Clinical trial NCT03028142
Conditions: Chronic Obstructive Pulmonary Disease Moderate
Sponsor: Verona Pharma plc
Start date: 2017-01-01; Completion date: 2017-08-01
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a phase II, randomised, double blind, placebo controlled, complete block, three way crossover study to investigate treatment with nebulised RPL554 and tiotropium together in patients with moderate to severe chronic obstructive pulmonary disease (COPD). The purpose of this study is to assess the bronchodilator effect (opening of the airways) of RPL554 when used in combination with a long acting anti-muscarinic receptor antagonist (tiotropium) whilst dosing the RPL554 to steady state blood levels. It is planned to randomise up to 30 patients to have 24 evaluable patients at one study centre. In each treatment period, patients will receive an open label dose of tiotropium from a dry power inhaler (DPI) followed immediately by a double blind dose of either RPL554 6mg, 1.5mg or placebo (depending on treatment sequence) from a nebuliser in the morning on Day 1, Day 2 and Day 3. The dose of RPL554 or placebo will be repeated in the evening on Day 1 and Day 2; there will not be an evening dose on Day 3.

Detailed description:

Arms: arm 1: 1.5 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days arm 2: 6 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days arm 3: Nebulised RPL554 matched placebo twice daily plus 10 mcg tiotropium DPI once daily for 3 days
Interventions: intervention 1: 1.5 mg RPL554 plus tiotropium intervention 2: 6 mg RPL554 plus tiotropium intervention 3: Placebo plus tiotropium
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
THIS STUDY WILL BE CONDUCTED IN ACCORDANCE WITH THE 
INERNATIONAL CONFERENCE ON HARMONISATION GUIDELINES FOR 
GOOD CLINICAL PRACTICE (DIRECTIVE CPMP/ICH/135/95), THE 
DECLARATION OF HELSINKI (1964) AS AMENDED AND APPLICABLE 
REGULATORY REQUIREMENTS 
 
 
 
CLINICAL STUDY PROTOCOL 
 
A PHASE II, RANDOMISED, DOUBLE BLIND, PLACEBO 
CONTROLLED, THREE WAY CROSSOVER STUDY TO ASSESS THE 
BRONCHODILATOR EFFECT OF RPL554 ADMINISTERED IN 
ADDITION TO OPEN LABEL TIOTROPIUM IN PATIENTS WITH COPD 
 
STUDY NO. RPL554-CO-202 
 
Version: 
2.0 
Date: 
26 April 2017  
Phase: 
II 
Investigational 
 
Medicinal Product:  
RPL554 
EudraCT Number: 
2016-004450-15 
 
 
 


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SPONSOR SIGNATURE PAGE 
THIS DOCUMENT HAS BEEN APPROVED BY VERONA PHARMA PLC: 
Name and Title 
Signature 
Date 
Kenneth Newman MD, MBA 
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 ethics 
committee. 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 
treatment 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 ethics committees 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 
Investigator:   
 
 
Prof S Dave Singh 
Study Location: 
 
 
Medicines Evaluation Unit Ltd 
 
 
 
 
 
The Langley Building 
 
 
 
 
 
Southmoor Road 
Manchester, M23 9QZ 
 
 
United Kingdom 
+44 (0)161 946 4050 
 
Sponsor 
 
 
 
Verona Pharma plc 
 
 
 
 
 
3 More London Riverside 
London, SE1 2RE 
United Kingdom 
+44 (0)203 283 4200 
 
Sponsor’s Medical Monitor:   
Dr Kenneth Newman 
 
 
 
 
 
+1 914 767 5007 
 
 
 
 
 
ken.newman@veronapharma.com 
 
Email address for reporting SAEs: 
RPL554-SAE-SUSAR@veronapharma.com 
 
Central Laboratory 
 
 
LGC 
(Pharmacokinetics) 
 
 
Newmarket Road 
Fordham  
Cambridgeshire, CB7 5WW 
United Kingdom 
+44 (0) 1638 720 500 
Local Laboratory 
 
 
The Doctors Laboratory 
(Safety Laboratory Tests) 
 
60 Whitfield Street 
London, W1T 4EU 
United Kingdom 
Central Review of ECGs and  
ERT 
Holter Monitoring 
 
 
Peterborough Business Park, 
Lynch Wood 
Peterborough, PE2 6FZ 


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DETAIL OF AMENDMENTS SINCE THE PREVIOUS VERSION 
Section 4.2:  Exclusion Criterion no. 6 has been amended to remove the prohibition against 
prior exposure to RPL554.


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SYNOPSIS 
Title of Study:  
A Phase II, randomised, double blind, placebo controlled, three way crossover 
study to assess the bronchodilator effect of RPL554 administered in addition to 
open label tiotropium in patients with COPD. 
Protocol Number: 
RPL554-CO-202 
EudraCT Number: 
2016-004450-15 
Phase: 
II 
Sponsor: 
Verona Pharma plc 
Principal Investigator:  
Prof S Dave Singh 
Study Centre(s):  
Medicines Evaluation Unit Ltd 
The Langley Building 
Southmoor Road 
Manchester, M23 9QZ 
 
United Kingdom (UK) 
Planned Study Period: 
Estimated: January to April 2017 
Objectives: 
Primary Objective 
To investigate the bronchodilator effect on peak forced expired volume in 
1 second (FEV1) (measured in first 4 hours after dosing) and average (measured as 
the area under the curve [AUC]) FEV1 over 12 hours of nebulised RPL554 dosed 
twice daily for 3 days (five total doses), as compared to placebo, when 
administered in addition to once daily tiotropium. 
Secondary Objectives 
• 
To investigate the effect of twice daily nebulised doses of RPL554, as 
compared to placebo, when administered in addition to tiotropium on lung 
volumes  
• 
To assess the bronchodilator effect on peak FEV1 (measured in the first 
4 hours after dosing) and average (measured as the area under the curve 
[AUC]) FEV1 over 12 hours of nebulised RPL554 after the first dose as 
compared to placebo, when administered in addition to tiotropium 
• 
To analyse plasma concentrations and assess the steady state 
pharmacokinetics of RPL554 when administered in addition to tiotropium 
• 
To assess the tolerability and safety of twice daily nebulised doses of 
RPL554 in addition to tiotropium 
• 
To assess the dose response of two different doses of RPL554 on peak, 
average (0 to 12 hours), and morning trough FEV1 on Day 3 when dosed in 
addition to tiotropium 
• 
To determine the onset of action of RPL554 when administered with 
tiotropium (after the first dose) 
• 
To investigate the bronchodilator effect of nebulised RPL554, or placebo, 
administered in addition to tiotropium on average FEV1 over 4 hours after 
each morning dose 
• 
To investigate the effects of RPL554 on specific airway conductance 
(sGaw) and lung volumes (residual volume [RV], functional residual 
capacity [FRC]) when administered in addition to tiotropium. 
Exploratory Objectives 
• 
To examine the effect of RPL554 on top of tiotropium on average FEV1 
over 24 hours after 3 days of dosing 
• 
To assess morning trough FEV1 prior to the final dose of study treatment 


