Conditions: Pulmonary Disease, Chronic Obstructive
Allocation: RANDOMIZED | Intervention model: FACTORIAL
Enrollment: 37
Healthy volunteers: no

Brief summary:
The purpose of this study is to investigate 5 doses of RPL554 and placebo, administered by dry powder inhaler (DPI), 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 RPL554 administered via dry powder inhaler (DPI). 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 placebo-controlled, complete block cross-over, repeat dose study to assess the bronchodilator effect of repeat doses of RPL554 delivered via a DPI.

Arms:
arm 1: Placebo controlled, parallel group single dose. Five of the 6 treatment arms will be double-blind and one will be single-blind arm 2: Double-blind, placebo-controlled, complete block cross-over

Interventions: intervention 1: Part A: RPL554 intervention 2: Part B: RPL554 intervention 3: Placebos
Intervention descriptions: intervention 1: 1 dose of either 50mcg/100mcg/1500mcg/3000mcg/6000mcg or placebo via dry powder inhaler intervention 2: Patients will receive 4 or 5 repeat dose treatments in crossover fashion - doses will be confirmed after Part A intervention 3: Part A: 1 dose of either 50ncg/100ncg/1500ncg/3000ncg/6000ncg or placebo via dry powder inhaler.

Part B: Patients will receive 4 or 5 repeat dose treatments in crossover fashion - doses will be confirmed after Part A.

Protocol document:
Prot_002.pdf: 
THIS STUDY WILL BE CONDUCTED IN ACCORDANCE WITH THE 
INTERNATIONAL CONFERENCE ON HARMONISATION GUIDELINES FOR GOOD 
CLINICAL PRACTICE (DIRECTIVE CPMP/ICH/135/95), THE DECLARATION OF 
HELSINKI (1964) AS AMENDED AND APPLICABLE REGULATORY 
REQUIREMENTS 
 
CONFIDENTIAL 
Page 1 of 64 
 
 
 
 
CLINICAL STUDY PROTOCOL 
A PHASE II, RANDOMIZED STUDY TO ASSESS THE 
PHARMACOKINETICS, SAFETY AND 
PHARMACODYNAMICS OF SINGLE AND REPEAT DOSES 
OF RPL554 ADMINISTERED BY DRY POWDER INHALER IN 
PATIENTS WITH COPD 
 
STUDY NO. RPL554-DP-201 
 
Version: 
2.0 
Date: 
12 February 2019  
Phase: 
II 
Investigational  
Medicinal Product:  
RPL554 
IND Number: 
133146 


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SPONSOR SIGNATURE PAGE 
THIS DOCUMENT HAS BEEN APPROVED BY VERONA PHARMA PLC: 


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INVESTIGATOR SIGNATURE PAGE 
I, the undersigned, am responsible for the conduct of the study at my study center 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 Institutional Review 
Board (IRB). 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 
authorized 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 IRBs 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 
Organization 
4820 Emperor Boulevard 
Durham, NC 27703 
USA 
Central Laboratory 
LGC 
(Pharmacokinetics) 
Newmarket Road 
Fordham 
Cambridgeshire, CB7 5WW 
UK 


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DETAIL OF AMENDMENTS SINCE THE PREVIOUS VERSION 
Throughout 
This amendment has been written primarily to specify the doses to be used in Part B of the study, 
now that Part A is complete and selected data have been analyzed. It has been decided that, with 
the exception of the 6000 µg dose (as stipulated in the original protocol), all four of the lower 
active doses from Part A will be administered in Part B. Consequently, all references to “up to 
four doses of RPL554” and “up to five treatment periods” have been replaced with “four doses of 
RPL554” and “five treatment periods,” respectively. 
Synopsis, Study Treatments 
Dose levels for Part B are now provided. 
List of Abbreviations  
International Non-proprietary Name (INN) has been added. 
Section 5.1.2, Treatments Administered in Part B 
Table 2 now lists the dose levels for Part B, and in the paragraph that follows has been amended 
to indicate that four capsules are to be inhaled twice daily, instead of “three or four capsules 
(depending on the doses chosen for Part B).” 
Section 5.2, Identity of Study Treatments 
The INN name for RPL554, ensifentrine, has been added. 
Section 6, Study Procedures 
In the first paragraph on p. 29, the time frame for commencement of Part B has been clarified, 
and the timing for the End of Study Visit has been corrected to indicate that it is performed after 
the completion of Treatment Period 5. 
In Table 6, the time at which spirometry and the dyspnea assessment are to be performed on Day 
7 of each treatment period has been changed from 11.5 hours post-dose to 11 hours post-dose. 
Section 6.4.2.3, Post-dose Assessments 
The time at which spirometry and the dyspnea assessment are to be performed on Day 7 of each 
treatment period has been changed from 11.5 hours post-dose to 11 hours post-dose. 
Section 7.3, Pharmacokinetic Assessments 
Instructions related to the plasma metabolite analysis of RPL554 have been provided. (This was 
previously documented in a Non-substantial Change Notification, dated 03 December 2018.) 
Section 9.4.3 
Reference to an alcohol breath test has been removed. (This was previously documented in a 
Non-substantial Change Notification, dated 28 October 2018.) 


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SYNOPSIS 
Title of Study: 
A Phase II, Randomized Study to Assess the Pharmacokinetics, Safety and 
Pharmacodynamics of Single and Repeat Doses of RPL554 Administered 
by Dry Powdered Inhaler in Patients with COPD 
Protocol Number: 
RPL554-DP-201 
IND Number: 
133146 
Phase: 
II 
Sponsor: 
Verona Pharma plc 
Study Center(s): 
One to two sites in US 
Planned Study Period: 
November 2018 to April 2019 
Objectives: 
Part A: 
Primary Objective 
To investigate the pharmacokinetic (PK) profile of single doses of RPL554, 
administered by dry powder inhaler (DPI), in patients with moderate to severe 
chronic obstructive pulmonary disease (COPD). 
Secondary Objectives 
•
To investigate the safety and tolerability of single doses of RPL554
administered by DPI, including effects on peak pulse and heart rate
•
To investigate the bronchodilator effect of single doses of RPL554
administered by DPI, 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 DPI, assessed in terms of peak FEV1. 
Secondary Objectives 
•
To investigate the safety and tolerability of repeat doses of RPL554,
administered by DPI
•
To investigate the bronchodilator effect of RPL554 administered by DPI,
in terms of average FEV1 AUC0-12h, average FEV1 AUC0-4h, and trough
FEV1
•
To determine the onset of action of RPL554 administered by DPI
•
To evaluate the PK profile of RPL554 administered by DPI
•
To evaluate the amount of rescue medication use during treatment periods
Exploratory Objectives
•
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
•
To examine the effect of RPL554 administered by DPI on a Likert
dyspnea scale


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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 DPI. 
There will be six treatment arms; five will be double-blind and one will be 
single-blind (due to the different number of capsules administered).  
Part B is a placebo-controlled, complete block cross-over, repeat dose study to 
assess the bronchodilator effect of repeat doses of RPL554 delivered via a DPI. 
The treatments will be double-blind. 
Subjects will be screened for eligibility, including a reversibility test 
(spirometry both pre- and post-4 puffs of albuterol) between 7 and 14 days 
before the first dose of study treatment. 
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 randomized 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 
analyzed 
prior 
to 
commencing 
with 
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 five treatment 
sequences in a crossover design, consisting of five 1-week treatment periods 
separated by a 7 to 10 day washout period. Each treatment sequence will 
include four dose levels of RPL554 administered by DPI (selected from Part A) 
and a double-blind placebo DPI 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.  


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Study Procedures: 
The following will be performed at each treatment visit: 
•
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
•
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
•
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
•
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
•
Laboratory safety tests
−
Part A: Screening Part B: Pre-dose on Days 1 and 7 of each
treatment period, and at End of Study Visit
Adverse events will be recorded throughout the study. 
Number of Patients Planned: 
Approximately 36 randomized 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/FVC ratio of 
≤0.70. They must have a baseline increase in FEV1 of >150 mL following four 
puffs of albuterol. They must have at least a 10 pack-year smoking history, and 
may be either a former smoker or current smoker. 
Exclusion Criteria 
Patients must be clinically stable without recent COPD exacerbations or 
hospitalizations. They must not have uncontrolled disease or chronic heart 
failure. 


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Study Treatments: 
Part A (single dose parallel group), administered once in the morning: 
Treatment Arm 1: RPL554 150 µg double blind 
Treatment Arm 2: RPL554 500 µg double blind 
Treatment Arm 3: RPL554 1500 µg double blind 
Treatment Arm 4: RPL554 3000 µg double blind 
Treatment Arm 5: RPL554 6000 µg single blind 
Treatment Arm 6: Placebo single blind 
Part B (double-blind, repeat dose crossover), administered morning and evening 
(except morning only on Day 7): 
Treatment 1: RPL554 150 µg  
Treatment 2: RPL554 500 µg  
Treatment 3: RPL554 1500 µg 
Treatment 4: RPL554 3000 µg 
Treatment 5: Placebo 
Duration of Treatment: 
Part A: 1 to 2 week screening period, followed by single dose treatment and 
then an analysis period (exact timing to be determined). 
Part B: 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 DPI 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 (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 to a difference of about 70 mL. To account 
for withdrawals, approximately 36 patients will be randomized 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 ..........................................10 
Table of Contents .................................................................................................................10 
List of Tables and Figures ....................................................................................................13 
LIST OF ABBREVIATIONS ........................................................................................................14 
1 
INTRODUCTION ................................................................................................................15 
1.1 
Disease and Study Medication Review .......................................................................15 
1.2 
Summary of Risks and Benefits ..................................................................................17 
2 
OBJECTIVES.......................................................................................................................18 
2.1 
Part A ..........................................................................................................................18 
2.1.1 
Primary Objective .........................................................................................18 
2.1.2 
Secondary Objectives ...................................................................................18 
2.2 
Part B ..........................................................................................................................18 
2.2.1 
Primary Objective .........................................................................................18 
2.2.2 
Secondary Objectives ...................................................................................18 
2.2.3 
Exploratory Objectives .................................................................................18 
3 
INVESTIGATIONAL PLAN ..............................................................................................19 
3.1 
Overall Study Design and Plan Description ...............................................................19 
3.2 
Discussion of Study Design, including the Choice of Control Groups ......................19 
3.3 
Planned Duration of the Study ....................................................................................20 
3.4 
Definition of the End of the Study ..............................................................................20 
4 
SELECTION OF STUDY POPULATION ..........................................................................21 
4.1 
Inclusion Criteria.........................................................................................................21 
4.2 
Exclusion Criteria .......................................................................................................22 
4.3 
Removal of Patients from Therapy or Assessment .....................................................23 
4.3.1 
Study Treatment Discontinuation .................................................................23 
4.3.2 
Patient Withdrawal .......................................................................................23 
4.3.3 
Study Discontinuation ...................................................................................24 
4.3.4 
Replacement Policy ......................................................................................24 
5 
STUDY TREATMENTS .....................................................................................................25 


