A Phase II, Randomised Study to Assess the Pharmacokinetics, Safety and Pharmacodynamics of Single and Repeat Doses of RPL554 Administered by Pressurised Metered Dose Inhaler in Patients With COPD
Phase: PHASE2
Conditions: COPD
Sponsor: Verona Pharma plc

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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those with allergic rhinitis and COPD, using a nebulised solution in citrate/phosphate buffered 
saline at pH 3.2 (Franciosi et al, 2013; summarised in the Investigator’s Brochure).  
RPL554 was subsequently re-formulated in a pH neutral suspension formulation for 
nebulisation. This formulation has been tested in seven completed clinical studies. It was found 
to have exceptional bronchodilator activity in healthy volunteers and patients with asthma and 
COPD, and to significantly improve symptoms and health status in patients with COPD. 
RPL554 was well tolerated in all seven studies, with adverse event rates that were similar to 
the subjects treated with placebo. All clinical studies are described in the Investigator’s 
Brochure.  
A new formulation has been developed to allow for delivery of RPL554 using a convenient,
hand-held pressurised metered dose inhaler (pMDI). Although the current study will be the 
first clinical assessment of the pMDI formulation of RPL554 in humans, the RPL554 active 
pharmaceutical ingredient used in the pMDI formulation is the identical physical form and 
morphology as that used in the nebuliser suspension product in previous studies. Furthermore, 
a non-clinical assessment of local and systemic toxic potential of a dry powder inhaler (DPI)
formulation of RPL554 (of the identical physical form and morphology) blended with lactose 
was conducted in a 2-week inhalation study in Han Wistar rats. The purpose of this non-clinical 
study was to support single and repeat dose clinical studies with both a DPI as well as a pMDI 
formulation, consisting of RPL554 suspended in hydrofluoroalkane (HFA)-134a propellant
only. Results from this initial bridging toxicology study with an RPL554 lactose dry powder 
blend showed no new findings when this vehicle formulation is used, and this body of data 
supports clinical evaluation of both the DPI and pMDI formulations over the same period. A
clinical study evaluating the DPI formulation has recently been initiated in the United States.
The purpose of this study is to assess the efficacy, safety and pharmacokinetics (PK) of RPL554 
administered via pMDI, in order to support further development of RPL554 in a pMDI format.
1.2
Summary of Risks and Benefits
Data from non-clinical studies had suggested a potential for hypotension and tachycardia at 
high doses. However, in the clinical studies to date, RPL554 has been well tolerated in healthy 
subjects as well as patients with moderate to severe COPD, asthma and allergic rhinitis. The 
most common adverse events that have been reported at least twice in subjects who have 
received single or multiple doses of the nebulised suspension of RPL554 were generally mild 
and in descending order of frequency were headache, cough, dizziness, and palpitations. 
Adverse events for single and multiple dose studies are summarised in the Investigator’s 
Brochure.  
RPL554 has been demonstrated to have favourable non-clinical toxicology and PK profiles 
when delivered via the inhaled route as both a nebulised suspension and as a DPI.
While there have been few adverse events related to the cardiovascular or gastrointestinal 
systems, small and transient increases in heart rate at doses of 6 and 12 mg have been reported. 
Holter assessments have indicated no arrhythmogenic potential in the completed studies.  
In single dose studies, there appears to be an increase in the rate of headache that is most 
pronounced at doses over 6 mg. Results from multiple dose data in patients with COPD 
suggests a transient increase in dizziness, the majority of which occurred during spirometry
manoeuvres or dosing; otherwise, the rate of adverse events was similar between RPL554 and 
placebo treated patients. 

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

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

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

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

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

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

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If a patient had signed a consent form but withdrew from the study without receiving any study 
treatment, no further follow-up is necessary.
4.3.3
Study Discontinuation
Conditions that may warrant termination of the study include, but are not limited to: 
x
The discovery of an unexpected, serious, or unacceptable risk to patients enrolled in the
study
x
The decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or
development of RPL554
x
Serious failure of the Investigator to comply with the International Council on
Harmonisation (ICH) Guidelines on Good Clinical Practice (GCP) or local regulations
x
Submission of knowingly false information from the research facility to the Sponsor, the
Independent Ethics Committee (IEC) or any national regulatory officials
x
Major, repeated, non-adherence to the protocol
The Sponsor must be informed immediately in the event of any major protocol deviation or 
serious breach of ICH GCP.
Study termination and follow-up will be performed in compliance with the conditions set forth 
in ICH GCP. The decision to discontinue the study is at the discretion of the Sponsor, the 
Investigator, the regulatory authority or IEC and should if possible be taken by mutual 
agreement. A record of such a discussion will be prepared and stored in the study file. The 
Sponsor will ensure the regulatory authorities and IECs are notified.
4.3.4
Replacement Policy
It is planned to have 30 patients complete the study; it is expected that approximately 
36 patients will be randomised to meet this target. Withdrawn patients may need to be replaced,
depending on the actual discontinuation rate. 