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Study Design and 
Methodology: 
This is a Phase II, randomised, double blind, placebo controlled, complete block 
three way crossover study to investigate combination treatment with nebulised 
RPL554 and tiotropium dry powder inhaler (DPI) in patients with moderate to 
severe chronic obstructive pulmonary disease (COPD). It is planned to randomise 
up to 30 patients to get 24 evaluable patients at one study centre.  
Patients will be screened for eligibility (Visit 1), including a reversibility test with 
salbutamol between 7 and 21 days before the first dose of study treatment. 
Eligible patients will then attend three separate 3 day treatment periods (Treatment 
Periods 1 to 3) each separated by a 7 to 21 day washout period (taken from last 
dose of study treatment).  
Study Procedures: 
During each treatment period, patients will be present at the study centre from the 
morning of Day 1 until the morning of Day 4, although they will be able to leave 
the facility at the discretion of the study centre personnel. Overnight residency is 
required on Day 3 of each treatment period. Patients will be randomised pre-dose 
on Day 1 of Treatment Period 1. 
During each treatment period, patients will be dosed with tiotropium once daily 
each morning (Day 1 to Day 3) and either RPL554 or placebo twice daily (in the 
morning and evening) on Day 1 and Day 2 and once in the morning only on Day 3 
(total of 5 doses of RPL554 or placebo in each treatment period; there is no 
evening dose of RPL554 or placebo on Day 3 of each treatment period). 
The pre-dose FEV1 at Day 1 of Treatment Period 2 and Day 1 of Treatment 
Period 3 must be within ±20% of the pre-dose FEV1 at Day 1 of Treatment 
Period 1, in order to ensure consistent baseline FEV1 for each study treatment.  
The following provides a brief overview of the major procedures to be performed 
during each treatment period.  
The following will be performed at Day 1 of each treatment period: 
• 
Measurements of lung function (FEV1 and forced vital capacity [FVC]) by 
spirometry pre-dose and up to 12 hours post-dose 
• 
12-lead electrocardiogram (ECG) pre-dose and up to 4 hours post dose and 
vital sign (supine) measurements pre-dose and up to 12 hours post-dose  
• 
Measurement of lung volumes by whole body plethysmography pre-dose 
The following will be performed on Day 2 of each treatment period: 
• 
Measurement of lung function (FEV1 and FVC) by spirometry pre-dose and 
for up to 4 hours post-dose 
• 
12-lead ECG pre-dose and up to 2 hours post dose and vital sign (supine) 
measurements pre-dose and up to 12 hours post-dose  
• 
Measurement of lung volumes by whole body plethysmography pre-dose and 
at 1.25 hours post-dose 
• 
Holter monitoring pre-dose and up to at least 24 hours post-dose. 
The following will be performed at Day 3 of each treatment period: 
• 
Measurements of lung function (FEV1 and FVC) by spirometry pre-dose and 
up to 24 hours post-dose 
• 
12-lead ECG and vital signs (supine) measurements pre-dose and up to 
24 hours post-dose  
• 
Pharmacokinetic blood sampling pre-dose and up to 24 hours post-dose 
• 
Laboratory safety tests (haematology and biochemistry) at 24 hours post-dose 
The 24-hour assessments and Holter removal will be performed prior to discharge 
from the study centre on Day 4. 
Adverse events will be recorded throughout the study. 
Number of Patients Planned: 
24 evaluable patients (randomise up to 30 patients) 


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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. They must have a baseline 
increase in FEV1 of >150 mL after use of four puffs of salbutamol. They must 
have at least a 10 pack-year smoking history, and may be an ex-smoker or current 
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: 
All study treatments will be administered using the inhaled route. 
Patients will receive the following three dose treatment combinations (DPI 
treatment plus nebulised treatment) in a randomised sequence during Treatment 
Periods 1 to 3: 
Tiotropium 18 µg once daily + RPL554 6 mg twice daily   
Tiotropium 18 µg once daily + Placebo twice daily 
Tiotropium 18 µg once daily + RPL554 1.5 mg twice daily 
Each morning during each 3 day period, the DPI treatment (tiotropium; Spiriva® 
HandiHaler®) will be administered first followed immediately (starting within 
2 minutes) by the nebulised treatment (RPL554 or placebo). The nebulised 
treatment (RPL554 or placebo) only will be repeated in the evening on Day 1 and 
Day 2, 12 hours after the morning dose; there is no evening dose of study 
treatment on Day 3 of each treatment period. 
The DPI treatment will be administered open label and the nebulised treatment 
will be administered double blind. 
The nebulised treatment (RPL554 or placebo) will be administered using a 
standard Jet nebuliser (PARI LC SPRINT® plus a PARI TurboBOY® SX 
compressor unit).  
The RPL554 formulation is a sterile suspension supplied as sterile stock 
suspensions of micronised RPL554 in pH 7 phosphate buffered saline, containing 
surfactants to aid suspension. The placebo is the same as the RPL554 suspension 
except that the active RPL554 ingredient is omitted, i.e. it consists of pH 7 
phosphate buffered saline and surfactants only. It is thus a clear solution rather 
than a pale yellow suspension; there is no known inert yellow solid that would 
be acceptable for inhalation, and therefore a visually matching placebo could not 
be developed.  
Duration of Treatment: 
The approximate planned duration for each patient will be up to 82 days: 7 to 
21 day screening period, up to 9 days treatment (three treatment periods of 3 days 
each separated by a 7 to 21 day washout period, taken from last dose of study 
treatment) and an end of study visit 4 to 10 days after the last treatment visit 
(Day 4 of Treatment Period 3).  
Statistical Methods: 
Treatments will be compared using analysis of covariance adjusting for treatment, 
period, patient and baseline. Multiplicative models will be used for FEV1 and 
outcome from whole body plethysmography and additive models for blood 
pressure, pulse rate and ECG heart rate. RPL554 treatments will first be compared 
to placebo using a closed test procedure starting with the highest dose of RPL554. 
Sample Size: 
This is a complete block three-way crossover study. Assuming a residual 
coefficient of variation of 6% for peak FEV1, 24 patients will give an 80% power 
to detect a pairwise difference in maximum FEV1 of 5.1%. 


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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 AND DEFINITION OF TERMS ............................................ 13 
1 
INTRODUCTION .......................................................................................................... 15 
1.1 
Disease and Study Treatment Review .................................................................. 15 
1.2 
Summary of Risks and Benefits ............................................................................ 17 
2 
OBJECTIVES................................................................................................................. 18 
2.1 
Primary Objective ................................................................................................. 18 
2.2 
Secondary Objectives ............................................................................................ 18 
2.3 
Exploratory Objectives ......................................................................................... 18 
3 
INVESTIGATIONAL PLAN ........................................................................................ 19 
3.1 
Overall Study Design and Plan Description ......................................................... 19 
3.2 
Discussion of Study Design, including the Choice of Control Groups ................ 20 
3.3 
Planned Duration of the Study .............................................................................. 20 
3.4 
Definition of the End of the Study ........................................................................ 21 
4 
SELECTION OF STUDY POPULATION .................................................................... 21 
4.1 
Inclusion Criteria................................................................................................... 21 
4.2 
Exclusion Criteria ................................................................................................. 22 
4.3 
Removal of Patients from Therapy or Assessment ............................................... 23 
4.3.1 
Study Treatment Discontinuation ........................................................... 24 
4.3.2 
Patient Withdrawal ................................................................................. 24 
4.3.3 
Study Discontinuation ............................................................................. 24 
4.3.4 
Replacement Policy ................................................................................ 24 
5 
STUDY TREATMENTS ............................................................................................... 25 
5.1 
Study Treatments Administered............................................................................ 25 
5.2 
Identity of Study Treatments................................................................................. 25 
5.2.1 
RPL554 and Placebo ............................................................................... 25 
5.2.2 
Tiotropium DPI ....................................................................................... 26 
5.3 
Preparation and Labelling ..................................................................................... 26 
5.3.1 
Nebulised RPL554 and Placebo ............................................................. 26 
5.3.2 
Tiotropium DPI ....................................................................................... 26 
5.4 
Selection of Doses, Dosing Schedule and Route of Administration..................... 26 