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5.1 
Study Treatments Administered..................................................................................25 
5.1.1 
Treatments Administered in Part A ..............................................................25 
5.1.2 
Treatments Administered in Part B ..............................................................25 
5.2 
Identity, Preparation and Labeling of Study Treatments ............................................26 
5.3 
Selection of Doses and Dosing Schedule ....................................................................26 
5.3.1 
Selection of Doses in the Study ....................................................................26 
5.3.2 
Timing of Dose for Each Patient ..................................................................26 
5.4 
Storage ........................................................................................................................26 
5.5 
Accountability .............................................................................................................27 
5.6 
Method of Assigning Patients to Treatment Groups ...................................................27 
5.7 
Blinding .......................................................................................................................27 
5.8 
Prior and Concomitant Therapies and Medications ....................................................28 
5.8.1 
Prior and Concomitant COPD Medications ..................................................28 
5.8.2 
Other (non-COPD) Prior and Concomitant Medications .............................29 
5.9 
Rescue Medications ....................................................................................................29 
5.10 Treatment Compliance ................................................................................................30 
6 
STUDY PROCEDURES AT EACH VISIT ........................................................................31 
6.1 
Pre-visit Restrictions ...................................................................................................34 
6.2 
Screening .....................................................................................................................34 
6.3 
Part A: Single Dose Treatment ...................................................................................35 
6.3.1 
Pre-dose Assessments ...................................................................................35 
6.3.2 
Study Medication Administration .................................................................36 
6.3.3 
Post-dose Assessments .................................................................................36 
6.4 
Part B: Repeat Dose Treatment ...................................................................................36 
6.4.1 
Day 1 of Each Treatment Period ...................................................................36 
6.4.1.1 
Pre-dose Assessments ..................................................................36 
6.4.1.2 
Study Medication Administration ................................................37 
6.4.1.3 
Post-dose Assessments .................................................................37 
6.4.2 
Day 7 of Each Treatment Period ...................................................................38 
6.4.2.1 
Pre-dose Assessments ..................................................................38 
6.4.2.2 
Study Medication Administration ................................................38 
6.4.2.3 
Post-dose Assessments .................................................................38 
6.5 
End of Study Visit .......................................................................................................39 
7 
STUDY METHODOLOGY .................................................................................................40 
7.1 
Demographics, Baseline Characteristics and Eligibility Assessments .......................40 
7.1.1 
Demographic Variables ................................................................................40 
7.1.2 
Medical and Disease History ........................................................................40 
7.1.3 
Reversibility Test ..........................................................................................40 


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7.1.4 
Screening Laboratory Assessments, Chest X-ray .........................................40 
7.1.5 
Prior and Concomitant Medications and Therapies ......................................41 
7.1.6 
Eligibility Check ...........................................................................................41 
7.2 
Efficacy/Pharmacodynamic Assessments ...................................................................41 
7.2.1 
Pulmonary Function Tests ............................................................................41 
7.2.2 
Dyspnea Scale ...............................................................................................41 
7.2.3 
Rescue Medication ........................................................................................41 
7.3 
Pharmacokinetic Assessments ....................................................................................41 
7.4 
Safety Assessments .....................................................................................................42 
7.4.1 
Adverse Events .............................................................................................42 
7.4.1.1 
Adverse Event Definitions ...........................................................42 
7.4.1.2 
Recording and Assessing Adverse Events ...................................43 
7.4.1.2.1 Severity ........................................................................43 
7.4.1.2.2 Chronicity ....................................................................43 
7.4.1.2.3 Causality ......................................................................43 
7.4.1.2.4 Action and Outcome ....................................................44 
7.4.1.3 
Reporting Procedure for SAEs .....................................................44 
7.4.2 
Pregnancy ......................................................................................................44 
7.4.3 
Laboratory Assessments ...............................................................................45 
7.4.3.1 
Hematology ..................................................................................45 
7.4.3.2 
Blood Chemistry ..........................................................................45 
7.4.3.3 
Urinalysis .....................................................................................45 
7.4.4 
Vital Signs .....................................................................................................45 
7.4.5 
Physical Examination ...................................................................................45 
7.4.6 
12-Lead ECG ................................................................................................46 
8 
QUALITY ASSURANCE AND QUALITY CONTROL ...................................................47 
8.1 
Audit and Inspection ...................................................................................................47 
8.2 
Monitoring and Source Document Verification ..........................................................47 
8.3 
Data Management and Coding ....................................................................................48 
9 
STATISTICAL METHODS ................................................................................................50 
9.1 
Statistical and Analytical Plans ...................................................................................50 
9.2 
Populations to be Analyzed.........................................................................................50 
9.3 
Study Endpoints ..........................................................................................................50 
9.3.1 
Part A ............................................................................................................50 
9.3.1.1 
Primary Endpoint .........................................................................50 
9.3.1.2 
Secondary Endpoints ....................................................................51 
9.3.2 
Part B ............................................................................................................51 
9.3.2.1 
Primary Endpoint .........................................................................51 


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9.3.2.2 
Secondary Endpoints ....................................................................51 
9.3.2.3 
Exploratory Endpoint ...................................................................52 
9.4 
Statistical Methods ......................................................................................................52 
9.4.1 
Patient Disposition ........................................................................................52 
9.4.2 
Protocol Deviations .......................................................................................52 
9.4.3 
Demographics and Other Baseline Characteristics .......................................52 
9.4.4 
Extent of Exposure and Treatment Compliance ...........................................52 
9.4.5 
Efficacy/Pharmacodynamics ........................................................................53 
9.4.6 
Pharmacokinetics ..........................................................................................53 
9.4.7 
Safety ............................................................................................................54 
9.4.8 
Handling of Withdrawals or Missing Data ...................................................54 
9.4.9 
Interim Analyses ...........................................................................................55 
9.5 
Determination of Sample Size ....................................................................................55 
10 
ETHICAL CONSIDERATIONS .........................................................................................56 
10.1 Guidelines ...................................................................................................................56 
10.2 Ethics and Regulatory Approval .................................................................................56 
10.3 Informed Consent Process ..........................................................................................56 
10.4 Patient Confidentiality ................................................................................................56 
10.5 Record Maintenance/Retention ...................................................................................57 
11 
FINANCE AND INSURANCE ...........................................................................................58 
12 
PUBLICATION POLICY ....................................................................................................59 
13 
REFERENCES .....................................................................................................................60 
14 
APPENDICES ......................................................................................................................62 
14.1 Birth Control Methods for Women of Childbearing Potential Which May Be 
Considered As Highly Effective .................................................................................62 
14.2 Interpreting Adverse Event Causality .........................................................................64 
List of Tables and Figures 
Figure 1 
Study Flow Chart ....................................................................................................... 19 
Table 1 
Treatment Arms and Capsules Combinations in Part A ............................................ 25 
Table 2 
Treatments in Part B .................................................................................................. 25 
Table 3 
Composition of RPL554 DPI*.................................................................................... 26 
Table 4 
Restrictions for COPD Medications Prior to Screening ............................................ 28 
Table 5 
Schedule of Assessments for Part A .......................................................................... 32 
Table 6 
Schedule of Assessments for Part B, Days 1 and 7 of Each Treatment Period 
and End of Study Visit .............................................................................................. 33 


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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 
DPI 
Dry powder inhaler 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
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 
HDPE 
High density polyethylene 
HRT 
Hormone replacement therapy 
ICH 
International Council on Harmonization 
ICS 
Inhaled corticosteroid 
INN 
International Non-proprietary Name 
IRB 
Institutional Review Board 
IUPAC 
International Union of Pure and Applied Chemistry 
LABA 
Long acting β2-agonists 
LAMA 
Long acting muscarinic antagonists 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHANES 
National Health and Nutrition Examination Survey 
PDE 
Phosphodiesterase 
PK 
Pharmacokinetics 
pMDI 
Pressurized 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 characterized 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 remodeling, and 
excessive mucus production are believed to contribute to the airflow obstruction and lung 
parenchymal destruction. COPD is predicted to be the third leading cause of death and fourth 
most common cause of disability worldwide by 2030 and chronic tobacco smoke exposure is 
believed to be a key etiological factor [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 
2005; Calverley 2007; Rennard 2011; Singh 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 β2-agonists [LABA]) remain uncontrolled and 
continue to experience airway obstruction, COPD symptoms and exacerbations [Vestbo 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), while 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 (reviewed by 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 unfavorable gastrointestinal side effects such as nausea, emesis, 
diarrhea, 
abdominal 
pain, 
loss 
of 
appetite 
and 
weight 
loss 
[Harbinson 
1997; 
van Schalkwyk 2005; Compton 2001; Rabe 2005; Rennard 2006; Calverley 2007; Gamble 2003; 
Grootendorst 2007]. Dual PDE3/PDE4 inhibitors (administered by inhalation) have exhibited 
both bronchodilator and anti-inflammatory actions, with a more favorable side effect profile 
[Ukena 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 
antimuscarinic agents, as well as additive properties with β2-agonists [Calzetta 2013; Calzetta 
2015]. Therefore, RPL554 has the potential to benefit patients not satisfactorily treated with 
existing medicines. 


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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-moderate persistent asthma and those with 
allergic rhinitis and COPD, using a nebulized solution in citrate/phosphate buffered saline at pH 
3.2 [Franciosi 2013; summarized in the Investigator’s Brochure]. 
RPL554 was subsequently re-formulated in a pH neutral suspension formulation for 
nebulization. This formulation has been tested in seven completed clinical studies: 
1.
Study RPL554-007-2014 was a Phase I study in which single and multiple ascending doses
up to 24 mg were administered to healthy subjects and COPD patients. No maximum
tolerated dose of RPL554 could be determined and there was a large bronchodilator
response observed. Pharmacokinetics demonstrated a terminal serum half-life of about 10
to 12 hours [RPL554-007-2014 Clinical Study Report 2016].
2.
Study RPL554-008-2014 was a Phase II crossover study that enrolled patients with mild to
moderate chronic asthma who received four single doses of RPL554 (0.4 mg, 1.5 mg, 6 mg
and 24 mg), two doses of nebulized albuterol (2.5 mg and 7.5 mg) and placebo. RPL554
produced a dose-dependent bronchodilation with a magnitude that was comparable to a
maximal dose of albuterol, but with fewer of the well described albuterol side effects (e.g.
hypokalemia, tachycardia, tremor and palpitations) [Bjermer 2016].
3.
Study RPL554-009-2015 was a Phase II crossover study in moderate to severe COPD
patients who received albuterol (200 µg), ipratropium (40 µg) or placebo using a
pressurized metered dose inhaler (pMDI) followed immediately by nebulized RPL554
(6 mg) or placebo. RPL554 alone was as effective as standard of care bronchodilators, and
importantly produced significant additive bronchodilation. Indeed, there was an
approximately 60% additional increase in peak forced expiratory volume in 1 second
(FEV1) in COPD patients administered RPPL554 in addition to either albuterol or
ipratropium [RPL554-009-2015 Clinical Study Report 2017].
4.
Study RPL554-PK-101 was a Phase I study of the oral bioavailability of RPL554 in
healthy subjects. Subjects were randomized to RPL554 6 mg given with, or without, a
charcoal block. The study demonstrated a low oral bioavailability of 10.6% and a terminal
half-life of 11.9 hours [RPL554-PK-101 Clinical Study Report 2017].
5.
Study RPL554-CO-202 was a Phase II crossover study in patients with moderate to severe
COPD who received tiotropium 18 µg once daily, plus RPL554 1.5 mg, RPL554 6 mg or
placebo twice daily for 3 days. This study demonstrated a significant increase in peak
FEV1 (103 mL and 127 mL for RPL554 1.5 mg and 6 mg, respectively) as compared to
tiotropium + placebo. There was also significant improvement in both trough FEV1 and
lung volumes, including residual volume and functional residual capacity. The time of
onset of RPL554 + tiotropium was dramatically faster than with tiotropium alone (4.2
versus 37 minutes) [Clinical Study Report pending].
6.
Study RPL554-CO-203 was a Phase II parallel group study in 403 patients with COPD
who were administered either placebo or RPL554 at doses ranging from 0.75 mg to 6 mg
over 4 weeks. Clinically and statistically significant improvements in peak FEV1 compared
to placebo were observed in all active dose groups at all time points. Secondary endpoints
of average FEV1, COPD symptoms and quality of life were also met [Clinical Study
Report pending].


