXXXX 
X.XXX [a] 
XX.X 
 
 
 
 
XXXXXX 
 
 
 
 
 
 
 
 
… 
 
 
 
FEV1: Forced expiratory volume in 1 second.  PFT: Pulmonary function test.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
The assessment timepoints can be Pre PFT -60 min, Immediately Pre-dose, Post PFT 5min, 15min, 30min, 1h, 1.5h, 2h, 4h, 8h, 12h and 
EOS. Order by treatment sequence (as per shell) and within group by patient ID and treatment period. 
 
Output ID: L014  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 

 
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Version 1.0; 17 May 2021
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Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.6.6 Spirometry: FEV1 Derived Measurements (Full Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Listing 16.2.6.6  
Spirometry: FEV1 Derived Measurements  
(Full Analysis Set in Part B) 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient 
ID 
Treatment 
group 
Treatment 
period/ 
Timepoint 
Date/ 
Relative day 
Peak FEV1 
4h (CFB) 
Morning 
trough FEV1 (CFB) 
Average FEV1 
(AUC) 4h (CFB) 
Average FEV1 
(AUC) 12h (CFB) 
XXXXX 
XXXXXX 
XXXXXXX/ 
XXXXXXX 
DDMMYYY/ 
xx 
X.XXX (X.XXX) 
X.XXX (X.XXX) 
X.XXX (X.XXX) 
X.XXX (X.XXX) 
… 
 
 
… 
 
 
 
… 
AUC: Area under the curve. CFB: Change from Baseline. FEV1: Forced expiratory volume in 1 second.  
Peak FEV1: Maximum post-dose value among the values collected up to timepoint of interest hours.  
Morning trough FEV1: average of the FEV1 pre dose assessments (-60 minutes and -5 minutes) on Day 7.  
Average FEV1 AUC: AUC of the FEV1 values (maximum value of the three assessments at each timepoint) divided by the length of the time 
(in hours) interval of interest (per visit).  
Relative day: Relative to day of the first dose of study medication in each treatment period.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
The assessment timepoints can be Pre PFT, Post PFT, Pre PFT -60 min, Immediately Pre-dose, Post PFT 5min, 15min, 30min, 1h, 1.5h, 
2h, 4h, 8h, 11h, 12h and EOS. Order by treatment sequence (as per shell) and within sequence by patient ID and treatment period. 
 
Output ID: L015  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 

 
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Version 1.0; 17 May 2021
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Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.6.7 Spirometry: FEV1 Time to First Occurrence of Onset of Action (Full Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
Listing 16.2.6.7  
Spirometry: FEV1 Time to First Occurrence of Onset of Action  
(Full Analysis Set in Part B) 
 
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient 
ID 
Treatment 
group 
Date/ 
Study day 
Time of  
pre-dose  
(HH:MM) 
Time of onset 
of 
action 
(HH:MM) 
Time to first 
occurrence of onset 
of action (mins) 
Censored 
(Yes/No)* 
XXXXXX 
XXXXXX 
YYYY-MM-DD/XX 
HH:MM 
HH:MM 
XX 
XX 
XXXXXX 
XXXXXX 
YYYY-MM-DD/XX 
HH:MM 
HH:MM 
XX 
XX 
…  
 
 
 
 
 
 
  
  
  
  
  
  
  
Time to first occurrence of onset of action (mins): Time of onset of action (defined as >10% increase in FEV1 from pre-first dose) = 
Time of onset of action (or censoring time) – time of end of inhalation (mins).  
* Patients not experiencing onset of action are censored at 120 mins or at time of premature discontinuation (if withdrawn before 
120 minutes).  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
 