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5.4.1 
Selection of Doses in the Study .............................................................. 26 
5.4.2 
Selection and Timing of Dose for each Patient ...................................... 27 
5.4.2.1 
Nebulised RPL554 and Placebo ............................................. 27 
5.4.2.2 
Tiotropium DPI ...................................................................... 27 
5.5 
Storage .................................................................................................................. 28 
5.6 
Accountability ....................................................................................................... 28 
5.7 
Method of Assigning Patients to Treatment Groups ............................................. 28 
5.8 
Blinding ................................................................................................................. 29 
5.9 
Prior and Concomitant Therapies and Medications .............................................. 29 
5.9.1 
Prior and Concomitant Therapies ........................................................... 29 
5.9.2 
Prior and Concomitant Medications ....................................................... 30 
5.10 Rescue Medications .............................................................................................. 30 
5.11 Treatment Compliance .......................................................................................... 30 
6 
STUDY PROCEDURES AT EACH VISIT .................................................................. 31 
6.1 
Screening ............................................................................................................... 35 
6.2 
Treatment Period 1; Day 1 .................................................................................... 35 
6.2.1 
Pre-Dose Assessments ............................................................................ 36 
6.2.2 
Study Treatment Administration ............................................................ 36 
6.2.3 
Post-Dose Assessments (after morning doses only) ............................... 36 
6.3 
Treatment Period 1; Day 2 .................................................................................... 36 
6.3.1 
Pre-Dose Assessments ............................................................................ 36 
6.3.2 
Study Treatment Administration ............................................................ 37 
6.3.3 
Post-Dose Assessments (after morning doses only) ............................... 37 
6.4 
Treatment Period 1; Days 3 to 4 ........................................................................... 37 
6.4.1 
Pre-Dose Assessments ............................................................................ 37 
6.4.2 
Study Treatment Administration ............................................................ 37 
6.4.3 
Post-Dose Assessments ........................................................................... 37 
6.5 
End of Study Visit ................................................................................................. 38 
7 
STUDY METHODOLOGY ........................................................................................... 39 
7.1 
Demographics, Baseline Characteristics and Eligibility Assessments ................. 39 
7.1.1 
Demographic Variables .......................................................................... 39 
7.1.2 
Medical/Surgical and Disease History .................................................... 39 
7.1.3 
Reversibility Test .................................................................................... 39 
7.1.4 
Screening Laboratory Eligibility Assessments ....................................... 39 
7.1.5 
Prior and Concomitant Medications and Therapies ................................ 39 
7.1.6 
Eligibility Check ..................................................................................... 40 
7.2 
Pharmacodynamic Assessments ........................................................................... 40 
7.2.1 
Pulmonary Function Tests ...................................................................... 40 
7.2.2 
Whole Body Plethysmography ............................................................... 40 
7.3 
Pharmacokinetic Assessments .............................................................................. 40 
7.4 
Safety Assessments ............................................................................................... 41 


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7.4.1 
Adverse Events ....................................................................................... 41 
7.4.2 
Laboratory Safety Tests .......................................................................... 41 
7.4.2.1 
Haematology .......................................................................... 41 
7.4.2.2 
Biochemistry .......................................................................... 41 
7.4.2.3 
Urinalysis ............................................................................... 41 
7.4.3 
Vital Signs ............................................................................................... 41 
7.4.4 
Physical Examination ............................................................................. 42 
7.4.5 
12-Lead ECG .......................................................................................... 42 
7.4.6 
Holter Monitoring ................................................................................... 42 
7.5 
Appropriateness of Measurements ........................................................................ 43 
8 
HANDLING OF ADVERSE EVENTS AND PREGNANCIES ................................... 44 
8.1 
Adverse Event Definitions .................................................................................... 44 
8.2 
Recording and Assessing Adverse Events ............................................................ 45 
8.2.1 
Severity ................................................................................................... 45 
8.2.2 
Chronicity ............................................................................................... 45 
8.2.3 
Causality ................................................................................................. 45 
8.2.4 
Action and Outcome ............................................................................... 46 
8.3 
Reporting Procedure for SAEs .............................................................................. 46 
8.4 
Management of Pregnancies ................................................................................. 47 
9 
QUALITY ASSURANCE AND QUALITY CONTROL ............................................. 48 
9.1 
Audit and Inspection ............................................................................................. 48 
9.2 
Monitoring and Source Document Verification.................................................... 48 
9.3 
Data Management and Coding .............................................................................. 49 
10 
STATISTICAL METHODS .......................................................................................... 51 
10.1 Statistical and Analytical Plans ............................................................................. 51 
10.2 Populations to be Analysed ................................................................................... 51 
10.3 Study Endpoints .................................................................................................... 51 
10.3.1 
Primary Endpoints .................................................................................. 51 
10.3.2 
Secondary Endpoints .............................................................................. 51 
10.3.3 
Exploratory Endpoints ............................................................................ 52 
10.4 Statistical Methods ................................................................................................ 52 
10.4.1 
Patient Disposition .................................................................................. 52 
10.4.2 
Protocol Deviations ................................................................................. 52 
10.4.3 
Demographics and Other Baseline Characteristics ................................. 52 
10.4.4 
Extent of Exposure and Treatment Compliance ..................................... 52 
10.4.5 
Efficacy/Pharmacodynamics .................................................................. 52 
10.4.6 
Pharmacokinetics .................................................................................... 53 
10.4.7 
Safety ...................................................................................................... 53 
10.4.8 
Handling of Withdrawals or Missing Data ............................................. 54 
10.4.9 
Interim Analyses ..................................................................................... 54 
10.5 Determination of Sample Size .............................................................................. 54 


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11 
ETHICAL CONSIDERATIONS ................................................................................... 55 
11.1 Guidelines ............................................................................................................. 55 
11.2 Ethics and Regulatory Approval ........................................................................... 55 
11.3 Informed Consent Process .................................................................................... 55 
11.4 Patient Confidentiality .......................................................................................... 55 
11.5 Record Maintenance/Retention ............................................................................. 56 
11.6 Availability of Study Results ................................................................................ 56 
12 
FINANCE AND INSURANCE ..................................................................................... 57 
13 
PUBLICATION POLICY .............................................................................................. 58 
14 
REFERENCES ............................................................................................................... 59 
15 
APPENDICES ................................................................................................................ 61 
15.1 Instructions for Tiotropium Use ............................................................................ 61 
 
List of Tables and Figures 
Figure 1 
Study Flow Chart .................................................................................................. 19 
 
Table 1 
Treatment Combinations in RPL554-CO-202 ...................................................... 25 
Table 2 
Composition of Nebulised RPL554 and Placebo Formulations ........................... 25 
Table 3 
Schedules of Assessments in RPL554-CO-202 .................................................... 32 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ANCOVA 
Analysis of covariance 
ATS 
American Thoracic Society  
AUC 
Area under the curve 
BMI 
Body mass index 
Cmax 
Maximum concentration 
COPD 
Chronic obstructive pulmonary disease 
CI 
Confidence interval 
CV 
Coefficient of variation 
DPI 
Dry Powder Inhaler 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDTA 
Ethylenediaminetetraacetic acid 
ERS 
European Respiratory Society 
G 
Gauge 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
FVC 
Forced vital capacity 
FEV1 
Forced expired volume in 1 second 
FRC 
Functional residual capacity 
ICH 
International Conference on Harmonisation 
IUPAC 
International Union of Pure and Applied Chemistry 
LABA 
Long acting beta2-agonists 
LAMA 
Long acting muscarinic antagonists 
LPS 
Lipopolysaccharide 
MedDRA 
Medical Dictionary for Regulatory Activities 
PC20MCh 
Provocative concentration of methacholine chloride causing a fall in 
FEV1 of 20% from placebo 
PDE 
Phosphodiesterase 
pMDI 
Pressurised metered dose inhaler 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
Raw 
Airway resistance 
RV 
Residual volume 
SAE 
Serious adverse event 
SAS 
Statistical analysis software 


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sGaw 
Specific airway conductance 
SOC 
System organ class 
SOP 
Standard operating procedure 
SUSAR 
Suspected, unexpected serious adverse reaction 
TLC 
Total lung capacity 
tmax 
Time to maximum concentration 
 
 
 
  