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7.
Study RPL554-010-2015 was a Phase II crossover study in adult patients with cystic
fibrosis. Patients received a single dose of RPL554, 1.5 mg, 6 mg, or placebo. This study
demonstrated a significant increase (6.6%) in peak FEV1, as well as demonstrating
pharmacokinetic levels that were similar to that seen in patients with COPD. RPL554 was
well tolerated in these patients [Clinical Study Report pending].
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 dry powder 
inhaler (DPI). The current study will be the first clinical assessment of the DPI formulation of 
RPL554 in humans. A non-clinical assessment of local and systemic toxic potential of a dry 
powder formulation of RPL554 was conducted in a 2-week inhalation study in Han Wistar rats. 
The purpose of this non-clinical study was to support the current single and repeat dose clinical 
study with a DPI formulation. The RPL554 active pharmaceutical ingredient used in the DPI 
formulation was the identical physical form and morphology as that used in the nebulizer 
suspension product in previous studies. Early results from this initial bridging toxicology study 
with a lactose dry powder blend shows no new findings when this vehicle formulation is used. 
The purpose of this study is to assess the efficacy, safety and pharmacokinetics (PK) of RPL554 
administered via DPI in order to support further development of RPL554 in a DPI format. 
1.2 
Summary of Risks and Benefits 
Data from non-clinical studies had suggested a potential for hypotension and tachycardia. 
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 nebulized 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 summarized in the Investigator’s Brochure. 
The suspension formulation of RPL554 has favorable non-clinical toxicology and 
pharmacokinetic data. 
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 maneuvers 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 dry powder inhaler 
(DPI), in patients with moderate to severe COPD. 
2.1.2 
Secondary Objectives 
•
To investigate the safety and tolerability of single doses of RPL554 administered by DPI,
including effects on peak pulse and heart rate
•
To investigate the bronchodilator effect of single doses of RPL554 administered by DPI, in
terms of peak 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 DPI, 
assessed in terms of peak FEV1.
2.2.2 
Secondary Objectives 
•
To investigate the safety and tolerability of repeat doses of RPL554, administered by DPI
•
To investigate the bronchodilator effect of RPL554 administered by DPI, in terms of
average FEV1 AUC0-4h, average FEV1 AUC0-12h and trough FEV1
•
To determine the onset of action of RPL554 administered by DPI
•
To evaluate the PK profile of RPL554 administered by DPI
•
To evaluate the amount of rescue medication use during treatment periods
2.2.3 
Exploratory Objectives 
•
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
•
To examine the effect of RPL554 administered by DPI on a Likert dyspnea scale


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 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 DPI. Part B is a complete 
block crossover, repeat dose assessment of RPL554 administered by DPI. 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: TP=Treatment Period 
In Part A, patients will be screened for eligibility, including a reversibility test with albuterol. 
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 one 
inhaler and will be administered either 4 or 8 capsules via DPI (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 analyzed 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 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. Specific treatments are shown in Table 2 
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 DPI 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 150 µg up to 6000 µg have been selected to evaluate the 
safety, PK and efficacy/pharmacodynamic characteristics of this formulation over a dose range 
covering a 40-fold increase in doses. A total of approximately 36 COPD patients aged 40 to 80 
years (inclusive) will be randomized. Patients in Part A will be randomly assigned to receive 
either RPL554 or placebo via DPI. Following an analysis of the safety, PK and 
efficacy/pharmacodynamics, four doses will be selected for Part B. Study medication 
administered via DPI will be double blind, except for the 6000 µg treatment arm in Part A which 
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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will be single blind due to the number of capsules required, in order to minimize any potential 
bias in the overall assessment of treatment effect and safety.  
Part B is designed as a crossover study to assess the steady state efficacy/pharmacodynamic 
effect of four dose levels of RPL554 administered by DPI after a week of twice daily dosing, and 
to compare that effect with placebo DPI. 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 nebulized formulation. 
In Part B, all patients from Part A will undergo five treatment periods in a double-blind 
randomized, 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 volunteers, 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 
was 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 
must 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, 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 is stable patients with moderate to severe COPD 
and 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:
•
Not donate sperm
•
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 ECG recording at Screening and pre-dose in Part A showing the following:
•
Heart rate between 50 and 90 beats per minute
•
QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≤450 msec for
males, and ≤470 msec for females
•
QRS interval ≤120 msec
•
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
DPI 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 albuterol) spirometry at Screening demonstrating the
following:
•
FEV1/forced vital capacity (FVC) ratio of ≤0.70
•
FEV1 ≥40 % and ≤80% of predicted normal


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• 
≥150 mL increase from pre-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. 
Current and former smokers with smoking history of ≥10 pack years.  
14. 
Capable of withdrawing from long acting bronchodilators for the duration of the study, and 
short acting bronchodilators for 8 hours prior to dosing. 
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 hospitalizations for COPD or pneumonia within 6 months of 
Screening or prior to Part A. 
4. 
Intolerance or hypersensitivity to albuterol 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 apnea, 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, hematological, urological, 
immunological, psychiatric, or ophthalmic diseases that the Investigator believes are 
clinically significant.  
13. 
Documented cardiovascular disease, including any history of arrhythmias, angina, recent 
(<1 year) or suspected myocardial infarction, congestive heart failure, unstable or 
uncontrolled hypertension, or diagnosis of hypertension within 3 months prior to 
Screening. 
14. 
Use of non-selective oral β-blockers. 
15. 
Major surgery (requiring general anesthesia) within 6 weeks prior to Screening, lack of full 
recovery from surgery at Screening, or planned surgery through the end of the study. 


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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 localized
skin cancers (basal or squamous cell).
19.
Clinically significant abnormal values for viral serology or laboratory safety tests
(hematology, biochemistry or urinalysis) at Screening, as determined by the Investigator
(see Section 7.1.4 and 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: 
•
Unacceptable toxicity related to study treatment
•
Intolerable or persistent adverse events of any severity
•
General or specific changes in the patient's condition rendering the patient unacceptable for
further treatment in the judgment of the Investigator
•
Clinically significant progression of disease
•
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 jeopardizing 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 treatment, 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 Randomization, 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: 
•
The discovery of an unexpected, serious, or unacceptable risk to patients enrolled in the
study
•
The decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or
development of RPL554
•
Serious failure of the Investigator to comply with the International Council on
Harmonisation (ICH) Guidelines on Good Clinical Practice (GCP) or local regulations
•
Submission of knowingly false information from the research facility to the Sponsor, the
IRB or any national regulatory officials
•
Major, repeated, non-adherence to the protocol
The Sponsor must be informed immediately in the event of any major protocol deviation or 
serious breach of ICH GCP. 
Study termination and follow-up will be performed in compliance with the conditions set forth in 
ICH GCP. The decision to discontinue the study is at the discretion of the Sponsor, the 
Investigator, the regulatory authority or IRB 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 IRBs 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 randomized 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. Each patient will be instructed to take two inhalations with each capsule, for a 
total of either eight or 16 inhalations depending on the assigned treatment arm. 
Table 1 
Treatment Arms and Capsules Combinations in Part A 
Arm 
No. of 
Patients 
Total 
Dose 
Capsule 
1 
2 
3 
4 
5 
6 
7 
8 
1 
6 
150 µg 
50 µg 
50 µg 
50 µg 
Placebo 
2 
6 
500 µg 
500 µg 
Placebo 
Placebo 
Placebo 
3 
6 
1500 µg 
500 µg 
500 µg 
500 µg 
Placebo 
4 
6 
3000 µg 
750 µg 
750 µg 
750 µg 
750 µg 
5* 
6 
6000 µg 
750 µg 
750 µg 
750 µg 
750 µg 
750 µg 
750 µg 
750 µg 
750 µg 
6 
6 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
* Single-blind (see Section 5.7)
5.1.2 
Treatments Administered in Part B 
Patients will receive five repeat dose treatments in a crossover fashion, as shown in Table 2, 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. 
Table 2 
Treatments in Part B 
Treatment 
Study Medication 
1 
RPL554 DPI, 150 µg 
2 
RPL554 DPI, 500 µg 
3 
RPL554 DPI, 1500 µg 
4 
RPL554 DPI, 3000 µg 
5 
Placebo DPI 
Abbreviations: DPI=dry powder inhaler 
The doses to be used in Part B have been determined from the analyses performed on data from 
Part A; however, the highest dose was not to exceed 3000 μg. Each patient will be instructed to 
inhale the contents of four capsules twice daily, via two inhalations for each capsule, for a total 
of eight inhalations. 


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5.2 
Identity, Preparation and Labeling of Study Treatments 
The recommended International Non-proprietary Name (INN) for RPL554 is ensifentrine. 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 capsules are manufactured in accordance 
with Good Manufacturing Practice (GMP) guidelines.  
The composition of the DPI formulation is shown in Table 3. 
[REDACTED]
The DPI capsules will be packaged in high density polyethylene (HDPE) bottles (40 capsules 
per bottle) and heat sealed in an aluminum foil pouch. The labelling on the bottles and foil 
pouches provided to the site will be open label format indicating the contents of each bottle. 
Once the pouch has been opened the in-use shelf-life of the capsules is 14 days. The double-
blind doses required will be dispensed at the site according to the randomization schedule 
and labelled appropriately. To maintain the blind, placebo capsules will also be required 
for the active treatment groups. Detailed dispensing instructions are provided in the study 
Pharmacy Manual. 
Administration will be via inhalation from a reusable Plastiape RS01 Monodose dry powder 
inhaler. 
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 40-fold dose range of the DPI formulation. 
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 be stored between 20°C and 25°C (68°F to 77°F). 
Excursions between 15°C and 30°C (59°F and 86°F) are allowed. Once the foil pouch containing 
the bulk capsules has been opened the ‘in-use’ shelf-life of the capsules is 14 days. Temperature 
logs should be maintained in areas where study treatment is stored. If temperature conditions 
have been compromised or any study treatment has not been stored appropriately, this should be 


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documented, and the study treatment 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 treatments that are to be returned by 
the Investigator/staff or have expired must be stored separately from the unused study treatments. 
5.5 
Accountability 
The Investigator will be responsible for the dispensing, inventory and accountability of study 
treatment, exercising accepted medical and pharmaceutical practices and ensuring that an 
accurate, timely record of the disposition is maintained. The study treatment supplies and 
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 center to their final removal from the 
center. 
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 authorization 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 center 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 randomized 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 randomization 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 Arm 5 will be single 
blind (sites staff will be aware of treatment assignment due to the number of study capsules). 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. 