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5
STUDY TREATMENTS
5.1
Study Treatments Administered
5.1.1
Treatments Administered in Part A
Patients will be randomly assigned to receive a single dose of one of six possible treatments,
as shown in Table 1. For Treatment Arms 1 through 4 and 6, each patient will be instructed to 
take two puffs (inhalations) from each of Inhalers 1 through 3, for a total of six inhalations. For 
Treatment Arm 5, each patient will be instructed to take four puffs from each of Inhalers 1 
through 3, for a total of 12 inhalations.
Table 1 
Treatment Arms, Inhaler and Puff Combinations in Part A
Arm
No. of 
Patients
No. of Puffs 
per Inhaler
Total Dose
Inhaler No.1 
Inhaler No.2
Inhaler No.3
1
6
2
100 μg
50 μg 
Placebo
Placebo
2
6
2
300 μg
150 μg 
Placebo
Placebo
3
6
2
1000 μg
500 μg 
Placebo
Placebo
4
6
2
3000 μg
500 μg
500 μg
500 μg
5*
6
4
6000 ug
500 μg
500 μg
500 μg
6
6
2
Placebo
Placebo
Placebo
Placebo
* Single-blind (see Section  5.7)
5.1.2
Treatments Administered in Part B
During Part B, patients will undergo four or five repeat dose treatment periods in a crossover 
fashion, with the sequence to be randomly assigned. Each treatment period will consist of 7 
days of dosing, which will occur in the morning and evening of Days 1 through 6 and morning 
only on Day 7.   
The doses to be used in Part B will be determined from the analyses performed on data from 
Part A; however, the highest dose will not exceed 3000 ȝJThe dosage strengths, in addition 
to placebo, will be as follows: 100 μg, and/or 300 μg, and/or 1000 μg, and/or 3000 μg (either 
3 or 4 of these values), dosed twice daily.  
Each patient will be instructed to inhale two puffs from each inhaler dispensed to them
(depending on the doses chosen for Part B) twice daily, for a total of six inhalations for each 
morning or evening dose.  
5.2
Identity, Preparation and Labelling of Study Treatments
The International Union of Pure and Applied Chemistry (IUPAC) name for RPL554 drug 
substance is 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-
3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one. The RPL554 pMDI is manufactured 
in accordance with Good Manufacturing Practice (GMP) guidelines. 
The compositions of the pMDI formulations are shown in Table 2. 

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RPL554 pMDI is supplied as a pressurised canister with a yellow plastic actuator. Each inhaler 
will be packed and labelled in kits as three inhalers in a carton and labelled with a unique 
medication identification (ID) number. Appropriate study centre personnel will dispense the 
appropriate double blind kit medication ID number according to the randomisation schedule 
and blinded kit list. Detailed dispensing instructions are provided in the study Pharmacy 
Manual.
5.3
Selection of Doses and Dosing Schedule
5.3.1
Selection of Doses in the Study
The doses of RPL554 have been selected to cover a 60-fold dose range of the pMDI
formulation. The top dose level in Part B will not exceed 3000 Pg, dosed twice daily, due to 
the logistical infeasibility of repeated administration of 12 puffs required to deliver a 6000 Pg
dose, and the enhanced possibility for poor treatment compliance. In prior studies, up to 24 mg 
of RPL554 has been evaluated as a twice daily nebulised suspension, and was well tolerated
clinically. 
Efficacy and safety data from Part A will be evaluated to determine if a dose can be dropped 
from the dose range in Part B.  
5.3.2
Timing of Dose for Each Patient
In Part A and the first dose of each treatment period in Part B study medication is to be 
administered between 7 and 11 am. All subsequent doses in Part B are to be taken at 12-hour 
intervals (±30 minutes) relative to the Day 1 first dose. 
5.4
Storage 
RPL554 and placebo drug products should not be stored above 25°C. Temperature logs should 
be maintained in areas where study medication is stored. If temperature conditions have been 
compromised or any study medication has not been stored appropriately, this should be 
documented, and the study medication quarantined until the Sponsor has been notified and 
confirmed whether it may be used.  
Study medication will be stored under the control of the Investigator or designee in a secure 
facility appropriate for the advised storage conditions. Study medications that are to be returned 
by the Investigator/staff or have expired must be stored separately from the unused study 
medications.
5.5
Accountability
The Investigator will be responsible for the dispensing, inventory and accountability of study 
medication, exercising accepted medical and pharmaceutical practices and ensuring that an 
accurate, timely record of the disposition is maintained. The study medication supplies and 
>5('$&7('@