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1 
INTRODUCTION 
1.1 
Disease and Study Treatment Review 
RPL554, a small molecule isoquinolone derivative, is a dual inhibitor of two isoforms (type 3 
and 4) of the phosphodiesterase (PDE) family of enzymes. PDE3 and PDE4 are known to 
have a role in modulating the inflammatory airway response in respiratory diseases, including 
chronic obstructive pulmonary disease (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 and there is also evidence to 
suggest that combined inhibition of PDE3 and PDE4 can have additive or synergistic 
anti-inflammatory and bronchodilator effects (reviewed by Abbott-Banner & Page, 2014). 
Pharmacological evidence from pre-clinical experiments with dual PDE3/4 inhibitors 
suggests that RPL554 may have potential therapeutic activity in allergic asthma, COPD, 
cystic fibrosis and allergic rhinitis.  
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 
inhibitors (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 
antimuscarinic agents, as well as additive properties with beta2-agonists (Calzetta et al, 2013; 
Calzetta et al, 2015).   
The safety, bronchodilator, bronchoprotective and anti-inflammatory activities of RPL554 
have been evaluated in five completed studies in healthy subjects, patients with 
mild-moderate persistent asthma and those with allergic rhinitis and COPD, using a nebulised 
solution of RPL554 in citrate/phosphate buffered saline at pH 3.2 (Franciosi et al, 2013; 
summarised in Investigator Brochure). Systemic exposure following inhalation using this 
solution formulation was low and somewhat variable, with maximum concentration (Cmax) 
values ranging from about 0.9 ng/mL following administration at 0.018 mg/kg to about 
4 ng/mL at 0.072 mg/kg. Area under the curve (AUC)0-t values ranged from about 
1.5 ng.h/mL to 11 ng.h/mL over the same dose range. Mean half-life values ranged from 
approximately 3 to 7 hours. 
RPL554 delivered by inhalation as a nebulised solution was well tolerated. Adverse events 
were generally mild and generally of equal frequency between placebo and active treatment 
groups. RPL554 produced a rapid bronchodilation in both COPD and asthmatic patients, and 
increased the provocative concentration of methacholine chloride (PC20MCh) by 1.5 doubling 
doses compared with placebo (95% confidence interval [CI]: 0.63-2.28; p=0.004). In healthy 
subjects, RPL554 also produced a significant inhibition of the lipopolysaccharide 
(LPS)-induced recruitment of the total number of inflammatory cells to the airways 
(p=0.002), as well as an inhibition of the absolute numbers of neutrophils (p=0.002), 
eosinophils (p=0.001), lymphocytes (p=0.001) and macrophages (p=0.04) in sputum. 


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RPL554 has subsequently re-formulated in a neutral pH phosphate buffered suspension 
formulation for nebulisation. This suspension formulation has been tested in three completed 
clinical studies: 
1. 
Study RPL554-007-2014 was a Phase I randomised, double blind, placebo controlled 
study in which single ascending doses in the range 1.5 mg to 24 mg were administered 
to 35 healthy subjects, multiple ascending doses in the range 6 mg to 24 mg twice daily 
for up to 5.5 days were administered to 21 healthy subjects and multiple ascending 
doses in the range 1.5 mg to 12 mg twice daily for 5.5 days were administered to 
23 COPD patients (RPL554-007-2014 Clinical Study Report, 2016). RPL554 was well 
tolerated and no maximum tolerated dose could be determined. There was a large 
bronchodilator response in both healthy subjects and patients with COPD. 
Pharmacokinetics demonstrated a terminal serum half-life of about 10 to 12 hours. 
2. 
Study RPL554-008-2014 was a Phase II double blind, placebo controlled seven way 
complete block crossover study. This study enrolled 29 patients with mild-moderate 
chronic asthma and patients received four single doses of RPL554 (0.4 mg, 1.5 mg, 
6 mg and 24 mg), two doses of nebulised salbutamol (2.5 mg and 7.5 mg) and placebo 
in a randomised sequence. RPL554 produced a dose-dependent bronchodilation with a 
magnitude that was comparable to a maximal dose of salbutamol, but with fewer of the 
well described salbutamol side effects (e.g. hypokalaemia, tachycardia, tremor and 
palpitations) (Bjermer et al, 2016). 
3. 
Study RPL554-009-2015 was a Phase II, double blind, double dummy, placebo 
controlled, six way complete block crossover study in moderate to severe COPD 
patients. This study enrolled 36 patients who received salbutamol (200 mcg), 
ipratropium (40 mcg) or placebo using a pressurised metered dose inhaler (pMDI) 
followed immediately by nebulised RPL554 (6 mg) or placebo in a randomised 
sequence. RPL554 alone was as effective as standard of care bronchodilators (two puffs 
of either a salbutamol or ipratropium pMDI), and importantly produced significant 
additive bronchodilation (peak and average over 8 hours) when dosed with either 
salbutamol or ipratropium (p<0.001). Indeed, there was an approximately 60% 
additional increase in peak forced expired volume in 1 second (FEV1) in COPD patients 
administered RPPL554 6 mg in addition to two puffs of either a salbutamol or 
ipratropium pMDI (RPL554-009-2015 Clinical Study Report, in preparation).  
RPL554 was well tolerated in all three studies. There were no serious adverse events (SAEs) 
or adverse events of concern. 
The pharmacokinetics of RPL554, following single nebulised inhaled doses of this 
suspension formulation, were characterised by approximately dose proportional systemic 
exposure in all three studies. Values of Cmax were generally attained around 1 to 1.5 hours 
after dosing, suggesting a steady and somewhat prolonged absorption of the RPL554 dose 
from the lungs into the systemic circulation; plasma concentrations declined slowly with a 
mean terminal half-life in the range 8 to 13 hours. Peak plasma concentrations obtained with 
the suspension formulation were one third to one quarter of those seen with the solution 
formulation. In study RPL554-007-2014, the twice-daily dosing regimen adopted for the 
multiple ascending dose phase led to some accumulation and steady state exposure appeared 
to be achieved by Day 3 of twice daily dosing in both healthy subjects and COPD patients. 
Systemic exposure to RPL554 was generally lower in COPD and asthma patients than in 
healthy subjects, which is consistent with the expected reduced lung deposition in patients 
with obstructive lung disease. Overall, the studies performed with inhaled nebulised 


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suspension doses of RPL554 have shown reproducible pharmacokinetic behaviour between 
studies and across patient cohorts. 
All clinical studies with the solution and suspension formulations are described in the 
Investigator’s Brochure. 
This study is intended to examine the dose ranging effect of RPL554 when dosed on top of a 
long acting anti-muscarinic receptor antagonist (tiotropium) whilst dosing the RPL554 to 
steady state blood levels. 
1.2 
Summary of Risks and Benefits 
Data from non-clinical studies suggest a potential for hypotension and tachycardia. However, 
RPL554 has been administered to over 240 subjects in clinical studies to date and has been 
well tolerated in moderate-severe COPD patients, healthy subjects, asthmatics and allergic 
rhinitics. No SAEs have been reported with RPL554 to date. 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 are headache, cough, dizziness, and palpitations. Adverse events for single and 
multiple dose studies are summarised in Investigator’s Brochure Section 6.3.  
The suspension formulation of RPL554 is pH balanced, and has favourable non-clinical 
toxicology and pharmacokinetic data. There were no effects on embryo-foetal survival and 
development in the rat. In the rabbit there was an effect on implantation at the highest dose 
tested which could be related to a pharmacological effect of RPL554, however there was no 
effect on embryo-foetal survival and development. 
There has been no evidence of significant adverse events related to the cardiovascular or 
gastrointestinal systems, except associated with an increase in heart rate at high doses (12 mg 
to 24 mg). These small increases in heart rate may relate to the PDE3 inhibitory activity of 
the compound. In single dose studies there appears to be an increase in the rate of headache, 
which is most pronounced at doses over 6 mg. There was no other apparent dose related 
adverse events, with the exception of palpitations in patients dosed at 24 mg. Results from 
multiple dose data in patients with COPD suggests a transient increase in dizziness, the 
majority of which occurred during spirometry or dosing; otherwise, the rate of adverse events 
was similar in RPL554 and placebo treated patients. There was an apparent increase in mild 
adverse events in healthy subjects treated with high doses of RPL554, which may be 
associated with the higher serum levels in healthy subjects than in those with obstructive lung 
disease. 
As RPL554 is currently planned to be administered for only 3 days (five doses) in this study, 
any benefit to the patients will be restricted to the immediate short-term. 