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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 site 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 treatment 
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. 
Upon providing informed consent, patients will discontinue COPD medications for the time 
periods described in Table 4 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, subjects must 
discontinue these prohibited medications according to the time periods described in Table 4 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 4 
Restrictions for COPD Medications Prior to Screening 
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) 
•
Once-daily bronchodilators
•
Twice daily bronchodilators
•
48 hours
•
24 hours
Inhaled corticosteroids 
Allowed if dose is stable ≥4 weeks prior to Screening and 
expected to remain stable throughout the study 
Abbreviations: COPD=chronic obstructive pulmonary disorder; LABA=long acting β2-agonist; LAMA=long acting 
muscarinic antagonist 
The following therapies are subject to restriction as indicated: 
•
Patients taking LAMAs and LABAs should be placed on short acting bronchodilators
(e.g. albuterol, 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)
•
Patients taking LABA/inhaled steroid combination products should be prescribed the
inhaled steroid at the same or equivalent dose contained in the combination product to


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allow continuation of steroid use regularly throughout the study while stopping the LABA 
component. Inhaled steroid medication should be procured via prescription for patients 
requiring its use 
•
No scheduled regular use of albuterol 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 8 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:
-
8 hours prior to pre-reversibility spirometry for Screening
-
8 hours prior to pre-dose spirometry (in Part A as well as Days 1 and 7 in each of the
treatment periods in Part B)
-
Post dose:

Part A: Until after +12 hours spirometry

Part B, Days 1 and 7: Until after +12 hours spirometry for each treatment
period
If following the above requirements provides inadequate symptom control, patients should 
contact the Investigator.  
•
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
•
Oxygen therapy and non-selective oral β-blockers are Exclusion Criteria and are not to be
used at any time during the study
•
Oral mucolytics and ocular β-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 treatment 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. Albuterol is to be used for 
primary rescue use. Rescue medication will be sourced by the study center 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.  


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Rescue medication use during each study visit must be separately documented in the eCRF 
(medication, dose, route, and date and time of each administration). Rescue use between visits 
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 in clinic by study personnel. 
In Part B, patients will also 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). The number of capsules dispensed and returned will be 
recorded. 
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. 


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6 
STUDY PROCEDURES AT EACH VISIT 
The study will consist of the following: 
• 
Screening will take place in the period between 7 and 14 days prior to the first study 
treatment administration in Part A. Screening procedures may be performed as a single 
visit or more than one visit 
• 
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 
• 
Part B will commence once IRB approval for the protocol amendment has been obtained, 
and will consist of five 7-day treatment periods of repeat doses of study medication, each 
separated by 7 to 10 days 
• 
An End of Study Visit will occur between 4 and 10 days after the completion of Treatment 
Period 5 
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 5 for Part A and Table 6 for Part B. 
Assessments are listed by visit in Section 6.2 to 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 (prioritized on the timepoint). 


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Table 5 
Schedule of Assessments for 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 
11.5h 
12h 
24h 
Informed consent 
X 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rescue medication dispensing 
X 1 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Demographics including height & weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral serology test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH test (if required) 
X 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical and disease history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
Full 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief 
 
X 
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 tests 4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
X 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
Chest X-ray (as required) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reversibility testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spirometry 
X 
X 5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Rescue canister weight 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Inhalation training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
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; 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. 
Hematology 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-
albuterol value obtained at Screening 


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Table 6 
Schedule of Assessments for Part B, Days 1 and 7 of Each Treatment Period and End of Study Visit 
Abbreviations: ECG=electrocardiogram; h=hours; m=minutes; TP=Treatment Period 
1. 
Patients will be contacted by phone the night before their Day 7 visits 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, 3) bring their medication to the visit and 4) follow other medication and activity restrictions as described in Section 5.8.1 and 6.1 
2. 
Additional rescue medication may be dispensed if needed 
3. 
For women of childbearing potential only. Urine pregnancy test 
4. 
Hematology and blood chemistry 
5. 
Pre-dose spirometry shall be conducted at -60 (±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 
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  
 
Day 1 
Day 7 1 
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 
Rescue canister weight 2 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Recording of prior evening dose time 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (as applicable) 3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory safety tests 4 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Spirometry 
X 5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dyspnea scale 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Inhalation training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inhaler, study and rescue medication 
dispensed 6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study medication administered 
in-clinic 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Study and rescue medication collected 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study medication compliance 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic sample 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Adverse events 
X 
X 
X 
Prior/concomitant medications 
X 
X 
X 


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6.1 
Pre-visit Restrictions 
The following restrictions should be adhered to (for all study visits except where noted): 
• 
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 
• 
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 
• 
Patients must fast (water permitted) from 2 hours pre-dose until 1 hour post-dose (does not 
apply to Screening) 
• 
Patients should refrain from smoking at least 1 hour pre-dose, and at least 1 hour before 
any measurement of lung function 
• 
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 treatment. 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):  
• 
Obtain informed consent (if not done prior to Screening) 
• 
Recording of demographic information, including height and weight 
• 
Recording of medical/surgical and disease history 
• 
Recording of prior medications and therapies; confirming that medications were withheld 
as required 
• 
Vital signs  
• 
Full physical examination (see Section 7.4.5) 
• 
12-lead ECG 
• 
Reversibility test: 
- 
Pre-reversibility spirometry 
- 
Four puffs of albuterol 
- 
Post-reversibility spirometry (20 to 30 minutes after albuterol) 


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• 
Blood samples for laboratory screening and safety tests: 
- 
Viral serology 
- 
Follicle stimulating hormone (FSH; if required to confirm post-menopausal status) 
- 
Serum pregnancy (for women of childbearing potential only) 
- 
Hematology and blood chemistry 
• 
Urinalysis  
• 
Urine pregnancy (for women of childbearing potential only) – results should be obtained 
prior to the chest X-ray 
• 
Chest X-ray (unless historical X-ray performed in last 12 months is available) 
• 
Questioning for adverse events 
If the patient meets all of the Inclusion and none of the Exclusion Criteria: 
• 
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: 
• 
Assess concomitant medications; confirm that medications were withheld as required, and 
that all eligibility criteria continue to be met 
• 
Question for adverse events 
• 
Weigh rescue medication canister  
• 
Urine pregnancy test (women of childbearing potential only) 
• 
12-lead ECG 
• 
Vital signs  
• 
Brief physical examination (see Section 7.4.5) 
• 
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-albuterol value at 
Screening; otherwise, the patient will be screen failed in accordance with Inclusion 
Criterion #10 
• 
PK sampling 
• 
Inhalation training 
• 
Assign randomization number from next in sequence available at the study center 


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6.3.2 
Study Medication Administration 
Patients will be dosed once with either blinded RPL554 or placebo according to the 
randomization scheme. 
6.3.3 
Post-dose Assessments 
The following assessments will be performed, at the times indicated relative to the end of dosing: 
• 
12-lead ECGs at 1, 2, 4 and 8 hours (±10 minutes) 
• 
Vital signs at 1, 2, 4, 8, 12 and 24 hours (±10 minutes)  
• 
PK sampling at 15 (±5) minutes, 30 (±10) minutes and 1, 1.5, 2, 4, 8, 12 and 24 hours (the 
latter assessments all ±15 minutes) 
• 
Spirometry at 5 (±2), 15 (±5) and 30 (±10) minutes and 1, 1.5, 2, 4, 8, 11.5, 12 and 
24 hours (the latter assessments all ±15 minutes) 
• 
Weigh rescue medication canister again, if used during the visit 
• 
Dispense new rescue medication after the 24 hour assessment 
• 
Question for adverse events 
Patients will be discharged from the study center after the 12-hour assessments and instructed to 
return the next morning; alternatively, they may remain resident at the study center 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 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 drug that evening at the scheduled time and 2) not to take study drug 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: 
• 
Assess concomitant medications and confirm that medications were withheld as required 
• 
Counsel/remind patient of daily dosing schedule as needed 
• 
Question for adverse events 
• 
Dyspnea scale 


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• 
PK sampling  
• 
Blood samples for laboratory safety tests (hematology and blood chemistry) 
• 
Urine pregnancy test (women of childbearing potential only) 
• 
Urinalysis 
• 
12-lead ECG 
• 
Vital signs  
• 
Brief physical examination (see Section 7.4.5) 
• 
Spirometry; 1 hour (±5 minutes) and immediately (within 5 minutes) pre-dose 
• 
Inhalation training  
• 
Dispense inhaler, study medication and rescue medication 
• 
At Treatment Period 1 only, assign randomization number from next in sequence available 
at the study center 
6.4.1.2 
Study Medication Administration 
Patients will be dosed once with either RPL554 or placebo according to the randomization 
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 (±10 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: 
• 
Vital signs at 1, 2, 4, 8 and 12 hours (±10 minutes)  
• 
Dyspnea scale at 30 (±10) minutes and 1, 1.5, 2, 4, 8 and 12 hours (the latter assessments 
all ±15 minutes) 
• 
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) 
• 
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) 
• 
Question for adverse events  
• 
Weigh rescue medication canister  
• 
Dispense study medication to patient 
Patients will be discharged from the study center 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 Section 5.8.1 and 
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: 
• 
Collect study medication 
• 
Weigh rescue medication canister 
• 
Assess study medication compliance (see Section 5.10);  
• 
Assess concomitant medications; confirm that medications were withheld as required and 
record time of prior evening dose of study drug 
• 
Question for adverse events 
• 
Dyspnea scale 
• 
PK sampling 
• 
Blood samples for laboratory safety tests (hematology and blood chemistry) 
• 
12-lead ECG 
• 
Vital signs  
• 
Brief physical examination (see Section 7.4.5) 
• 
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 randomization 
scheme.  
6.4.2.3 
Post-dose Assessments 
The following assessments will be performed, at the times indicated relative to dosing: 
• 
Vital signs at 1, 2, 4, 8 and 12 hours (±10 minutes)  
• 
Dyspnea scale at 30 (±10) minutes and 1, 1.5, 2, 4, 8, 11 and 12 hours (the latter 
assessments all ±15 minutes) 
• 
PK sampling at 30 (±10) minutes and 1, 1.5, 2, 4, 8 and 12 hours (the latter assessments all 
±15 minutes) 
• 
Spirometry at 30 minutes (±10) and 1, 1.5, 2, 4, 8, 11 and 12 hours (the latter assessments 
all ±15 minutes) 
• 
Question for adverse events  
Patients will be discharged from the study center 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: 
• 
Assess concomitant medications  
• 
Full physical examination 
• 
Vital signs 
• 
Blood samples for laboratory safety tests (hematology and blood chemistry) 
• 
Urinalysis 
• 
Urine pregnancy test (women of childbearing potential only) 
• 
Spirometry 
• 
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 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 albuterol will be assessed at Screening as an eligibility measure. 
Spirometry (FEV1 and FVC) assessment before and after four puffs (400 µg) of albuterol, 
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 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: 
• 
Post-bronchodilator FEV1/FVC ratio of ≤0.70 
• 
Post-bronchodilator FEV1 ≥40 % and ≤80% of predicted normal * 
• 
Demonstrates ≥150 mL increase from pre-bronchodilator FEV1  
*National Health and Nutrition Examination Survey (NHANES) III [Hankinson 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 analyzed for viral serology (human 
immunodeficiency virus, hepatitis B and hepatitis C). A serum pregnancy test will be performed 
on women of childbearing potential. A 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 analyzed locally. 
A chest X-ray (post-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 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. 
7.2.2 
Dyspnea Scale 
Patients will be interviewed by a blinded member of study staff to assess their dyspnea. An 
11-point Likert scale will be utilized, which will be anchored from 0 to 10 [Davis 2006]. The 
interview will be worded as follows: “On a scale from 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 you can imagine.” This scale will be an instantaneous measurement of their 
dyspnea 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 venipuncture 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 primary plasma samples from both 
Part A and Part B will then be transported in dry ice to the external laboratory performing the 