Output ID: L032  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 

 
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Version 1.0; 17 May 2021
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Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.6.8 Dyspnea Scale Score (Full Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
Listing 16.2.6.8 
Dyspnea Scale Score  
(Full Analysis Set in Part B) 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient 
ID 
Treatment 
group 
Treatment period/ 
Timepoint 
Assessment performed/ 
Date and time/ 
Relative day 
Dyspnea scale score 
XXXXXX 
XXXXXX 
XXXXXX/ 
XXXXXX 
XXX/ 
YYYY-MM-DD/HH:MM/ 
XX 
XX 
  
  
  
  
  
Dyspnea scale score: Likert scale assessment ranging from 0 to 10, where 10 represents the “worst shortness of breath that you can 
imagine” and 0 represents “no shortness of breath”.  
Relative day: Relative to day of the first dose of study medication in each treatment period.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID and treatment period. 
 
 
 
 
 
Output ID: L033  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 

 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
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Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.6.9 Rescue Medications (All Randomized Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
Listing 16.2.6.9  
Rescue Medications  
(All Randomized Analysis Set in Part B)  
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient 
ID 
Treatment 
group 
Treatment 
period 
Date of 
administration/ 
Relative day 
Rescue Medication Taken 
Number of puffs 
XXXXXX 
XXXXXX 
XXXXXXX 
DDMMMYYYY/x 
Yes/No 
X 
  
  
  
  
  
  
Rescue medications = Short acting bronchodilators used to relieve i.e. rescue symptoms immediately.  
Relative day: Relative to day of the first dose of study medication in each treatment period.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID and treatment period. 
 
 
 
 
 
 
Output ID: L034  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 

 
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RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.6.10 Rescue Medications Canister Dispensed, Weight and Collection Information (All Randomized Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Listing 16.2.6.10  
Rescue Medications Canister Dispensed, Weight and Collection Information  
(All Randomized Analysis Set in Part B)  
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient 
ID 
Inhaler 
number 
Treatment 
Period 
Inhaler Dispensed 
Inhaler Weighed 
Inhaler Collected 
Inhaler 
dispensed? 
If no, 
specify 
Date/time Weight(g) 
Inhaler 
weighed? 
If no, 
specify 
Date/time Weight(g) 
Inhaler 
collected? 
If no, 
specify 
Date/time Weight(g) 
XXXXXX 
XX 
XXXXXXXX 
X / XXXXX  DDMMYYYY 
HH:MM 
XX.X 
X / XXXXX  DDMMYYYY 
HH:MM 
XX.X 
X / XXXXX  DDMMYYYY 
HH:MM 
XX.X 
  
 
 
 
 
 
 
 
 
 
 
 
Rescue medications = Short acting bronchodilators used to relieve i.e. rescue symptoms immediately.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID. 
 
Output ID: L038  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 

 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.7.6 List of All Adverse Events (Safety Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.7.6  
Listing of All Adverse Events  
(Safety Analysis Set in Part B)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment groups: <RPL554 300μg/RPL554 1000μg/RPL554 3000μg/Placebo> 
Patient 
ID 
Study day 
of last 
dose of 
study 
medicatio
n [a] 
SOC/PT/Reported 
term [b] 
Treatment 
period 
Start/End 
date 
or ongoing 
(Study day) 
[c] 
Sev  
[d] 
Rel  
[e] 
Act  
[f] 
Ser  
[g] 
Out  
[h] 
Chronic-
ity 
[i] 
Treatment 
given 
Disconti- 
nued from  
study 
Blind  
broken 
XXXXX 
XX 
XXXXXX/XXXXX/ 
XXXXX 
XXXXX 
DDMMMYYYYY 
MI 
Y 
NC 
N 
Rsl
v 
XX/X/X 
Yes 
Yes 
Yes 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
SOC: System organ class. PT: Preferred Term. 
AEs which started within a treatment period are assigned to that treatment period. 
[a] Day of last dose of study medication relative to day of the first dose of study medication (i.e., Treatment period 1, Day 1).  
[b] An asterisk “*” indicates a non-treatment-emergent adverse event.  
[c] Study day: Day relative to day of the first dose of study medication (i.e., Treatment period 1, Day 1).  
[d] Severity: MI=Mild, MO=Moderate, SE=Severe.  
[e] Related to study drug.  
[f] Action taken with respect to study drug: NC = Dose Not Changed, DD = Drug Discontinued, DI = Drug Interrupted, O = Other, NA = Not 
Applicable.  
[g] Serious AE.  
[h] Outcome: Fatal = Fatal, NRslv = Not recovered/not resolved, Rslv = Resolved/Recovered, RslvG = Recovering/Resolving, RslvS = 
Recovered/Resolved with sequelae, Unk = Unknown.  
[i] S = Single Occasion, I = Intermittent, P = Persistent. 
SOCs and PT are coded using the MedDRA (Version 21.0). 
 