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

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

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

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

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

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

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

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

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

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

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

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

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7.1.5
Prior and Concomitant Medications and Therapies
Prior COPD therapies and medications will be recorded at Screening and concomitant use 
during the study recorded as described in Section 5.8.1.
Other prior medications will be separately recorded at Screening and concomitant use during 
the study recorded as described in Section 5.8.2. 
7.1.6
Eligibility Check
Patients will be confirmed as eligible according to the Inclusion and Exclusion Criteria from 
assessments made at Screening with a final check of all results pre-dose in Part A.
7.2
Efficacy/Pharmacodynamic Assessments
7.2.1
Pulmonary Function Tests
Post-dose measurements will be taken in relation to the morning dose of RPL554 or placebo. 
Spirometry assessments (FEV1 and FVC) will be made in accordance with ATS/ERS 
guidelines (Miller et al, 2005). At all timepoints, three technically acceptable measurements 
will be made and recorded. Spirometry assessments may be performed up to eight times to 
obtain three acceptable readings. The highest FEV1 and FVC readings from each assessment 
will be used for analysis even if the FEV1 and FVC values come from two different forced 
exhalations. 
Spirometry will be performed using site-owned equipment and reviewed centrally, and sites 
will be instructed in proper use of the equipment prior to study initiation. 
7.2.2
Dyspnoea Scale 
Patients will be interviewed by a blinded member of study staff to assess their dyspnoea. An 
11-point Likert scale will be utilised, which will be anchored from 0 to 10 (Davis et al, 2006).
The interview will be worded as follows: “On a scale from zero to 10, please rate your current
shortness of breath, with zero indicating no shortness of breath and 10 indicating the worst
shortness of breath you can imagine.” This scale will be an instantaneous measurement of their
dyspnoea at that moment, and not reflective.
7.2.3
Rescue Medication 
The use of rescue medication will be assessed as follows: 1) during study visits, by recording 
the amount of and time that rescue was taken, and 2) between Days 1 and 7 of each treatment 
period, by recording the weight of the canister.  
7.3
Pharmacokinetic Assessments
Samples of 4 mL per time point will be collected by venepuncture or via indwelling cannula in 
the forearm into lithium heparin tubes and will be immediately chilled (ice bath). The blood 
will be centrifuged within 15 minutes of collection. The plasma will be separated in a 
refrigerated centrifuge (about 4°C) at 1100g for 15 minutes and transferred into polypropylene 
tubes. After each blood collection, the plasma will be dispensed into two aliquots. After 
appropriate labelling, the plasma samples will be stored at, or below -20°C. The plasma 
samples will then be transported in dry ice to an external laboratory where they will be stored 