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2 
OBJECTIVES 
2.1 
Primary Objective 
To investigate the bronchodilator effect on peak FEV1 (measured in first 4 hours after dosing) 
and average (measured as the AUC) FEV1 over 12 hours of nebulised RPL554 dosed twice 
daily for 3 days (five total doses), as compared to placebo, when administered in addition to 
once daily tiotropium. 
2.2 
Secondary Objectives 
• 
To investigate the effect of twice daily nebulised doses of RPL554, as compared to 
placebo, when administered in addition to tiotropium on lung volumes  
• 
To assess the bronchodilator effect on peak FEV1 (measured in first 4 hours after 
dosing) and average (measured as the AUC) FEV1 over 12 hours of nebulised RPL554 
after the first dose as compared to placebo, when administered in addition to tiotropium 
• 
To analyse plasma concentrations and assess the steady state pharmacokinetics of 
RPL554 when administered in addition to tiotropium 
• 
To assess the tolerability and safety of twice daily nebulised doses of RPL554 in 
addition to tiotropium 
• 
To assess the dose response of two different doses of RPL554 on peak, average (0 to 
12 hours), and morning trough FEV1 on Day 3 when dosed in addition to tiotropium 
• 
To determine the onset of action of RPL554 when administered with tiotropium (after 
the first dose) 
• 
To investigate the bronchodilator effect of nebulised RPL554, or placebo, administered 
in addition to tiotropium on average FEV1 over 4 hours after each morning dose 
• 
To investigate the effects of RPL554 on specific airway conductance (sGaw) and lung 
volumes (residual volume [RV], functional residual capacity [FRC]) when administered 
in addition to tiotropium 
2.3 
Exploratory Objectives 
• 
To examine the effect of RPL554 on top of tiotropium on average FEV1 over 24 hours 
after 3 days of dosing 
• 
To assess morning trough FEV1 prior to the final dose of study treatment 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan Description 
This is a Phase IIb, randomised, double blind, placebo controlled, complete block three way 
crossover study to investigate treatment with nebulised RPL554 and tiotropium together in 
patients with moderate to severe COPD. It is planned to randomise up to 30 patients to have 
24 evaluable patients at one study centre. The study comprises the following shown in Figure 
1: screening, three treatment periods each lasting 3 days and an end of study visit. The 
procedures performed at each visit are summarised in Section 6 and the study assessments are 
described in Section 7. 
Figure 1 
Study Flow Chart 
 
 
 
                                                7 to 21 days                                                  7 to 21 days                    7 to 21 days                               4-10 days     
 
 
 
 
 
 
 
 
Patients will be screened for eligibility, including a reversibility test with salbutamol between 
7 and 21 days before the first dose of study treatment.  
Eligible patients will then attend for three separate treatment periods (Treatment Periods 1 
to 3) which each last 3 days and are separated by a 7 to 21 day washout period (taken from 
last dose of study treatment). Patients will be randomised pre-dose at Day 1 of Treatment 
Period 1. During each treatment period, patients will be present at the study centre from the 
morning of Day 1 until the morning of Day 4, although they will be able to leave the facility 
at the discretion of the study centre personnel. Overnight residency is not required except on 
Day 3 of each treatment period. 
In each treatment period, patients will receive an open label dose of tiotropium from a dry 
power inhaler (DPI) followed immediately (starting within 2 minutes) by a double blind dose 
of either RPL554 or placebo (depending on treatment sequence) from a nebuliser in the 
morning on Day 1, Day 2 and Day 3. The dose of RPL554 or placebo will be repeated in the 
evening on Day 1 and Day 2; there will not be an evening dose on Day 3.  
The assessments performed in each treatment period will be the same. Lung function (FEV1 
and forced vital capacity [FVC]) will be measured by spirometry pre-dose and up to 12 hours 
post-dose on Day 1, up to 4 hours post-dose on Day 2 and up to 24 hours post-dose on Day 3 
(i.e. Day 4). Whole body plethysmography will be performed pre-dose on Days 1 and 2 of 
each treatment period, and 1.25 hours after dosing on Day 2. Vital signs will be measured 
pre-dose and up to 4 hours post-dose on Day 1, up to 12 hours post-dose on Day 2 and up to 
24 hours post-dose on Day 3 (i.e. Day 4). 12-lead electrocardiograms (ECGs) will be 
RANDOMISATION 
30 patients planned  
 
END OF 
STUDY VISIT 
 
SCREENING 
TREATMENT 
PERIOD 1 
1ST Treatment 
TREATMENT 
PERIOD 2 
2ND Treatment 
TREATMENT 
PERIOD 3 
3RD Treatment 
THREE WAY CROSSOVER OF THE FOLLOWING 
TREATMENTS: 
Tiotropium 18 µg once daily + RPL554 6 mg twice daily   
Tiotropium 18 µg once daily + Placebo twice daily 
Tiotropium 18 µg once daily + RPL554 1.5 mg twice daily  


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performed pre-dose and up to 4 hours post-dose on Day 1, at 2 hours post-dose on Day 2 and 
up to 24 hours post-dose on Day 3 (i.e. Day 4). Adverse events will be recorded throughout 
the study. 
Patients will be discharged from the study centre on the morning of Day 4, and after 
Treatment Period 3 will then attend an end of study visit between 4 and 10 days later. 
3.2 
Discussion of Study Design, including the Choice of Control Groups 
A total of up to 30 COPD patients (to get 24 evaluable patients), either male or female, aged 
40 to 75 years (inclusive) will be randomised. The purpose of the study is to investigate if 
RPL554 has an additive bronchodilator effect when administered in combination with a 
commonly used anticholinergic medication, tiotropium, in this patient population.   
All patients will receive all three nebulised treatments (1.5 mg RPL554, 6 mg RPL554 and 
placebo) in this study in a randomised, crossover design; therefore, each patient will act as his 
or her own control in the study. This design makes it possible to obtain unbiased inferences 
about differences between treatments, based on intra-patient differences. Treatments will be 
administered double blind with the Investigator and patient unaware of the treatment identity 
to further minimise any potential bias in the overall assessment of treatment effect and safety.  
The washout period between the three treatments has been selected based upon the available 
single dose pharmacokinetics of the suspension formulation of RPL554 in healthy male 
subjects (single ascending dose part of Study RPL554-007-2014). The mean (range) 
half-lives were 8.3 (6.0 to 10.5) hours at the 1.5 mg dose, 8.5 (7.6 to 9.21) hours at the 3.0 mg 
dose, 10.5 (9.1 to 11.7) hours at the 6 mg dose, 9.4 (7.8 to 11.8) hours at the 12 mg dose and 
10.2 (8.1 to 12.5) hours at the 24 mg dose. Five half-lives is considered as the time for 
elimination of study treatment from the body. In this study, a washout period of 7 to 21 days 
from the last dose of study medications has been deemed adequate to ensure there was no 
overlap between the pharmacokinetic profiles of treatments with RPL554 in consecutive 
treatment periods. Whilst tiotropium has a prolonged terminal half-life of 5 to 6 days, the 
clinical bronchodilator effects are gone before this timepoint. As such, and in the absence of 
measuring pharmacokinetic levels of tiotropium, this was felt to be an adequate washout 
between treatment periods. 
Study treatment administration, pharmacodynamics, safety and tolerability assessments will 
be performed whilst patients are resident at the study centre. This is to ensure standardised 
conditions for dosing and other study procedures. The pre-dose FEV1 on Day 1 of both 
Treatment Period 2 and Treatment Period 3 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 is greater than 20% different then the start of the treatment period must 
be rescheduled. 
3.3 
Planned Duration of the Study 
The approximate planned duration for each patient could be up to 82 days: 7 to 21 days 
screening, up to 9 days treatment (three treatment periods of 3 days each separated by 7 to 
21 days, taken from last dose of study treatment) and an end of study visit 4 to 10 days after 
the last treatment visit (Day 4 of Treatment Period 3).  
Repeat, rescheduled and unscheduled visits are permitted at the discretion of the Investigator.  