Programming Notes 
Order by treatment group (as per shell) and within sequence by patient ID, adverse event start date and adverse event end date (in that 
order). 
 
Output ID: L016  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 276 of 291


Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
 
Listing 16.2.7.7 Treatment-emergent Adverse Events Leading to Study Discontinutation (Safety Analysis Set in Part B) 
 
L017: This output uses shell L016 [Listing 16.2.7.6] 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.7.8 Treatment-emergent Adverse Events Leading to Death (Safety Analysis Set in Part B) 
 
L018: This output uses shell L016 [Listing 16.2.7.6] 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.7.9 Serious Treatment-emergent Adverse Events (Safety Analysis Set in Part B) 
 
L019: This output uses shell L016 [Listing 16.2.7.6] 
 
 
 
 
 
 

 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 277 of 291


Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.7.10 Serious Treatment-emergent Adverse Events - Details (Safety Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201  
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
Listing 16.2.7.10  
Serious Treatment-emergent Adverse Events – Details  
(Safety Analysis Set in Part B) 
 
 
 
 
Treatment groups: <RPL554 300μg/RPL554 1000μg/RPL554 3000μg/Placebo> 
Patient ID 
SOC/PT/ 
Reported Term 
SAE details 
Answer 
XXXXXXXXXXX 
XXXXXXX/XXXXXXX/XXXXXX 
Date Investigator became aware of SAE  
DDMMMYYYY 
 
 
Death  
XXXXX 
 
 
Life-threatening  
XXXXX 
 
 
Initial or prolonged hospitalization  
XXXXX 
 
 
Date of admission (DD MMM YYYY)  
DDMMMYYYY 
 
 
Date of discharge (DD MMM YYYY)  
DDMMMYYYY 
 
 
Persistent or significant disability/incapacity  
XXXXX 
 
 
Congenital anomaly/birth defect  
XXXXX 
 
 
Occurred with overdose  
XXXXX 
 
 
Other medically important event  
XXXXX 
 
 
Was the SAE caused by other medication? (e.g. Concomitant 
medication, background medication, rescue medication) 
XXXXX 
 
 
If Yes, Please Specify  
XXXXX 
 
 
Was the SAE caused by study procedure(s)?  
XXXXX 
 
 
If Yes, Please Specify  
XXXXX 
 
 
Describe treatment for event including medications (1)  
XXXXX 
 
 
Describe treatment for event including medications (2) 
XXXXX 
 
 
Describe treatment for event including medications (3) 
XXXXX 
 
 
List all diagnostic tests that were done to confirm event (1)  
XXXXX 
 
 
List all diagnostic tests that were done to confirm event (2)  
XXXXX 
 
 
List all diagnostic tests that were done to confirm event (3)  
XXXXX 
 
 
Description of SAE/narrative  
XXXXX 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
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Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201  
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
Listing 16.2.7.10  
Serious Treatment-emergent Adverse Events – Details  
(Safety Analysis Set in Part B) 
 
 
 
 
Treatment groups: <RPL554 300μg/RPL554 1000μg/RPL554 3000μg/Placebo> 
Patient ID 
SOC/PT/ 
Reported Term 
SAE details 
Answer 
 
 
Additional information 
XXXXX 
  
  
  
  
PT: Preferred Term. SAE: Serious Adverse Event. SOC: System Organ Class. 
SOCs and PTs are coded using the MedDRA (version 21.0). 
 