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quantitative analysis of plasma RPL554 concentrations (LGC), where they will be stored at or 
below -20°C until they are submitted for analysis with a validated method. 
RPL554 plasma metabolite analysis will be performed on a proportion of the back-up plasma 
samples corresponding to the patients receiving the highest dose of RPL554 in Part B. Further 
details of how these back-up samples will be selected will be provided in the bioanalytical 
protocol for the metabolite analysis. These plasma samples will be transported in dry ice to LGC, 
who will forward them to the external laboratory performing the plasma metabolite analysis 
(YBS/Unilabs) where they will be stored at or below -20°C until they are submitted for analysis. 
These data will be considered exploratory, will not form part of the study statistical analysis and 
will be reported separately in a bioanalytical report by YBS/Unilabs. The remaining back-up 
samples from Part A will be transported to LGC in a separate shipment from the primary plasma 
samples. 
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: 
• 
A new illness 
• 
An exacerbation of a sign or symptom of the underlying condition under treatment or of a 
concomitant illness 
• 
Unrelated to participation in the clinical study or an effect of the study medication 
• 
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 
hospitalization, 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: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity, OR 


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• 
Is a congenital anomaly/birth defect 
• 
Other medical events * 
*Important medical events that may not be immediately life-threatening or result in death or 
hospitalization may be considered a SAE when, based on appropriate medical judgement, they 
may jeopardize 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). 
7.4.1.2 
Recording and Assessing Adverse Events 
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. 


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7.4.1.2.4 
Action and Outcome 
• 
Action taken with study medication (none, study medication stopped, study medication 
temporarily interrupted) 
• 
Other actions (none, concomitant medication, study discontinuation, hospitalization, other) 
• 
The outcome and date of outcome according to the following definitions: 
- 
Recovered or resolved (adverse event disappeared) 
- 
Recovering or resolving (patient is recovering) 
- 
Not recovered or not resolved (adverse event remains without signs of improvement) 
- 
Recovered or resolved with sequelae (adverse event has resulted in permanent 
disability or incapacity) 
- 
Fatal 
- 
Unknown (only applicable if patient has been lost to follow-up) 
• 
Seriousness (yes or no) 
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 
drug must also be reported. 
SUSARs will be determined by the Sponsor’s Medical Monitor. 
SAEs will be reported to the IRB 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 center 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. 


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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 analyzed locally. 
7.4.3.1 
Hematology 
The following will be measured: hemoglobin, hematocrit, total white cell count, leukocyte 
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: 
leukocytes, blood, ketones, bilirubin, urobilinogen, protein and glucose. If urinalysis on dipstick 
is positive for leukocytes and/or blood/hemoglobin, a microscopic examination including 
erythrocytes, leukocytes, 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. 


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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. 
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: 
• 
Compliance with the protocol 
• 
Consent procedure 
• 
Source documents 
• 
Adverse event procedures 
• 
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 IRB, 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. 


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Source data include, but is not limited to, the following and will be identified in a source data 
location log: 
• 
Screening/enrolment log 
• 
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 
• 
Informed consent form 
• 
12-lead ECGs 
• 
Laboratory reports 
• 
Visit dates  
• 
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 
customized 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 site and/or the laboratory until the 
electronic data and the database are reconciled. 


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All updates to queried data will be made by authorized study center 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 authorize 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. 
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 Organization 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 Analyzed 
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 randomized patients with sufficient data collected after 
intake of study treatment to compute the efficacy/pharmacodynamic parameters. 
The safety set will consist of all randomized and treated patients. 
The PK data set will consist of all randomized patients with blood sampling performed after an 
RPL544 treatment and with data sufficient to calculate PK parameters. 
Part B: 
The full analysis set will consist of all randomized 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 randomized patients that complete all treatment 
periods. 
The safety set will consist of all randomized patients who took at least one dose of study 
treatment during at least one period. 
The PK data set will consist of all randomized patients with blood sampling performed after at 
least one dose of RPL544 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. 


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9.3.1.2 
Secondary Endpoints 
• 
Safety and tolerability: 
− 
Continuous monitoring of adverse events 
− 
Laboratory safety tests [hematology, blood chemistry and urinalysis] 
− 
12-lead ECG (including QTcF and heart rate), supine vital signs (blood pressure and 
pulse rate) 
• 
Change from baseline in average FEV1 AUC0-4h measured after single dose  
• 
Change from baseline in average FEV1 AUC0-12h measured after single dose 
• 
Change from baseline in peak FEV1 measured after single dose  
• 
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 
• 
Safety and tolerability: 
− 
Continuous monitoring of adverse events 
− 
Laboratory safety tests (hematology, blood chemistry and urinalysis) 
− 
12-lead ECG (including QTcF and heart rate), supine vital signs (blood pressure and 
pulse rate) 
• 
Change from baseline in (morning) trough FEV1 measured prior to morning dosing on Day 
7  
• 
Change from baseline in peak FEV1 measured after first dose 
• 
Change from baseline in average FEV1 AUC0-4h measured after morning dosing on Day 7  
• 
Change from baseline in average FEV1 AUC0-12h measured after first dose and after 
morning dosing on Day 7  
• 
Determination of onset of action (>10% increase in FEV1 from pre- to post- first dose, 
censored at 120 minutes) after first dose  
• 
RPL554 steady state pharmacokinetics (AUC0-12h, Cmax, tmax, accumulation ratio) after dose 
13 on Day 7  
• 
Change from baseline in peak pulse after first dose on Day 1 and after morning dosing on 
Day 7  
• 
Change from baseline in average FEV1 AUC0-4h and average FEV1 AUC0-12h on Day 1 
• 
Change from baseline in rescue medication use 


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9.3.2.3 
Exploratory Endpoint 
• 
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  
• 
Change from baseline in Likert dyspnea scale measured after single dose and after morning 
dose on Day 7  
9.4 
Statistical Methods 
In general, unless stated otherwise, continuous variables will be summarized 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, randomized, completed or withdrawn (with reason for 
withdrawal) will be summarized. 
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 
liters 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 summarized 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 treatment 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 calculated based on the number of capsules dispensed and 
returned. Total exposure will be based on the compliance with dose and the dose group the 
subject was randomized into. 


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9.4.5 
Efficacy/Pharmacodynamics 
FEV1 and FVC will be summarized 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 pharmacodynamic parameters for FEV1 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, computed 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 analyzed 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 DPI, 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 DPI 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 summarized 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 summarized 
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 dyspnea 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 dyspnea. 
9.4.6 
Pharmacokinetics 
The following PK parameters will be calculated from plasma concentrations of RPL554 using 
standard non-compartmental methods. 
• 
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 
• 
Part A: Half-life=ln(2)/λz 
• 
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 


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estimate of the AUC at steady state. Cmax denotes the highest plasma concentration 
measured 
• 
tmax denotes the time point corresponding to Cmax 
PK parameters will be summarized 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, dose-normalized parameters (AUC 0-t and AUC 0-12h , Cmax) will be compared using 
analysis of variance  models with fixed factor treatment. In Part B, dose-normalized 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 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 summarized 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 summarized. 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 treatment. 
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 summarized 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 summarized 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 
summarized. 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 


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due to variability in FEV1 or other reason, the rescheduled visit will be listed and summarized 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 
to a difference of about 70 mL. To account for withdrawals, 36 patients will be randomized 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 
IRBs 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 authorized 
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 IRB 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 


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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. 
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 finalized, 
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. 
Bjermer L, Stewart J, Abbott-Banner KH et al. RPL554, a first-in-class dual PDE3/4 inhibitor is 
equi-effective as a bronchodilator to maximal doses of salbutamol in asthmatics but with fewer 
adverse events. Am J Resp Crit Care Med 2016; 193:A7770. 
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 randomized, 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 randomized 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. 
Rennard SI, Calverley PM, Goehring UM, et al. Reduction of exacerbations by the PDE4 
inhibitor roflumilast-the importance of defining different subsets of patients with COPD. Respir 
Res 2011; 12(18). 
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, May 2018.  
Verona Pharma plc RPL554 Investigational Medicinal Product Dossier current version. 
Verona Pharma plc. RPL554-007-2014 Clinical Study Report, August 2016. 
Verona Pharma plc. RPL554-009-2015 Clinical Study Report (February 2017). 
Verona Pharma plc. RPL554-010-2015 Clinical Study Report (in preparation). 
Verona Pharma plc. RPL554-PK-101 Clinical Study Report (December 2017). 
Verona Pharma plc. RPL554-CO-202 Clinical Study Report (in preparation). 
Verona Pharma plc. RPL554-CO-203 Clinical Study Report (in preparation). 
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 sterilization 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: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
Note: Documentation can come from the study center staff’s: review of participant’s 
medical records, medical examination, or medical history interview. 
2. 
Premenarchal 
3. 
Postmenopausal female 
Females who are postmenopausal (age-related amenorrhea ≥12 consecutive months and 
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 enrollment. 
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: 
• 
Combined (oestrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
- 
Oral 
- 
Intravaginal 
- 
Transdermal 


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• 
Progestogen-only hormonal contraception associated with inhibition of ovulation 1: 
- 
Oral 
- 
Injectable 
- 
Implantable 1 
• 
Intrauterine device 1 
• 
Intrauterine hormone-releasing system 1 
• 
Bilateral tubal occlusion 1 
• 
Vasectomized partner 1,2  
• 
Sexual abstinence 3 
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 vasectomized 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. 
• 
Time Course. Exposure to suspect study medication. Has the subject actually received the 
suspect study medication? Did the adverse event occur in a reasonable temporal 
relationship to the administration of the suspect study medication? 
• 
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? 
• 
Dechallenge experience. Did the adverse event resolve or improve on stopping or reducing 
the dose of the suspect study medication? 
• 
No alternative cause. The adverse event cannot be reasonably explained by another 
etiology such as the underlying disease, other drugs, other host or environmental factors 
• 
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: 
• 
Is this a recognized feature of overdose of the study medication? 
• 
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. 