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3.4 
Definition of the End of the Study 
The end of the study is defined as the date of the last end of study visit of the last patient in 
the study.  
4 
SELECTION OF STUDY POPULATION 
The population to be recruited into this study is stable patients with moderate to severe 
COPD and without significant heart disease. It is expected that current smokers will not 
comprise more than half the study population. 
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 75 years inclusive, at the time of informed 
consent. 
3. 
If male: must agree to meet the following from the first dose up to 2 months after the 
last dose of study treatment: 
• 
Not donate sperm  
• 
Either: be sexually abstinent in accordance with a patient’s usual and preferred 
lifestyle (but agree to abide by the contraception requirements below should their 
circumstances change) 
 
Or: use a condom with all sexual partners. If the partner is of childbearing 
potential the condom must be used with spermicide and a second highly effective 
form of contraception must also be used (as defined in Section 8.4) 
4. 
If female: either be: 
a) Of non-childbearing potential defined as being:  
• 
Either: post-menopausal (being spontaneously amenorrhoeic for at least 
1 year with an appropriate clinical profile [e.g. age appropriate, history of 
vasomotor symptoms] 
• 
Or: permanently sterilised e.g. tubal occlusion, hysterectomy, bilateral 
oophorectomy, bilateral salpingectomy 
b) Of childbearing potential and agreeing to use a highly effective method of 
contraception (as defined in Section 8.4) until completion of the end of study 
visit. 
5. 
Have a 12-lead ECG recording at screening and randomisation (pre-dose in Treatment 
Period 1) showing the following: 
• 
Heart rate between 45 and 90 beats per minute (bpm) 
• 
QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≤450 msec 
for males and ≤470 ms for females 
• 
QRS interval ≤120 msec 
• 
No clinically significant abnormalities (as judged by the Investigator) including 
morphology (e.g. left bundle branch block, atrio-ventricular nodal dysfunction, 
ST segment abnormalities) 
6. 
Have a screening Holter report with a minimum of 18 hours recording that is able to be 
evaluated for rhythm analysis which shows no abnormality which indicates a 


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significant impairment of patient safety or which may significantly impairs 
interpretation in the opinion of the Investigator including:  
• 
Significant arrhythmias including atrial flutter, atrial fibrillation, ventricular 
tachycardia  
• 
Any symptomatic arrhythmia (except isolated extra systoles)  
• 
Any sustained second or third degree heart block  
7. 
Capable of complying with all study restrictions and procedures including ability to use 
the study nebuliser and HandiHaler® DPI correctly. 
8. 
Body mass index (BMI) between 18 and 33 kg/m2 (inclusive) with a minimum weight 
of 45 kg. 
9. 
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. 
10. 
Post-bronchodilator (four puffs of salbutamol) spirometry at screening: 
• 
Post-bronchodilator FEV1/FVC ratio of ≤0.70 
• 
Post-bronchodilator FEV1 ≥40 % and ≤80% of predicted normal 
• 
Demonstrates ≥150 mL increase from pre-bronchodilator FEV1 
11. 
Clinically stable COPD in the 4 weeks prior to screening and randomisation (pre-dose 
in Treatment Period 1). 
12. 
A chest X-ray (post-anterior) at screening, or in the 12 months prior to screening 
showing no abnormalities, which are both clinically significant and unrelated to COPD. 
13. 
Meet the concomitant medication restrictions and be expected to do so for the rest of 
the study.  
14. 
Smoking history of ≥10 pack years.  
15. 
Capable of withdrawing from long acting bronchodilators for the duration of the study, 
and short acting bronchodilators for 8 hours prior to spirometry. 
4.2 
Exclusion Criteria  
1. 
A history of life-threatening COPD exacerbation including Intensive Care Unit 
admission and/or requiring intubation. 
2. 
COPD exacerbation requiring oral steroids, or lower respiratory tract infection 
requiring antibiotics, in the 3 months prior to screening or randomisation (pre-dose in 
Treatment Period 1). 
3. 
A history of one or more hospitalisations for COPD in the 12 months prior to screening 
or randomisation (pre-dose in Treatment Period 1). 
4. 
Lactation (female patients only).  
5. 
Positive urine or serum pregnancy test at screening, or a positive urine pregnancy test 
prior to randomisation (female patients of childbearing potential only). 
6. 
Known hypersensitivity to RPL554 or its components. 
7. 
Intolerance or hypersensitivity to tiotropium. 
8. 
Evidence of cor pulmonale. 
9. 
Other respiratory disorders: Patients with a current diagnosis of asthma, active 
tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, interstitial lung 


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diseases, sleep apnoea, known alpha-1 antitrypsin deficiency or other active pulmonary 
diseases. 
10. 
Previous lung resection or lung reduction surgery. 
11. 
Use of oral COPD medications (e.g. oral steroids, theophylline and romifulast) in the 
3 months prior to screening or randomisation (pre-dose in Treatment Period 1). 
12. 
History of, or reason to believe, a patient has drug or alcohol abuse within the past 
3 years. 
13. 
Inability to perform technically acceptable spirometry or whole body plethysmography 
(at screening or randomisation [pre-dose in Treatment Period 1]) 
14. 
Received an experimental drug within 30 days or five half-lives, whichever is longer.  
15. 
Patients with a history of chronic uncontrolled disease including, but not limited to, 
endocrine, active hyperthyroidism, neurological, hepatic, gastrointestinal, renal, 
haematological, urological, immunological, or ophthalmic diseases that the Investigator 
believes are clinically significant. 
16. 
Documented cardiovascular disease: arrhythmias, angina, recent or suspected 
myocardial infarction, congestive heart failure, a history of unstable, or uncontrolled 
hypertension, or has been diagnosed with hypertension in the 3 months prior to 
screening or randomisation. 
17. 
Concurrent use of non-cardioselective oral beta-blockers. 
18. 
Has had major surgery, (requiring general anaesthesia) in the 6 weeks prior to screening 
or randomisation (pre-dose in Treatment Period 1), or will not have fully recovered 
from surgery, or planned surgery through the end of the study. 
19. 
A disclosed history or one known to the Investigator, of significant non-compliance in 
previous investigational studies or with prescribed medications. 
20. 
Requires oxygen therapy, even on an occasional basis. 
21. 
Clinically significant prostatic hyperplasia (judged by the Investigator) or bladder-neck 
obstruction or with narrow-angle glaucoma. 
22. 
Any other reason that the Investigator considers makes the patient unsuitable to 
participate. 
4.3 
Removal of Patients from Therapy or Assessment 
Investigators have the authority to ask for the withdrawal of 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. 
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 data and all adverse event data. If a patient agreed to enter the study and signed a 
consent form but withdrew from the study, or was withdrawn from the study, without 
receiving any study treatment, no further follow-up is necessary. 
End of study visits will occur at 4 to 10 days after completing Day 4 of Treatment Period 3. 
All withdrawn patients will follow this routine 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. 
Patients who do not complete all treatment periods should have an end of study visit. 


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If a patient decides to withdraw voluntarily, or is withdrawn by the Investigator responsible at 
any time, the reasons for withdrawal and results of all relevant tests will be recorded in the 
electronic case report form (eCRF). Patients who withdraw may be replaced. 
4.3.1 
Study Treatment Discontinuation 
Study treatment must be discontinued for the following reasons: 
• 
Unacceptable toxicity related to study treatment 
• 
Intolerable or persistent adverse events of any severity 
• 
General or specific changes in the patient's condition rendering the patient unacceptable 
for further treatment in the judgment of the Investigator 
• 
Clinically significant progression of disease 
• 
Pregnancy in a female patient 
4.3.2 
Patient Withdrawal 
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 treatment, or to the 
conduct of the study. Patients can also be withdrawn in case of protocol violations and 
non-compliance. 
It should be made clear that the patient is free to withdraw from the study at any time.  
4.3.3 
Study Discontinuation 
Conditions that may warrant termination of the study include, but are not limited to: 
• 
The discovery of an unexpected, serious, or unacceptable risk to patients enrolled in the 
study 
• 
The decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of RPL554 
• 
Serious failure of the Investigator to comply with the International Conference on 
Harmonisation (ICH) Guidelines on Good Clinical Practice (GCP) or local regulations 
• 
Submission of knowingly false information from the research facility to the Sponsor, 
the ethics committee or any national regulatory officials 
• 
Major, repeated, non-adherence to the protocol 
The Sponsor must be informed immediately in the event of any major protocol deviation or 
serious breach of 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 ethics committee 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 ethics committees are notified. 
4.3.4 
Replacement Policy 
It is planned to randomise 30 patients. Replacement patients may be required due to any 
patient withdrawal. This should be discussed with the Sponsor on a case by case basis, but it 