Programming Notes 
Order by treatment group (as per shell) and within group by patient ID. 
 
Output ID: L020  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 

 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 279 of 291


Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.8.5 Hematology (Safety Analysis Set in Part B) 
Verona Pharma 
 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
Listing 16.2.8.5 
Hematology  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient ID 
Parameter 
Reference 
Range 
(Lower-
Upper) 
Treatment 
group 
Treatment 
period/ 
Timepoint 
Date/Time of  
assessment/ 
Relative day 
Value 
(unit) 
L/H [a] 
Change  
from  
Baseline 
XXXXXXXXXXX 
Hemoglobin 
XX.X – XX.X 
XXXXXXX 
XXXXXXX/ 
XXXXXXX 
DDMMMYYYY/HH:MM/ 
xx 
XX (unit) 
XX.X 
  
  
  
  
  
  
  
  
[a] L = Below low normal range. H = Above high normal range. 
Baseline: Defined as the pre-dose assessment for each treatment period.  
Relative day: Relative to day of the first dose of study medication in each treatment period.  
End of Study: Defined as the last available assessment assigned to study.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment sequence (as per shell), hematology parameter (in alphabetical order), patient ID and treatment period. 
 
Output ID: L021  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 
 
 
 
Listing 16.2.8.6 Biochemistry (Safety Analysis Set in Part B) 
 
 
 
 
 
 
L022: This output uses shell L021 [Listing 16.2.8.5] 
 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 280 of 291


Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.8.7 Urinalysis (Safety Analysis Set in Part B) 
Verona Pharma 
 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
Listing 16.2.8.7  
Urinalysis  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient  
ID 
Parameter 
Treatment 
group 
Treatment 
period 
Date/Time of assessment/ 
Relative day 
Result [a] 
XXXXXXXXXXX 
Ketones 
XXXXXX 
XXXXXX 
DDMMMYYYY/HH:MM/xx 
NEGATIVE (N) 
 
Leukocyte Esterase 
 
 
DDMMMYYYY/HH:MM/xx 
TRACE (T) 
 
Occult Blood 
 
 
DDMMMYYYY/HH:MM/xx 
1+ (P) 
 
…  
 
 
 
 
  
  
  
  
  
  
[a] Category assigned and used in the shift table: N = Normal or ‘Negative’; T = ‘Trace’ P = ‘1+’,’2+’,’3+’,’ or ‘4+’. The flag 
appears only for the following parameters: Leucocyte Esterase, Bilirubin, Glucose, Ketones, Occult blood, Protein and Urobilinogen.  
Relative day: Relative to day of the first dose of study medication in each treatment period.  
Baseline: Defined as the pre-dose assessment for each treatment period.  
End of Study: Defined as the last available assessment assigned to study.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment sequence (as per shell), urinalysis parameter (in alphabetical order) and by patient ID and treatment period. 
 
Output ID: L023  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 

 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 281 of 291


Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.9.11 Electrocardiogram Local Reading Overall Evaluation (Safety Analysis Set in Part B) 

 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
Listing 16.2.9.11  
Electrocardiogram Local Reading Overall Evaluation  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient 
ID 
Treatment 
group 
Treatment Period/Day 
/Timepoint 
Date/Time of 
assessment/Relative 
day 
Overall ECG 
Evaluation 
Abnormal 
Significant/ 
Specify 
XXXXXXXXXXXX 
XXXXXXXXX 
XXXX/XXXX 
DDMMMYYYY/HH:MM/xx 
Normal 
Y/XXXXXX 
XXXXXXXXXXXX 
XXXXXXXXX 
XXXX/XXXX 
DDMMMYYYY/HH:MM/xx 
Normal 
Y/XXXXXX 
  
  
  
  
  
  
ECG: Electrocardiogram.  
Relative day: Relative to day of the first dose of study medication in each treatment period.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID and treatment period. 
 