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STATISTICAL ANALYSIS PLAN – PART A
RPL554-DP-201
A Phase II, Randomized Study to Assess the Pharmacokinetics, Safety 
and Pharmacodynamics of Single and Repeat Doses of RPL554 
Administered by Dry Powder Inhaler in Patients with COPD
AUTHOR: NICHOLAS ROUBINIS
VERSION NUMBER AND DATE: V1.0, 19DEC2018




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MODIFICATION HISTORY
Unique 
Identifier for 
this Version
Date of the 
Document 
Version
Author
Significant Changes from 
Previous Authorized Version
1.0
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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)............................................................................................................10
4.2.
Interim Analysis.............................................................................................................................................11
4.3.
Part A Analysis ..............................................................................................................................................11
5.
ANALYSIS SETS.............................................................................................................. 11
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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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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10.1.
Derivations .................................................................................................................................................20
11.
SURGICAL, MEDICAL AND CHRONIC OBSTRUCTIVE PULMONARY 
DISEASE/SMOKING HISTORY............................................................................................. 20
12.
MEDICATIONS ............................................................................................................... 21
13.
STUDY MEDICATION EXPOSURE ............................................................................ 22
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 ....................................................................................................................................23
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).........................................................................................................................................24
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) ....................................................................25
15.2.3.
Analysis of Secondary Efficacy Variables...............................................................................................25
16.
SAFETY OUTCOMES .................................................................................................... 27
16.1.
Adverse Events...........................................................................................................................................27
16.1.1.
All TEAEs ...............................................................................................................................................27
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 ...........................................................................................................................28
16.1.4.
Adverse Events Leading to Death............................................................................................................28


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16.2.
Laboratory Evaluations ............................................................................................................................29
16.2.1.
Laboratory Reference Ranges and Markedly Abnormal Criteria ............................................................29
16.3.
ECG Evaluations .......................................................................................................................................30
16.4.
Vital Signs...................................................................................................................................................31
16.5.
Physical Examination ................................................................................................................................32
16.6.
Other Safety Assessments .........................................................................................................................32
17.
PHARMACOKINETIC EVALUATIONS..................................................................... 32
18.
REFERENCES.................................................................................................................. 35
APPENDIX 1.
PROGRAMMING CONVENTIONS FOR OUTPUTS.............................. 36
IQVIA Output Conventions......................................................................................................................................36
Table and Listing Output Conventions ...................................................................................................................36
Figure Output Conventions ......................................................................................................................................39
Dates & Times............................................................................................................................................................39
Spelling Format..........................................................................................................................................................39
Presentation of Treatment Groups ..........................................................................................................................39
Presentation of Visits.................................................................................................................................................40
Listings .......................................................................................................................................................................40
APPENDIX 2.
PARTIAL DATE CONVENTIONS ............................................................. 41
Algorithm for Treatment Emergence of Adverse Events.......................................................................................41


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Algorithm for Prior / Concomitant Medications ....................................................................................................42
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-DP-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 1.0, dated 02OCT2018. 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 dry 
powder inhaler (DPI), in patients with moderate to severe chronic obstructive pulmonary disease (COPD).
2.2. SECONDARY OBJECTIVES
The secondary objectives of this part are as follows:
To investigate the safety and tolerability of single doses of RPL554 administered by DPI, including effects on 
peak pulse and heart rate. 
To investigate the bronchodilator effect of single doses of RPL554 administered by DPI, 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 DPI to evaluate the safety and terminal PK profile of a range of doses 
of RPL554. Five dose levels, 150 μg, 500 μg, 1500 μg, 3000 μg and 6000 μg were selected, covering a 
40-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 up to 2 sites in the Unites States (US). At 
the end of Part A, the database will be locked and the 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 DPI to evaluate the steady state 
efficacy/PD effect of the doses compared to the effect with placebo DPI. 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 each part, the database will 
be locked and unblinded, and the analyses for each part will be performed.
4.1. DATA MONITORING COMMITTEE (DMC)
There will be no DMC analyses for this study.


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4.2. INTERIM ANALYSIS
No formal interim analysis is planned for the study.
4.3. PART A ANALYSIS 
All Part A analyses identified in this SAP will be performed by IQVIA Biostatistics following Database Lock on a 
clean database: 
All outstanding data issues and queries resolved.
All irresolvable data issues documented in the Data Handling Report (DHR) from Data Management.
All coding of medications and adverse events (AEs) completed.
Serious AE (SAE) reconciliation completed.
All reconciliation of vendor data with electronic case report form (eCRF) data completed successfully.
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 
database lock. 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), however details of this analysis 
will be specified in this SAP.
5. ANALYSIS SETS
Agreement and authorization of patients included/excluded from each analysis set will be conducted prior to the 


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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 actual treatment received.


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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: 
Study day = (date of event – reference date) + 1.
If the date of the event is prior to the reference date, then: 
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:
Test value at post-dose timepoint – baseline value.
For quantitative measurement values of FEV1 and FEV1 AUCs will be calculated based on:
The highest FEV1 reading from each assessment.
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:
Maximum value in the first 4 hours after dosing.
Average effect will be calculated as:
FEV1 AUC divided by the length of the time interval of interest.
Log-transformations will be performed on FEV1 data:
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.
Randomized treatment (fixed).
o
RPL554 150μg
o
RPL554 500μg
o
RPL554 1500μg
o
RPL554 3000μg
o
RPL554 6000μg
o
Placebo
Baseline value of analyzed variable (covariate).
7.2. MULTICENTER STUDIES
This study will be conducted at up to 2 study centers, in the US.


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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 μg). 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 μi, 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: μj - μ0 = 0 and will be tested against the 
2-sided alternative Ki: μj - μ0 ≠ 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 α 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 ≤ α reject H5 and go to Step 2. Otherwise, fail to reject H5, H4, H3, H2 and H1 and stop.
x
Step 2: If p4 ≤ α reject H4 and go to Step 3. Otherwise, fail to reject H4, H3, H2 and H1 and stop.
x
Step 3: If p3 ≤ α reject H3 and go to Step 4. Otherwise, fail to reject H3, H2 and H1 and stop.
x
Step 4: If p2 ≤ α reject H2 and go to Step 5. Otherwise, fail to reject H2 and H1 and stop.
x
Step 5: If p1 ≤ α 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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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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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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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:
Age (years)
Sex
Childbearing potential
Race 
Ethnicity
Height (inches)
Weight (pounds)
BMI (kg/m2)
Pre (prior to dosing at baseline)/post (post dosing at baseline) bronchodilator FEV1 (both in liters and in 
percentage of predicted normal)
Post-bronchodilator FEV1/FVC
FEV1 reversibility test (mL and %)
10.1. DERIVATIONS
Age (years) = (Informed consent date – date of birth)
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.
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 


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set. 
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). 
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.
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) 
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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. 
‘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. 
‘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.
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 SAF 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. 


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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited.
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)
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.
15.2. SECONDARY EFFICACY
The secondary efficacy analyses will be performed for the FAS.


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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. 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.
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 patient misses hours 11.5 and 12 then the AUC0-12h is set to missing.


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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.
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 α=0.05 level (2-sided):


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H0: μj = μ0 versus H1: μj ≠ μ0
where μj and μ0 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, 150μg, 500μg, 1500μg, 3000μg and 6000μg and 
placebo)
BASELINE = log (baseline parameter)
The primary comparison will be the contrast (difference in least squares mean [LSMEAN]) between 6000μg
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 / 
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.


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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. 
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.


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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) 
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 


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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited.
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:
Actual results at Screening.
Incidence of abnormal values at Screening according to normal range criteria
Listing of all laboratory evaluations and abnormal values at Screening.
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:
Low: Below the lower limit of the laboratory reference range. 
Normal: Within the laboratory reference range (upper and lower limit included).
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.


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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 μmol/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:
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 


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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:
Supine Systolic Blood Pressure (mmHg)
Supine Diastolic Blood Pressure (mmHg)
Supine Pulse Rate (bpm)
The following summaries will be provided for vital signs data:
Actual assessments at screening, baseline (pre-dose of single dose) and each post-dose timepoint (1, 2, 4, 8, 12 
and 24 hours [Day 2])
Change from Baseline at each post-dose timepoint assessment
Incidence of markedly abnormal values based on the criteria presented in the table below:
Low
High
Systolic blood pressure (mmHg)
≤90 mmHg or decrease from 
Baseline of ≥ 20 mmHg
≥180 mmHg, or increase from 
Baseline of ≥ 20 mmHg
Diastolic blood pressure (mmHg)
≤50 mmHg or decrease from 
Baseline of ≥ 20 mmHg
≥105 mmHg, or increase from 
Baseline of ≥ 20 mmHg
Pulse rate (bpm)
≤ 50 bpm or decrease from 
Baseline of ≥ 20 bpm
≥110 bpm or increase from 
Baseline of ≥ 20 bpm


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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):
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):
Incidence of abnormalities pre-dose.
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
The primary endpoints of the study are the PK parameters AUC0-12h and AUC0-t, maximum concentration (Cmax), 
time to maximum concentration (tmax) and half-life. 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 


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derived.
AUC0-t represents the area under the plasma concentration curve from time 0 to last observed value above the lower 
limit of quantification and AUC0-12h represents the area under the plasma concentration curve from time 0 to 12 
hours. Cmax denotes the highest plasma concentration measured and tmax denotes the timepoint corresponding to Cmax. 
Half-life is the time required for the concentration to reduce to half its initial value, estimated as ln (2)/λz.
Descriptive statistics (see Appendix 1 [Programming conventions for outputs]) for the AUC parameters, Cmax, tmax
and half-life will be presented for all patients assigned to the PK analysis set for each treatment group. 
Dose-normalization, the process of dividing the parameters by the administered dose, will be performed for each PK
dose-dependent parameter (AUC0-t, AUC0-12h, Cmax). No imputations for missing data will be applied.
The Power Model: log(Yk)= β x log(Dk) + εk where D is the total number of doses, N are the total number of doses
k=1,..,D. Yk is the measured response variable, AUCs or Cmax on the kth dose. εk is the error will be applied to 
assess dose proportionality. Dose proportionality requires β to be close to unity for dose dependent parameters. The 
estimate of β together with appropriate confidence interval (βL, βU) can be used to quantify the degree of non-
proportionality. Analysis will be implemented using the SAS® procedure MIXED as follows:
PROC MIXED DATA = …;
CLASS PATIENT;
MODEL PARAMETER = TREATMENT;
ESTIMATE ‘LOGTREATMENT – 1 unit’ TREATMENT 1/CL ALPHA=0.1;
ODS OUTPUT ESTIMATES = ESTIMATE;
ODS OUTPUT SOLUTIONR = SOLUTION;
RUN;
where PATIENT = patient ID
PARAMETER = separate models for each of the log(parameters): log(AUC0-12h) log(AUC0-t) and log(Cmax)
TREATMENT = log (treatment group [RPL554 treatment groups])


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Summary statistics (For AUC and Cmax parameters: n, geometric mean, coefficient of variation [CV], minimum, 
maximum and median and for tmax parameter: n, arithmetic mean, standard deviation, minimum, maximum and 
median) will also be presented.