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is expected that at least 24 patients will complete at least two treatment periods. Replacement 
patients will be allocated the next randomisation number in the treatment sequence. 
5 
STUDY TREATMENTS 
5.1 
Study Treatments Administered 
Patients will receive the three dose treatment combinations (DPI plus nebulised treatment) 
shown in Table 1 in a randomised sequence during Treatment Periods 1 to 3. All study 
treatments will be administered using the inhaled route. In each case, the DPI treatment will 
be administered first, followed immediately (within 2 minutes) by the nebulised RPL554 or 
placebo using a standard Jet nebuliser (PARI LC SPRINT® attached to a PARI TurboBOY® 
SX compressor unit). The DPI treatment will be open label and the nebulised treatment will 
be double blind. 
Table 1 
Treatment Combinations in RPL554-CO-202 
TREATMENT 
COMBINATION 
DPI TREATMENT 
NEBULISED TREATMENT 
1 
Tiotropium 18 mcg qd 
RPL554 6 mg bid 
2 
Tiotropium 18 mcg qd 
Placebo bid 
3 
Tiotropium 18 mcg qd 
RPL554 1.5 mg bid 
Abbreviation: bid=twice daily; DPI=dry powder inhaler; qd=once daily  
5.2 
Identity of Study Treatments 
5.2.1 
RPL554 and Placebo 
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 composition of the nebulised RPL554 and placebo formulations is shown in Table 2.  
Table 2 
Composition of Nebulised RPL554 and Placebo Formulations 
Constituent 
Concentration (mg/mL) 
RPL554 (micronised) 
 0.5 or 6.0 mg/mL or 0 mg/mL (=placebo) 
Polysorbate 20 (Tween 20) 
0.5 
Sorbitan Monolaurate (Span 20) 
0.05 
Monosodium Phosphate Dihydrate 
7.44 
Di-Sodium Hydrogen Phosphate Anhydrous 
6.80 
Sodium Chloride 
4.80 
Water 
N/A 
The RPL554 and placebo Investigational Medicinal Products are manufactured using 
aseptic manufacturing techniques in accordance with Good Manufacturing Practice (GMP) 
guidelines.  
The RPL554 formulation is a sterile suspension for nebulisation, supplied as sterile stock 
suspensions of micronised RPL554 in pH 7 phosphate buffered saline with surfactants to aid 
suspension. Two concentrations of RPL554 (0.5 mg/mL and 6.0 mg/mL) and a placebo will 


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be provided as a nominal 5 mL fill in 10 mL clear glass vials sealed with an ethylene 
tetrafluoroethylene coated rubber stopper and flip tear-up cap.  
The placebo is the same as the RPL554 suspension except that the active RPL554 ingredient 
is omitted, i.e. it consists of pH 7 phosphate buffered saline and surfactants only. It is thus a 
clear solution rather than a pale yellow suspension; there is no known inert yellow solid that 
would be acceptable for inhalation, and therefore a visually matching placebo could not be 
developed. The placebo will also be used as a diluent, enabling the preparation of the 6 mg 
dose concentration required for the study.  
For nebulisation, the 1.5 mg dose of RPL554 will be dispensed as 3 mL of the 0.5 mg/mL 
concentration. The 6.0 mg dose of RPL554 will be dispensed as 1 mL of the 6.0 mg/mL 
solution diluted with 2 mL of placebo. The placebo will be dispensed as 3 mL. 
5.2.2 
Tiotropium DPI 
Tiotropium DPI (Spiriva® HandiHaler®; Boehringer Ingelheim International GmbH; 
Anatomic Therapeutic Chemical Code R03BB04) is a marketed anticholinergic for the 
treatment of COPD. Capsules containing 18 mcg tiotropium for use with a HandiHaler® (see 
Section 15.1) will be provided by the study centre.  
5.3 
Preparation and Labelling 
5.3.1 
Nebulised RPL554 and Placebo 
Stock clear glass vials of RPL554 and placebo will be labelled in compliance with GMP, 
released by a qualified person and then shipped to the study centre. 
RPL554 and placebo will be prepared as a 3 mL volume for nebulisation by an unblinded 
individual who will not disclose the identity study treatment to the blinded Investigator and 
study centre staff. Standard aseptic technique will be used. Standard glass or medical grade 
plastic syringes and 25 gauge (G) syringe needles may be used. Narrower gauge needles must 
be avoided. Details of the dilution technique for the 6 mg dose will be provided in the 
pharmacy brochure. 
5.3.2 
Tiotropium DPI 
Each tiotropium DPI HandiHaler® will be labelled by the site with the randomisation number 
and in accordance with local regulations. 
5.4 
Selection of Doses, Dosing Schedule and Route of Administration  
5.4.1 
Selection of Doses in the Study 
The dose of tiotropium, 18 mcg once daily, is the approved dose for this medication, and is 
the standard of care.  
The 
doses 
of 
RPL554 
have 
been 
selected 
based 
on 
the 
results 
from 
Studies RPL554-007-2014, RPL554-008-2014, and RPL554-009-2015 investigating single 
and multiple ascending dosing in healthy subjects, single doses in asthmatics and 
single/multiple ascending dosing study in COPD patients. These doses were demonstrated to 
be both effective as a bronchodilator and well tolerated. 


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5.4.2 
Selection and Timing of Dose for each Patient 
The first dose of each treatment period (Day 1) should be given at approximately the same 
time of day (±1 hour). All subsequent doses should be given at 12 hour intervals 
(±30 minutes) relative to the Day 1 first dose.  
For the morning dose, the tiotropium DPI will be given first, followed immediately (starting 
within 2 minutes) by nebulised RPL554 or placebo. The evening dose on Day 1 and Day 2 is 
12 hours (±30 minutes) later is nebulised RPL554 or placebo. 
The following restrictions in relation to dosing should be adhered to: 
• 
Patients should refrain, where possible, from xanthine (chocolate, caffeine containing 
drinks and food), for at least 24 hours before and during all visits. Decaffeinated 
beverages are permitted 
• 
Patients should refrain from alcohol for 24 hours before and during all visits (including 
visits for safety laboratory tests) and until all procedures for that study visit are 
completed 
• 
Patients must fast (water permitted) from 2 hours pre-dose until 2 hours post-dose  
• 
Patients should refrain from smoking within 1 hour of dosing, and at least 1 hour before 
any measurement of lung function 
• 
Patients should refrain from strenuous exercise for 72 hours prior to all study visits and 
should undertake no unaccustomed strenuous exercise from screening till the end of 
study visit 
5.4.2.1 
Nebulised RPL554 and Placebo 
RPL554 and placebo will be administered by inhalation of an aerosol generated by a reusable 
PARI LC Sprint® jet nebuliser attached to a PARI TurboBOY® SX compressor. Wherever 
possible, the same compressor unit should be used for each dose within a patient. 
The dosing cup on each nebuliser will be obscured with tape to visually blind the study 
treatment.  
The end time of nebulisation (sputtering) will be considered Time 0 for the purposes of 
scheduling all post-dose study procedures. Nebulisation time should not exceed 10 minutes. 
Patients must wear a protective gown on Day 3 during the dosing procedure to prevent 
contamination of the cannula for pharmacokinetic samples. 
The following must be recorded in the eCRF: 
• 
Compressor unit number 
• 
Start and end times of nebulisation (times will be rounded down to the nearest minute) 
• 
The volume of residual product at the end of nebulisation  
5.4.2.2 
Tiotropium DPI 
Prior to use of the DPI, the capsule of tiotropium will be placed into the HandiHaler®. 
Patients will be instructed to inhale rapidly through their mouth (see instructions in 
Appendix 1). They will be instructed to hold their breath for 10 seconds, or as long as 
comfortable. A second inhalation is required to ensure the capsule is completely empty. The 
time of dosing will be recorded in the eCRF.  
Further information is provided in Section 15.1. 