Output ID: L024  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 282 of 291


Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.9.12 12-lead ECG (Safety Analysis Set in Part B) 

 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
Listing 16.2.9.12 
12-lead ECG 
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient ID 
Treatment 
Group 
Treatment 
Period/Day 
/Timepoint 
Date/Time of 
assessment/Relative 
day 
ECG parameter (unit) 
Result 
Baseline 
CFB 
XXXXXXXXXXXXX 
XXXXX 
XXXXX 
DDMMMYYY/HH:MM/xx 
HR (bpm) 
XX.X 
XX.X 
XX.X 
 
 
 
 
PR interval (msec) 
XX.X 
XX.X 
XX.X 
 
 
 
 
QRS duration (msec) 
XX.X 
XX.X 
XX.X 
 
 
 
 
QT interval (msec) 
XX.X 
XX.X 
XX.X 
 
 
 
 
QTcF 
XX.X 
XX.X 
XX.X 
 
 
 
 
RR interval (msec) 
XX.X 
XX.X 
XX.X 
 
 
 
 
 
 
 
 
 
XXXXX 
XXXXX 
DDMMMYYY/HH:MM/xx 
… 
… 
… 
… 
  
  
 
  
  
  
  
  
bpm: beats per minute. CFB: Change from baseline. ECG: Electrocardiogram. HR: Heart rate. QTcF: QT interval using Fridericia’s 
correction formula.  
Baseline: Defined as the assessment performed pre-dose for each treatment period.  
Relative day: Relative to day of the first dose of study medication in each treatment period.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment group (as per shell) and within group by patient ID. 
 
Output ID: L025  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 283 of 291


Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.9.13 Vital Signs (Safety Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
Listing 16.2.9.13  
Vital Signs  
(Safety Analysis Set in Part B)  
 
 
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient  
ID 
Treatment 
group 
Treatment 
period/ 
Timepoint 
Date/Time of 
assessment/Relative 
day 
Vital sign 
parameter (unit) 
Result 
Baseline 
CFB 
XXXXXXXXXXX 
XXXXX 
XXXXX 
DDMMMYYYY/HH:MM/xx 
SBP (mmHg) 
XX.X 
XX.X 
XX.X 
 
 
 
 
DBP (mmHg) 
XX.X 
XX.X 
XX.X 
 
 
 
 
Pulse (beats/min) 
XX.X 
XX.X 
XX.X 
 
 
XXXXX 
DDMMMYYYY/HH:MM/xx 
… 
… 
… 
… 
  
  
  
  
  
  
  
  
CFB: Change from baseline. DBP: Diastolic blood pressure. SBP: Systolic blood pressure. 
Relative day: Relative to day of the first dose of study medication in each treatment period.  
Baseline: Defined as the assessment performed pre-dose for each treatment period.  
End of Study: Defined as the last available assessment assigned to study.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID and treatment period. 
 
Output ID: L026  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 

 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 284 of 291


Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.9.14 Vital Signs – Patients with at Least One Markedly Abnormal Finding (Safety Analysis Set in Part B) 
 
 
 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
 
Listing 16.2.9.14 
Vital Signs - Patients with at Least One Markedly Abnormal Finding  
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient  
ID 
Treatment 
group 
Treatment 
period/ 
Timepoint 
Date/Time of 
assessment/Relative 
day 
Vital sign 
parameter 
(unit) 
Result 
Baseline 
CFB 
Markedly 
abnormal 
XXXXXXXXXXX 
XXXXX 
XXXXX 
DDMMMYYYY/HH:MM/xx 
SBP (mmHg) 
XX.X 
XX.X 
XX.X 
 
 
 
 
 