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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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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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Statistical Analysis Plan v1.0 – Part A
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Document:
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Author:
Nicholas Roubinis
Version Number:
1.0
Version Date: 
[19DEC2018]
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 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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Statistical Analysis Plan v1.0 – Part A
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Author:
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Version Number:
1.0
Version Date: 
[19DEC2018]
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.
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 3 decimal places, except values <1.000 but >0.999 will be presented as ‘>0.999’ 
(e.g., 0.9998 is presented as >0.999); and values <0.001 will be presented as ‘<0.001’ (e.g., 0.0009 is presented as 
<0.001). Rounding will be applied after the <0.001 and >0.999 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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Statistical Analysis Plan v1.0 – Part A
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Document:
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Author:
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Version Number:
1.0
Version Date: 
[19DEC2018]
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 150 μg double blind 
RPL554 150μg
RPL554 500 μg double blind
RPL554 500μg


Verona Pharma
PROTOCOL RPL554-DP-201
Statistical Analysis Plan v1.0 – Part A
Page 40 of 44
Document:
Z:\ RPL554\AZA40375\Biostatistics\Documentation\SAP\Verona RPL554-DP-201 SAP v1.0 – Part A
Author:
Nicholas Roubinis
Version Number:
1.0
Version Date: 
[19DEC2018]
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 1500 μg double blind 
RPL554 1500μg
RPL554 3000 μg double blind 
RPL554 3000μg
RPL554 6000 μg double blind 
RPL554 6000μg
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 v1.0 – Part A
Page 41 of 44
Document:
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Author:
Nicholas Roubinis
Version Number:
1.0
Version Date: 
[19DEC2018]
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
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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PROTOCOL RPL554-DP-201
Statistical Analysis Plan v1.0 – Part A
Page 42 of 44
Document:
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Author:
Nicholas Roubinis
Version Number:
1.0
Version Date: 
[19DEC2018]
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.
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


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PROTOCOL RPL554-DP-201
Statistical Analysis Plan v1.0 – Part A
Page 43 of 44
Document:
Z:\ RPL554\AZA40375\Biostatistics\Documentation\SAP\Verona RPL554-DP-201 SAP v1.0 – Part A
Author:
Nicholas Roubinis
Version Number:
1.0
Version Date: 
[19DEC2018]
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


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Statistical Analysis Plan v1.0 – Part A
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Author:
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Version Number:
1.0
Version Date: 
[19DEC2018]
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.
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


 
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PROTOCOL RPL554-DP-201 
 
Statistical Analysis Plan v2.0 – Part B 
Page 1 of 47 
 
 
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Version Number: 
2.0 
 
Version Date:  
[08JUL2019] 
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-DP-201 
A Phase II, Randomized Study to Assess the Pharmacokinetics, Safety 
and Pharmacodynamics of Single and Repeat Doses of RPL554 
Administered by Dry Powder Inhaler in Patients with COPD 
 
 
 
 
 
AUTHOR: NICHOLAS ROUBINIS / JENNIFER ALLSOPP 
VERSION NUMBER AND DATE: V2.0, 08JUL2019 
 
 
 


 
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PROTOCOL RPL554-DP-201 
 
Statistical Analysis Plan v2.0 – Part B 
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Version Number: 
2.0 
 
Version Date:  
[08JUL2019] 
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 B SIGNATURE PAGE 
Statistical Analysis Plan V2.0 – Part B (Dated 08JUL2019) for Protocol RPL554-DP-201. 
 
 
Name 
Signature 
Date 
Author: 
Jennifer Allsopp 
 
 
 
 
Position: 
Biostatistician II 
 
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: 
Reynold Daniel 
 
 
 
 
Position: 
Sr. Clinical Trial Manager 
 
Company: 
Verona Pharma 


 
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PROTOCOL RPL554-DP-201 
 
Statistical Analysis Plan v2.0 – Part B 
Page 3 of 47 
 
 
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Version Number: 
2.0 
 
Version Date:  
[08JUL2019] 
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 
21JUN2019 
Nicholas Roubinis / 
Jennifer Allsopp 
Not Applicable – First Version 
2.0 
08JUL2019 
Jennifer Allsopp 
Update treatment sequences from blinded 
sequences to unblinded sequences. 
 
 
 


 
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Statistical Analysis Plan v2.0 – Part B 
Page 4 of 47 
 
 
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Version Number: 
2.0 
 
Version Date:  
[08JUL2019] 
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 ................................................................................................................................... 9 
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) ............................................................................................................ 11 
4.2. 
Interim Analysis ............................................................................................................................................. 11 
4.3. 
Part B Analysis ............................................................................................................................................... 12 
5. 
ANALYSIS SETS 
12 
5.2. 
All Patients Randomized Set in Part B [RND] ............................................................................................ 13 
5.3. 
Safety Analysis Set [SAF] .............................................................................................................................. 13 
5.4. 
Full Analysis Set [FAS] ................................................................................................................................. 13 
5.5. 
Completers Analysis Set [CAS] .................................................................................................................... 13 


 
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Statistical Analysis Plan v2.0 – Part B 
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Version Date:  
[08JUL2019] 
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. 
 
 
 
 
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 ............................................................................................................................... 15 
6.5. 
Statistical Tests .............................................................................................................................................. 16 
6.6. 
Common Calculations ................................................................................................................................... 16 
6.7. 
Software Version ............................................................................................................................................ 17 
7. 
STATISTICAL CONSIDERATIONS 
17 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses ....................................................... 17 
7.2. 
Multicenter Studies ........................................................................................................................................ 18 
7.3. 
Missing data ................................................................................................................................................... 18 
7.4. 
Multiple Comparisons/ Multiplicity ............................................................................................................. 18 
7.5. 
Examination of Subgroups ............................................................................................................................ 19 
8. 
OUTPUT PRESENTATIONS 
19 
9. 
DISPOSITION AND WITHDRAWALS 19 
10. 
DEMOGRAPHIC AND OTHER SCREENING CHARACTERISTICS 
20 
10.1. 
Derivations ................................................................................................................................................. 21 
11. 
SURGICAL, MEDICAL AND CHRONIC OBSTRUCTIVE PULMONARY 


 
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Version Date:  
[08JUL2019] 
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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. 
 
 
 
 
DISEASE/SMOKING HISTORY 21 
12. 
MEDICATIONS 
22 
13. 
STUDY MEDICATION EXPOSURE 
23 
14. 
STUDY MEDICATION COMPLIANCE 24 
15. 
EFFICACY OUTCOMES 24 
15.1. 
Primary Efficacy ........................................................................................................................................ 24 
15.1.1. 
Primary Efficacy Variable(s) & Derivation(s) ......................................................................................... 24 
15.1.2. 
Missing Data Methods for Primary Efficacy Variable(s) ........................................................................ 25 
15.1.3. 
Primary Analysis of Primary Efficacy Variable(s) .................................................................................. 25 
15.2. 
Secondary Efficacy .................................................................................................................................... 27 
15.2.1. 
Secondary Efficacy Variables & Derivations .......................................................................................... 27 
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)
 
27 
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) ....................................................... 28 
15.2.1.5. 
Change from baseline in rescue medication use (Secondary variable 9) ......................................... 29 
15.2.2. 
Missing Data Methods for Secondary Efficacy Variable(s) .................................................................... 29 
15.2.3. 
Analysis of Secondary Efficacy Variables............................................................................................... 29 
15.2.3.1. 
Analysis of Secondary Variables 1, 2, 3, 4, 5 and 6......................................................................... 29 
15.2.3.2. 
Analysis of Secondary Variable 7 .................................................................................................... 31 
15.2.3.3. 
Analysis of Secondary Variable 8 .................................................................................................... 31 
15.2.3.4. 
Analysis of Secondary Variable 9 .................................................................................................... 31 
15.3. 
Exploratory Efficacy ................................................................................................................................. 32 
15.3.1. 
Exploratory Efficacy Variables & Derivations ........................................................................................ 32 
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.................................................................. 32 
15.3.1.2. 
Change from baseline in Likert dyspnea scale measured after morning dose on Day 7 .................. 32 
15.3.2. 
Missing Data Methods for Exploratory Efficacy Variable(s) .................................................................. 32 
15.3.3. 
Analysis of Exploratory Efficacy Variables ............................................................................................ 32 
16. 
SAFETY OUTCOMES 
33 
16.1. 
Adverse Events ........................................................................................................................................... 33 
16.1.1. 
All TEAEs ............................................................................................................................................... 33 
16.1.1.1. 
Severity ............................................................................................................................................ 33 


 
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Version Date:  
[08JUL2019] 
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. 
 
 
 
 
16.1.1.2. 
Relationship to Study Medication .................................................................................................... 34 
16.1.2. 
TEAEs Leading to Discontinuation from Study medication ................................................................... 34 
16.1.3. 
Serious Adverse Events ........................................................................................................................... 34 
16.1.4. 
Adverse Events Leading to Death............................................................................................................ 34 
16.2. 
Laboratory Evaluations ............................................................................................................................ 35 
16.2.1. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ............................................................ 35 
16.3. 
ECG Evaluations ....................................................................................................................................... 36 
16.4. 
Vital Signs ................................................................................................................................................... 37 
16.5. 
Physical Examination ................................................................................................................................ 38 
16.6. 
Other Safety Assessments ......................................................................................................................... 38 
17. 
REFERENCES 
39 
APPENDIX 1. 
PROGRAMMING CONVENTIONS FOR OUTPUTS 40 
IQVIA Output Conventions...................................................................................................................................... 40 
Table and Listing Output Conventions ................................................................................................................... 40 
Figure Output Conventions ...................................................................................................................................... 43 
Dates & Times ............................................................................................................................................................ 43 
Spelling Format.......................................................................................................................................................... 43 
Presentation of Treatment Groups .......................................................................................................................... 43 
Presentation of Visits ................................................................................................................................................. 44 
Listings ....................................................................................................................................................................... 45 
APPENDIX 2. 
PARTIAL DATE CONVENTIONS 
45 
Algorithm for Treatment Emergence of Adverse Events ....................................................................................... 45 


 
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Statistical Analysis Plan v2.0 – Part B 
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Algorithm for Prior / Concomitant Medications .................................................................................................... 46 
 
 


 
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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-DP-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 2.0, dated 12FEB2019. 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 DPI (Dry powder 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 DPI.  
x 
To investigate the bronchodilator effect of RPL554 administered by DPI, 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 DPI. 
x 
To evaluate the PK profile of RPL554 administered by DPI. 
x 
To evaluate the amount of rescue medication use during treatment periods. 
2.3. EXPLORATORY OBJECTIVES 
The exploratory objectives of this part are as follows: 


 
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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 DPI 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 DPI to evaluate the safety and terminal PK profile of a range of doses 
of RPL554. Five dose levels, 150 μg, 500 μg, 1500 μg, 3000 μg and 6000 μg were selected, covering a  
40-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 one site in the Unites States (US). At the end 
of Part A, the database was locked and the data unblinded and analyzed prior to commencing Part B.  Four dose 
levels, 150 μg, 500 μg, 1500 μg, 3000 μg were selected for Part B, using the same Part A patients. Part B is 
designed as a crossover, repeat dose assessment of RPL554 administered by DPI to evaluate the steady state 
efficacy/PD effect of the four RPL554 doses compared to the effect with placebo DPI. The patients in Part B will be 
expected to complete five treatment periods. 
 