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at or below -20°C until they are submitted for analysis with a validated method. Analysis will 
be performed by a central laboratory.
7.4
Safety Assessments
7.4.1
Adverse Events 
7.4.1.1
Adverse Event Definitions
An adverse event is defined as any undesirable experience occurring to a patient, or worsening 
in a patient, during a clinical study, whether or not considered related to the study medication. 
An adverse event may be any of the following: 
x
A new illness
x
An exacerbation of a sign or symptom of the underlying condition under treatment or of
a concomitant illness
x
Unrelated to participation in the clinical study or an effect of the study medication
x
A combination of one or more of the above factors
No causal relationship with the study medication is implied by the use of the term “adverse 
event.” An exacerbation of a pre-existing condition or illness is defined as a more frequent 
occurrence or as an increase in the severity of the pre-existing condition or illness during the 
study. Planned or elective surgical or invasive procedures for pre-existing conditions that have 
not worsened are not adverse events. However, any complication that occurs during a planned 
or elective surgery is an adverse event (if the event fits the serious criteria, such as an extended 
hospitalisation, it will be considered to be serious). Conditions leading to unplanned surgical 
procedures may be adverse events.
An adverse reaction is defined as all untoward and unintended responses to study medication 
related to any dose administered. 
A serious adverse event (SAE) is any adverse experience that:
x
Results in death
x
Is life-threatening
x
Requires inpatient hospitalisation or prolongation of existing hospitalisation
x
Results in persistent or significant disability/incapacity, OR
x
Is a congenital anomaly/birth defect
x
Other medical events*
*Important medical events that may not be immediately life-threatening or result in death or
hospitalisation may be considered a SAE when, based on appropriate medical judgement, they
may jeopardise the patient or may require medical or surgical intervention to prevent one of
the outcomes listed above.
An unexpected adverse reaction is an adverse reaction in which the nature or severity of which 
is not consistent with the Investigator Brochure. 
A suspected unexpected serious adverse reactions (SUSAR) is any suspected adverse reaction 
related to the study medication that is both unexpected and serious. 
Standard procedures for emergency care should be followed for any individual adverse event, 
whenever clinically needed (decision to be taken by the Investigator). 

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7.4.1.2
Recording and Assessing Adverse Events
Any adverse events occurring during the following times are to be recorded in the eCRF: 
x
Part A:  From signing of the Informed Consent form until 28 days after administration
of the single dose.
x
Part B:  From 2 days prior to the start of Treatment Period 1 until the End of Study
Visit, which for patients who complete the study will occur 4 to 10 days after the
completion of the final treatment period
In view of the above, the period starting 29 days after Part A up to and including 3 days prior 
to the start of Part B (assuming they are separated by at least 29 days) will be considered to be 
outside the reporting period for adverse events, given the length of time between treatments 
with study medication.
All adverse events, whether reported spontaneously by the patient, in response to open 
questioning on treatment days or observed by the Investigator or his/her staff, will be recorded 
from informed consent until the End of Study Visit. The start and stop time will be recorded 
and adverse events will be assessed by the Investigator for the following:
7.4.1.2.1
Severity
Mild:
Resolved without treatment 
Moderate: 
Resolved or was tolerated with specific treatment without affecting study 
activities
Severe:
Did not resolve or was not tolerated with treatment
7.4.1.2.2
Chronicity 
Single occasion: 
Single event with limited duration
Intermittent:  
Several episodes of an event, each of limited duration 
Persistent: 
Event which remained indefinitely
7.4.1.2.3
Causality 
The Investigator will assess causal relationship between the study medication and each adverse 
event, and answer "yes" or "no" to the question, "Do you consider that there is a reasonable 
possibility that the event may have been caused by the study medication?"
For SAEs, causal relationship will also be assessed for study procedures, additional study 
medication, and other medication. Note that for SAEs that could be associated with any study 
procedure, the causal relationship is implied as "yes".
A guide to the interpretation of the causality question is found in Section 14.2.
7.4.1.2.4
Action and Outcome
x
Action taken with study medication (none, study medication stopped, study medication
temporarily interrupted)
x
Other actions (none, concomitant medication, study discontinuation, hospitalisation,
other)