DBP (mmHg) 
XX.X 
XX.X 
XX.X L 
Y 
 
 
 
 
Pulse 
(beats/min) 
XX.X 
XX.X 
XX.X H 
Y 
 
 
XXXXX 
DDMMMYYYY/HH:MM/xx 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
CFB: Change from baseline. DBP: Diastolic Blood Pressure. SBP: Systolic Blood Pressure.  
Relative day: Relative to day of the first dose of study medication in each treatment period.  
L and H represents marked decrease or increase from baseline.  
Baseline: Defined as the assessment performed pre-dose for each treatment period.  
End of Study: Defined as the last available assessment assigned to study.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
 
 
 
 
 
 
 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID and treatment period. 
Only include subjects who have a markedly abnormal finding. 
 
 
 
 
 
 
 
 
 
 
Output ID: L035  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 285 of 291


Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.9.15 Derived Safety Measurements (Safety Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
 
 
 
Listing 16.2.9.15  
Derived Safety Measurements 
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient  
ID 
Treatment 
group 
Treatment period 
Date/ Relative day 
 
Peak Pulse Rate (bpm) (over 4 
hours) 
XXXXXXXXXXX 
XXXXX 
XXXXX 
DDMMMYYYY/xx 
 
X.XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXX 
DDMMMYYYY/xx 
 
… 
 
 
 
 
 
 
  
  
  
  
 
 
Peak = Maximum post-dose value among the values collected up to timepoint of interest hours.  
Relative day: Relative to day of the first dose of study medication in each treatment period.  
Baseline: Defined as the assessment performed pre-dose for each treatment period.  
End of Study: Defined as the last available assessment assigned to study.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
 
 
 
 
 
 
 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID and treatment period. 
 
 
 
 
 
 
 
 
 
 
Output ID: L035  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 

 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 286 of 291


Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.9.16 Brief Physical Examination (Safety Analysis Set in Part B) 

 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
Listing 16.2.9.16  
Brief Physical Examination 
(Safety Analysis Set in Part B) 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient  
ID 
Treatment 
group 
Visit 
Date/Time of 
examination/ 
Relative day 
Body system 
Result (if Abnormal, clinical 
significant), Specify 
XXXXXXXXXXX 
XXXXX 
XXXXX 
DDMMMYYYY/HH:MM/xx 
XXXXXXXXXXXXXX 
XXXXXXXXXXXXXX 
 
  
 
  
  
  
Relative day: Relative to day of the first dose of study medication in each treatment period.  
EOS: End of Study, defined as the last available assessment assigned to study. 
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID and treatment period. 
 
Output ID: L027  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 287 of 291


Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.9.17 Full Physical Examination (Safety Analysis Set in Part B) 
 

 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
 
 
Listing 16.2.9.17 
Full Physical Examination 
(Safety Analysis Set in Part B) 
 
 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient  
ID 
Treatment 
group 
Visit 
Date/Time of 
examination/ 
Relative day 
Body system 
Result (if Abnormal, clinical 
significant), Specify 
XXXXXXXXXXX 
XXXXX 
XXXXX 
DDMMMYYYY/HH:MM/xx 
XXXXXXXXXXXXXX 
XXXXXXXXXXXXXX 
  
  
  
  
  
  
Relative day: Relative to day of the first dose of study medication in each treatment period.  
EOS: End of Study, defined as the last available assessment assigned to study. 
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID and treatment period. 
 
Output ID: L027  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 288 of 291


Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.9.18 Inhalation Training (All Randomized Analysis Set in Part B) 
Verona Pharma 
 
Page X of Y 
Protocol: RPL554-MD-201 
 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
Listing 16.2.9.18  
Inhalation Training  
(All Randomized Analysis Set in Part B)  
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient ID 
Treatment 
Period 
Inhalation training 
given? 
Date of inhalation training/ 
Relative day 
XXXXXXX 
XXXXXXX 
XXXXXXX 
DDMMMYYYY/xx 
  
  
  
  
Relative day: Relative to day of the first dose of study medication in each treatment period.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
Programming Notes 
Order by treatment sequence (as per shell) and within group by patient ID. 
 