In Part B, the patients from Part A will be randomly assigned in crossover fashion to one of 10 treatment sequences 
(see Appendix 1; Presentation of Treatment Sequences) each consisting of 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 summarizes 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 
None. 
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. 
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. 


 
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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 performed the Part A analysis remained blinded at the time of the Part A 
database lock. 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). 
 
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. 
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. 


 
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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 10 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.  
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, FRC 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 


 
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periods i.e., a patient who receives a first and last dose intake plus 1 day for all 5 treatment periods per schedule of 
events (see section 6 of the protocol for schedule details). 
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. 
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 
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. 


 
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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 5). 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 
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. 


 
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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 
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 
treatment administration for that specific treatment period:  
o 
Treatment period 1  
o 
Treatment period 2 
o 
Treatment period 3 
o 
Treatment period 4  
o 
Treatment period 5 
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. 


 
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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.  
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 150μg 
o 
RPL554 500μg 
o 
RPL554 1500μg 
o 
RPL554 3000μg 
o 
Placebo 
x 
Treatment period (fixed). 
o 
Treatment period 1 
o 
Treatment period 2 
o 
Treatment period 3 
o 
Treatment period 4 
o 
Treatment period 5 
x 
Baseline value of analyzed variable (covariate). 


 
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7.2. MULTICENTER STUDIES 
This study is being conducted at 1 study center in the US.  
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 B and will be 
done for each of the doses of RPL554 against placebo, starting with the highest dose (3000 μg). 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 and 4 represent increasing dose levels, 0 denoting placebo. Also, let μi, i = 0, 1, 2, 
3 and 4 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: μj - μ0 = 0 and will be tested against the  
2-sided alternative Ki: μj - μ0 ≠ 0, j = 1, 2, 3 and 4. 
 
Finally, let p1, p2, p3, p4 denote the marginal p-values obtained from the statistical tests associated with H1, H2, H3, H4 
(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 α 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 p4 ≤ α reject H4 and go to Step 2. Otherwise, fail to reject H4, H3, H2 and H1 and stop. 
x 
Step 2: If p3 ≤ α reject H3 and go to Step 3. Otherwise, fail to reject H3, H2 and H1 and stop. 
x 
Step 3: If p2 ≤ α reject H2 and go to Step 4. Otherwise, fail to reject H2 and H1 and stop. 
x 
Step 4: If p1 ≤ α reject H1. Otherwise, accept H1. 


 
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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 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 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). 


 
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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 
9. Investigation Product (IP) Compliance 
10. Efficacy Criteria 
11. Administrative Criteria 
12. Source Document Criteria 
13. Regulatory or Ethics Approvals Criteria 
14. Other Criteria 
 
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 


 
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x 
Race  
x 
Ethnicity 
x 
Height (inches) 
x 
Weight (pounds) 
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 
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.  


 
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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]) 
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. 


 
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x 
Rescue medications will be recorded on the 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 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. Albuterol is to be used for primary rescue use, but 
others are also permitted (e.g. ipratropium). Rescue medications must be withheld for at least 8 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. 
  
Rescue medications used during study visits (by recording the time it was dispensed and collected) and the amount 
taken by treatment period (by recording the weight of the canister dispensed at the end of Day 1 and start of Day 7 
per period), will be described in Section 15.2.1.5. 
 
When a rescue medication is used less than 8 hours prior to study medication a sensitivity analysis will be carried 
out for the analysis detailed in Section 15.2.1.2 removed patients who took rescue medication. This will only be 
carried out if at least 1 patient has taken rescue medication less than 8-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 capsules used per treatment period, as measured on the Drug Exposure eCRF 
page will be summed to get the total number of capsules used and presented similarly to exposure, by treatment 
sequence for the SAF analysis set. 


 
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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 + Duration of 
exposure for period 5. 
x 
Drug accountability (number of capsules) = Number of capsules dispensed – number of capsules 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 capsules dispensed and returned, as per drug accountability described in 
Section 13. 
15. EFFICACY OUTCOMES  
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. 
 
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 


 
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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 3000μg, 
RPL554 1500μg, RPL554 500μg, RPL554 150μg) 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 α=0.05 level (2-sided): 
H0: μj = μ0 versus H1: μj ≠ μ0 
 
where μj and μ0 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 3000μg, RPL554 1500μg, RPL554 500μg, RPL554 150μg) and 
placebo respectively.  
 


 
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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 3000μg, RPL554 1500μg, RPL554 500μg, RPL554 150μg and placebo) 
PERIOD = treatment period (treatment period 1, 2, 3, 4 and 5) 
BASELINE = log (baseline FEV1) 
USUBJID = subject ID   
 
The primary comparison will be the contrast (difference in least squares mean [LSMEAN]) between RPL554 
3000μg 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) 
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. 


 
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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 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 (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. 
 
Change from baseline FEV1 to FEV1 AUC0-4 will be derived to test the hypothesis described in Section 15.2.3 with 


 
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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. 
 
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 
discontinuation (if withdrawn before 120 minutes). If the number of patient 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 


 
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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. 
Change from baseline in rescue medication use during treatment periods (Secondary 
variable 9) 
 
The average use, in terms of weight (mcg) of rescue medication during the treatment periods will be collected from 
the Rescue Medication Canister Dispensed and Rescue Medication Canister Weight eCRF pages and will be 
summarized by treatment group. Rescue medication used will be calculated from the difference in weight at time of 
dispensing and weight at time of collection. So, change from baseline is the difference in rescue medication from 
baseline (at pre-dose on Day 1) and the collection visit (12hr post-dose on Day 7). 
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 α=0.05 level (2-sided): 
H0: μj = μ0 versus H1: μj ≠ μ0 


 
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where μj and μ0 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, 150μg, 500μg, 1500μg and 3000μg and placebo) 
PERIOD = treatment period (treatment period 1, 2, 3, 4 and 5) 
BASELINE = log (baseline parameter) 
USUBJID = subject ID 
 
The primary comparison will be the contrast (difference in least squares mean [LSMEAN]) between 3000μg 
RPL554 and placebo. 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. 


 
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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, 150μg, 500μg, 1500μg and 3000μg) 
STATUS (1) = indicates an event of onset of action 
 
To calculate the mean difference to RPL554 3000μg, 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 
assessment time post-dose (1 indicates censored variables). Median differences to the highest dose (RPL554 3000 
μg) 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 of change from baseline will be presented at Days 1 to 7 of each treatment period 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. 


 
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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 handled 
by a third-party vendor. 
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 
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 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. 


 
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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 
first dose of study medication, 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 


 
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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 FROM STUDY MEDICATION 
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 medication, 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. 


 
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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 
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. 
 


 
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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 μmol/L 
Gamma Glutamyl Transferase (GGT) 
> 3 x ULN 
Bilirubin (TBL) 
> 3 x ULN 
ULN: Upper limit of normal.  
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. 


 
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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 
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)  
- ≤ 90 mmHg 
- Decrease from Baseline of ≥ 
40 mmHg 
- ≥ 180 mmHg 
- Increase from Baseline of ≥ 40 
mmHg 
Diastolic blood pressure (mmHg)  
- ≤ 50 mmHg 
- Decrease from Baseline of ≥ 
20 mmHg 
- ≥ 110 mmHg 
- Increase from Baseline of ≥ 20 
mmHg 
Pulse rate (bpm)   
- ≤ 50 bpm 
- Decrease from Baseline of ≥ 
30 bpm 
- ≥ 110 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. 


 
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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, 
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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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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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 linesize. 
 
Univariate Statistics: 


 
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• 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: 
• 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 


 
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• 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 >0.999 will be presented as ‘>0.999’ 
(e.g., 0.9998 is presented as >0.999); and values <0.001 will be presented as ‘<0.001’ (e.g., 0.0009 is presented as 
<0.001). Rounding will be applied after the <0.001 and >0.999 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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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 150 μg double blind  
RPL554 150μg 
RPL554 500 μg double blind 
RPL554 500μg 
RPL554 1500 μg double blind  
RPL554 1500μg 
RPL554 3000 μg double blind  
RPL554 3000μg 
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 150 mcg db/RPL554 1500 mcg db/ RPL554 3000 mcg db 
/RPL554 500 mcg db/Placebo 
Seq 1 


 
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Treatment Group 
For Tables, Graphs and Listings 
RPL554 150 mcg db/ RPL554 3000 mcg db /Placebo/RPL554 500 
mcg db/RPL554 1500 mcg db 
Seq 2 
RPL554 500 mcg db/ RPL554 3000 mcg db /RPL554 150 mcg 
db/Placebo/RPL554 1500 mcg db 
Seq 3 
RPL554 500 mcg db/RPL554 150 mcg db/RPL554 1500 mcg 
db/Placebo/ RPL554 3000 mcg db 
Seq 4 
RPL554 1500 mcg db/RPL554 500 mcg db/Placebo/RPL554 3000 
mcg db/RPL554 150 mcg db 
Seq 5 
RPL554 1500 mcg db/Placebo/RPL554 150 mcg db/ RPL554 3000 
mcg db /RPL554 500 mcg db 
Seq 6 
RPL554 3000 mcg db/RPL554 1500 mcg db/RPL554 500 mcg 
db/RPL554 150 mcg db/Placebo 
Seq 7 
RPL554 3000 mcg db/Placebo/RPL554 1500 mcg db/ RPL554 150 
mcg db /RPL554 500 mcg db 
Seq 8 
Placebo/RPL554 150 mcg db/RPL554 500 mcg db/RPL554 1500 
mcg db/RPL554 3000 mcg db 
Seq 9 
Placebo/RPL554 500 mcg db/RPL554 3000 mcg db/RPL554 1500 
mcg db/RPL554 150 mcg db 
Seq 10 
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 5 treatment periods (1 to 
5): 
Long Name (default) 
Short Name  
Screening 
Scr 
Day 1 
Day 1 
Day 7 
Day 7 
End of Study 
EOS 
Overall (where applicable) 
Overall 


 
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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’. 
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 


 
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Z:\ RPL554\AZA40375\Biostatistics\Documentation\SAP\Verona RPL554-DP-201 SAP v2.0 – Part B 
Author: 
Nicholas Roubinis / Jennifer Allsopp 
Version Number: 
2.0 
 
Version Date:  
[08JUL2019] 
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 
 
 
 
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  
 
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 


 
Verona Pharma 
PROTOCOL RPL554-DP-201 
 
Statistical Analysis Plan v2.0 – Part B 
Page 47 of 47 
 
 
Document: 
Z:\ RPL554\AZA40375\Biostatistics\Documentation\SAP\Verona RPL554-DP-201 SAP v2.0 – Part B 
Author: 
Nicholas Roubinis / Jennifer Allsopp 
Version Number: 
2.0 
 
Version Date:  
[08JUL2019] 
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 
 
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 
 
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