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x
The outcome and date of outcome according to the following definitions:
-
Recovered or resolved (adverse event disappeared)
-
Recovering or resolving (patient is recovering)
-
Not recovered or not resolved (adverse event remains without signs of
improvement)
-
Recovered or resolved with sequelae (adverse event has resulted in permanent
disability or incapacity)
-
Fatal
-
Unknown (only applicable if patient has been lost to follow-up)
x
Seriousness (yes or no)
7.4.1.3
Reporting Procedure for SAEs
The Investigator must report all SAEs to the Sponsor as soon as practical, but in call cases 
within 24 hours of awareness. Any fatal SAEs notified in the 28-day period after the last dose 
of study medication must also be reported. 
SUSARs will be determined by the Sponsor’s Medical Monitor. 
SAEs will be reported to the IEC and regulatory authority(ies) according to local requirements.
All adverse events will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical procedures 
as indicated, and/or referral to the patient’s general physician or a medical specialist.
It is the responsibility of the Investigator to ensure that any necessary additional therapeutic 
measures and follow-up procedures are performed. 
7.4.2
Pregnancy
In addition to the Screening serum pregnancy test (see Section 7.1.4), urine pregnancy tests 
will also be performed by the study centre on women of childbearing potential at Screening 
(confirmed to be negative prior to the chest X-ray) and during the study. 
Should a female patient become pregnant, or if a male patient fathers a child during the study 
or in the 30 days after the end of the study, the Investigator must be informed immediately. 
The Investigator will report this information to the Sponsor within 7 days of awareness. The 
Investigator will make all reasonable efforts to ascertain the progress and outcome of the 
pregnancy. If the outcome meets the criteria for immediate classification of a SAE 
(e.g. spontaneous or therapeutic abortion, stillbirth, neonatal death, congenital anomaly, birth 
defect), the Investigator must follow the procedure for reporting SAEs.
7.4.3
Laboratory Assessments
In addition to the laboratory tests detailed below, unscheduled and/or repeat testing may be 
performed at the discretion of the Investigator. Any additional laboratory results will also be 
merged into the final database. Laboratory results will be provided to the Investigator for each 
patient and each visit. The Investigator should assign whether each abnormal result is not 
clinically significant or a clinically significant. 
Samples will be taken and handled according to the laboratory manual and analysed locally. 

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

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

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

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

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

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

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
12-lead ECG (including QTcF and heart rate), supine vital signs (blood pressure
and pulse rate)
x
Change from baseline in average FEV1 AUC0-4h measured after single dose
x
Change from baseline in average FEV1 AUC0-12h measured after single dose
x
Change from baseline in peak FEV1 measured after single dose
x
Change from baseline in peak pulse and peak heart rate measured after single dose
9.3.2
Part B
9.3.2.1
Primary Endpoint 
The primary endpoint in Part B is change from baseline in peak FEV1 measured after morning 
dosing on Day 7. 
9.3.2.2
Secondary Endpoints 
x
Safety and tolerability:

Continuous monitoring of adverse events

Laboratory safety tests [haematology, blood chemistry and urinalysis]

12-lead ECG (including QTcF and heart rate), supine vital signs (blood pressure
and pulse rate)
x
Change from baseline in (morning) trough FEV1 measured prior to morning dosing on
Day 7
x
Change from baseline in peak FEV1 measured after first dose
x
Change from baseline in average FEV1 AUC0-4h measured after morning dosing on Day 7
x
Change from baseline in average FEV1 AUC0-12h measured after first dose and after
morning dosing on Day 7
x
Determination of onset of action (>10% increase in FEV1 from pre- to post- first dose,
censored at 120 minutes) after first dose
x
RPL554 steady state pharmacokinetics (AUC0-12h, Cmax, tmax, accumulation ratio) after
dose 13 on Day 7
x
Change from baseline in peak pulse after first dose on Day 1 and after morning dosing
on Day 7
x
Change from baseline in, average FEV1 AUC0-4h and average FEV1 AUC0-12h on Day 1
x
Change from baseline in rescue medication use
9.3.2.3
Exploratory Endpoint 
x
Evaluation of dose response of RPL554 on peak and average FEV1 AUC0-12h after
morning dose on Day 7, and morning trough FEV1 prior to the last dose on Day 7
x
Change from baseline in Likert dyspnoea scale measured after single dose and after
morning dose on Day 7