Output ID: L013  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 
 

 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 289 of 291


Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.9.19 Pregnancy Urine Test Results (All Randomized Analysis Set in Part B) 
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part B  
RPL554 pressurised Metered Dose Inhaler 
 
 
 
 
Listing 16.2.9.19 
Pregnancy Urine Test Results 
(All Randomized Analysis Set in Part B) 
 
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient ID 
Treatment  
Group 
Treatment Period      
Urine pregnancy test performed/Date of 
test/Relative day 
Urine pregnancy test 
result  
 
 
 
 
 
XXXXXXX 
XXXXXXXXXX 
XXXXXXX               XX/DDMMMYYYY/xx 
XXXXXXX 
 
 
 
 
 
  
 
  
 
  
Relative day: Relative to day of the first dose of study medication in each treatment period.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
 
 
 
Programming Notes 
Order by treatment group (as per shell) and within group by patient ID. 
Consider only female patients. 
Multiple pregnancy risk factors and multiple relevant family history will be presented as one result per row, as these are not 
presented separately in Pregnancy report eCRF. 
 
 
 
 
 
Output ID: L036  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
 

 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 290 of 291


Document: \\ieedc-vnasc01\biosdata\Verona_Pharma\RPL554\EZAA8488\Biostatistics\Documentation\SAP\Verona RPL554-MD-201 TLF Shells v2.0 
– Part B 
 
Version: 2.0 
Author: Jennifer Allsopp 
Date: 22JAN2021 
 
Listing 16.2.9.20 Pregnancy Report Results (All Randomized Analysis Set in Part B) 
 
Verona Pharma 
Page X of Y 
Protocol: RPL554-MD-201 
Part B 
RPL554 pressurised Metered Dose Inhaler 
 
 
 
Listing 16.2.9.20 
Pregnancy Report Results  
(All Randomized Analysis Set in Part B)  
 
 
 
Treatment sequence: <Seq 1/Seq 2/Seq 3/Seq 4> 
Patient ID 
Pregnancy report item 
Results 
XXXXXXXXXXXXX 
Date of last menstrual period/Relative day 
DDMMMYYYY/xx 
 
Date of expected delivery/Relative day 
DDMMMYYYY/xx 
 
Overall number of previous pregnancies 
XX 
 
Number of normal deliveries 
XX 
 
Number of spontaneous miscarriages 
XX 
 
Number of other previous pregnancies 
XX 
 
Relevant pregnancy risk factors 
XXXXXXXXX 
 
Relevant family history 
XXXXXXXXX 
  
  
  
 Relative day: Relative to day of the first dose of study medication in each treatment period.  
Seq 1 = RPL554 300 mcg/RPL554 1000 mcg/RPL554 3000 mcg/Placebo. Seq 2 = RPL554 1000 mcg/Placebo/RPL554 300 mcg/ RPL554 3000 mcg. Seq 
3 = RPL554 3000 mcg/RPL554 300 mcg/Placebo/RPL554 1000 mcg. Seq 4 = Placebo/RPL554 3000 mcg/RPL554 1000 mcg/RPL554 300 mcg. 
 
 
 
Programming Notes 
Order by treatment group (as per shell) and within group by patient ID. 
Consider only female patients. 
Multiple pregnancy risk factors and multiple relevant family history will be presented as one result per row, as these are not 
presented separately in Pregnancy report eCRF. 
 
 
 
Output ID: L037  
[Source: Filepath\Filename.sas] IQVIA DDMMMYYYY HH:MM 
Clinical Study Report
RPL554-MD-201
Version 1.0; 17 May 2021
Verona Pharma plc
CONFIDENTIAL
Page 291 of 291