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9.4
Statistical Methods
In general, unless stated otherwise, continuous variables will be summarised using descriptive 
statistics (number of patients, mean, standard deviation, median, minimum and maximum 
values) and for categorical (nominal) variables, the number and percentage of patients will be 
used.  
All hypothesis testing will be done using two-sided alternative hypotheses. P-values less than 
5% will be considered statistically significant. 
9.4.1
Patient Disposition
The number of patients enrolled, randomised, completed or withdrawn (with reason for 
withdrawal) will be summarised. 
9.4.2
Protocol Deviations 
All protocol deviations collected will be divided into critical, major or minor categories. Prior 
to database lock protocol deviations will be reviewed and consequences for inclusion of 
patients in various analysis population sets determined and documented. 
9.4.3
Demographics and Other Baseline Characteristics
Demographics and baseline characteristics (including pre- and post-bronchodilator FEV1 [both 
in litres and in percentage of predicted normal], post-bronchodilator FEV1/FVC, FEV1
reversibility, duration of COPD [time since diagnosis], smoking habits including number of 
pack-years, number of patients taking COPD medications by therapeutic class including ICS, 
LABA, LAMA or combinations thereof) will be listed and summarised appropriately. 
Medical history, prior and concomitant medications, viral serology results, pregnancy test 
results from females and chest X-ray findings will be listed. 
9.4.4
Extent of Exposure and Treatment Compliance
For Part A, all administration of study medication will be performed at the clinic under 
supervision of the study staff; therefore, no formal analysis of compliance will be performed. 
For Part B, compliance will be assessed based on: 1) patient-reported missed doses, and 2) the 
weights of pMDI units dispensed and returned. Total exposure will be based on the patient-
reported missed doses. 
9.4.5
Efficacy/Pharmacodynamics 
FEV1 and FVC will be summarised as actual value and change from baseline using descriptive 
statistics over time for all treatments and both study parts. 
The peak effect on FEV1 during these time intervals will be computed as the maximum value 
in the 4 hours after dosing. The average effect (average FEV1 AUC0-t) will be calculated as the 
AUC divided by the length of the time interval of interest. For analysis of the peak, average 
and trough FEV1, the change from baseline will be expressed as the parameter divided by the 
pre-dose Day 1 baseline value.  
In Part A, computed efficacy/pharmacodynamic parameters for FEV1 will be compared 
between the treatments using analysis of covariance models with fixed factor treatment, and 

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

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

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

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

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

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11
FINANCE AND INSURANCE
Financial arrangements are detailed in the Investigator Agreement between the Sponsor and 
Investigator.
The Sponsor will arrange clinical study insurance to compensate patients for any potential 
injury or death caused by the study.  

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

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13
REFERENCES
Abbott-Banner KH, Page CP. Dual PDE3/4 and PDE4 inhibitors: novel treatments for COPD 
and other inflammatory airway diseases. Basic Clin Pharmacol Toxicol. 2014 May;
114(5):365-376. Doi: 10.1111/bcpt.12209. Epub 2014 Mar 6. 
Calverley PM, Sanchez-Toril F, McIvor A et al. Effect of 1-year treatment with roflumilast in 
severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 
176(2):154-161. 
Calzetta L, Page CP, Spina D, et al. The effect of the mixed phosphodiesterase 3/4 inhibitor 
RPL554 on human isolated bronchial smooth muscle tone. J Pharmacol Exp Ther 2013; 346: 
414–423.
Calzetta L, Cazzola M, Page CP, et al. Pharmacological characterization of the interaction 
between the dual phosphodiesterase (PDE) 3/4 inhibitor RPL554 and glycopyrronium on 
human isolated bronchi and small airways. Pulm Pharmacol Ther 2015 Apr 18. pii: 
S1094-5539(15)00042-5.
Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of 
patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J, 2004; 
2:932-946. 
Compton CH, Gubb J, Nieman R et al. Cilomilast, a selective phosphodiesterase-4 inhibitor 
for treatment of patients with chronic obstructive pulmonary disease: a randomised,
dose-ranging study. Lancet 2001; 358(9278):265-270. 
Davis AH, Carrieri-Kohlman V, Janson SL et al. Effects of treatment on two types of 
self-efficacy in people with chronic obstructive pulmonary disease. J Pain Symptom Manage 
2006; 32(1):60-70. 
EU Directive 95/46/EC: The Data Protection Directive.
Franciosi LG, Diamant Z, Banner KH, et al. Efficacy and safety of RPL554, a dual PDE3 and 
PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive 
pulmonary disease: findings from four clinical trials. Lancet Respiratory Medicine 2013; 
1(9):714-727. 
Gamble E, Grootendorst DC, Brightling CE et al. Anti-inflammatory effects of the 
phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am 
J Respir Crit Care Med 2003; 168(8):976-982. 
Grootendorst D, Gauw SA, Verhoosel RM, et al. Reduction in sputum neutrophil and 
eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007; 
62(12); 1081-1087. 
Hankinson JL, Odencrantz JR, Fedan KB. Spirometry reference values from a sample of the 
general U.S. Population. Am J Respir Crit Care 1999; 159:179-187. 
Harbinson PL, MacLeod D, Hawksworth R et al. The effect of a novel orally active selective 
PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects. Eur 
Respir J 1997; 10(5):1008-1014. 
International Council for Harmonisation (ICH) Integrated addendum to ICH E6(R1): Guideline 
for Good Clinical Practice E6(R2)

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

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

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

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