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5.5 
Storage 
During transport RPL554 and placebo should be stored at room temperature and up to 25°C. 
The expiry date will be indicated on the box label.  
At the study centre, RPL554 and placebo should be stored at room temperature and up to 
25°C.  
Tiotropium HandiHaler® should be stored as specified in Section 15.1. 
Temperature logs should be maintained in areas where study treatment is stored. If 
temperature conditions have been seriously compromised or any study treatment has not been 
stored appropriately, this should be documented, and the study treatment quarantined until the 
Sponsor has been notified and confirmed whether it may be used.  
Study treatments will be stored under the control of the Investigator or designee in a secure 
facility appropriate for the advised storage conditions. Study treatments that are to be 
returned or destroyed by the Investigator/staff or have expired must be stored separately from 
the unused study treatments. 
5.6 
Accountability 
The Investigator will be responsible for the dispensing, inventory and accountability of study 
treatment, exercising accepted medical and pharmaceutical practices and ensuring that an 
accurate, timely record of the disposition is maintained. The study treatment supplies and 
inventory must be available for inspection by the designated representatives of the Sponsor 
upon request. 
Upon receipt of the study treatment, the Investigator or designee will inspect the contents and 
return the completed acknowledgement of receipt. Copies of all study treatment 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 or destruction.  
Written records must also be maintained to confirm the purpose and reason for any study 
treatment disposal, e.g. the amount contaminated, broken, or lost, and the name/signature of 
the personnel responsible for destruction. No study material (including used vials) may be 
destroyed until final study treatment accountability has been performed and written approval 
has been received from the Sponsor. 
At the end of the study, the unused study treatment will be destroyed locally after 
accountability has been verified. 
5.7 
Method of Assigning Patients to Treatment Groups 
All patients consented will be assigned a screening number using the study centre’s standard 
convention. 
Patients will receive three different treatment combinations in the study (see Section 5.1). 
Patients will be equally randomised to one of six treatment sequences (using a Latin Square 
design with the three different potential medication combinations) before the first study 
treatment administration in Treatment Period 1. 
Randomisation numbers will follow the convention XX-YYY where XX is the centre number 
and YYY is the sequential randomisation number. 
A dummy randomisation schedule will be approved by the Sponsor before the final 
randomisation schedule is produced. 


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5.8 
Blinding 
Tiotropium will be provided in trade dress and will not be blinded.    
RPL554 and placebo will be administered double blind. It has not been possible to 
completely match the placebo to RPL554, as the visual appearance is slightly different. The 
study personnel preparing the RPL554 and placebo, placing them into the nebuliser, and 
supervising dosing will therefore not be blinded to treatment identity. The dosing cup on each 
nebuliser will be obscured with tape to visually blind the study treatment. The Sponsor, 
Investigator (defined as Principal Investigator and all study physicians), all patients and all 
other research personnel (except bioanalytical personnel performing the pharmacokinetic 
assays) will therefore be blinded to the treatment allocation.  
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 discuss it with the Sponsor’s Medical monitor in advance. 
Otherwise, all blinding will be maintained until all queries are resolved and the database is 
locked. 
5.9 
Prior and Concomitant Therapies and Medications 
5.9.1 
Prior and Concomitant Therapies 
All prior therapies for COPD taken in the 3 months prior the first study treatment 
administration and all concomitant COPD therapies for 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. 
Oral therapies for COPD (e.g. oral steroids, theophylline, and roflumilast) are not allowed in 
the 3 months prior to screening and throughout the study. Inhaled steroids may continue 
during the study at a maintenance dose. 
All long acting (once or twice daily) bronchodilators will be stopped at the screening visit 
and are not allowed during the study. Patients should not use a long acting bronchodilator 
(long acting muscarinic antagonists [LAMA], long acting beta2-agonists [LABA], or 
combination LABA/inhaled steroid) on the day of screening. 
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 regular scheduled basis and/or as needed use. Patients taking 
LABA/inhaled steroid combination products should be prescribed the inhaled steroid at the 
same or equivalent dose contained in the combination product to allow continuation of 
steroid use regularly throughout the study whilst stopping the LABA component. Patients 
currently taking terbutaline will be switched to other short acting bronchodilators 
(e.g. salbutamol). 
If this is inadequate to control their symptoms, they should contact the Investigator. No 
scheduled use of salbutamol or ipratropium is allowed during the 3-day treatment periods; but 
may be used as a rescue medication (see Section 5.10). Salbutamol and ipratropium (or 
Combivent®) must be withheld for at least 8 hours prior to spirometry and this 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 


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should be withheld during each treatment period for the time periods stated below unless 
absolutely necessary: 
• 
8 hours prior to pre-dose spirometry for Day 1, Day 2 and Day 3. 
• 
Post-dose: 
- 
Day 1 until after +12 hours spirometry 
- 
Day 2 until after + 4 hours spirometry 
- 
Day 3 until after + 24 hours spirometry 
Patients may continue other prescribed non-respiratory therapies during the study; however, 
pulmonary rehabilitation programs should not be started or completed during this period. 
Oxygen therapy and beta blockers are exclusion criteria for this study. 
5.9.2 
Prior and Concomitant Medications 
Other prior prescription or non-prescription medications (medication, dose, route, treatment 
duration and indication) taken 3 months before the first study treatment administration must 
be recorded in order to confirm compliance with the inclusion and exclusion criteria.  
All concomitant medications must also be documented on the eCRF. The impact of any 
concomitant medications will be evaluated during the pre-database lock review and the 
decision taken whether to exclude the patient from any analysis populations. 
5.10 
Rescue Medications 
Standard procedures for emergency care should be followed for any individual adverse event, 
whenever clinically needed (decision to be taken by the Investigator). Short acting 
bronchodilators (e.g. salbutamol, ipratropium or Combivent) may be used as rescue 
medication. Rescue medication (salbutamol and ipratropium) will be sourced by the study 
centre and both will be dispensed at the screening visit. Salbutamol should be considered the 
primary rescue medication and ipratropium secondary. 
Rescue medication use during each treatment period must be separately documented on the 
eCRF (medication, dose, route, date and time of each administration). Protocol procedures 
must still continue even if rescue medication has been taken. Salbutamol is to be used for 
primary rescue use.  
5.11 
Treatment Compliance 
Study treatment administration will take place at the study centre and will be administered by 
the Investigator or designated and trained study centre personnel. The precise date and time 
of administrations shall be documented in the eCRF. 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.   


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6 
STUDY PROCEDURES AT EACH VISIT 
The study will consist of the following: 
• 
Screening will take place in the period between 7 and 21 days prior to the first study 
treatment administration 
• 
Three treatment periods (Treatment Period 1 to Treatment Period 3), each 3 days in 
duration and separated by 7 to 21 days (from last dose of study treatment on Day 3 of 
each treatment period) 
• 
An end of study visit between 4 and 10 days after Day 4 of Treatment Period 3 
Screening may be performed as a single visit or more than one visit. Eligible patients may be 
re-screened at the discretion of the Investigator, and following discussion with the Sponsor, if 
the reason for screen failure was considered temporary in nature. All screening data must be 
obtained within 21 days prior to administration of study treatment. 
Repeat, rescheduled, and unscheduled visits and procedures are permitted at the discretion of 
the Investigator. 
The overall schedule of assessments at each visit is shown in Table 3 and the schedule of 
assessments on each day of each treatment period is shown in Table 4. Assessments are listed 
by visit in Section 6.1 to Section 6.5 and are described in Section 7. 
Post-dose assessments should be performed in the following order (1) ECG, (2) vital signs, 
(3) pharmacokinetic blood sample, (4) spirometry (prioritised on the timepoint)  
Permitted time windows on assessments will be specified in the study reference manual. 
 


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Table 3 
Overall Schedule of Assessments at each Visit in RPL554-CO-202 
 
 
Procedures 
Screen 
Treatment Periods 1 to 3 
(7 to 21 days between Treatment Periods) 
End of Study 
Day -21 to -7 
Day 1 
Day 2 
Day 3 
Day 4 
 4 – 10 days after Day 4 
Informed consent 
X 
 
 
 
 
 
Demographics including height and weight 
X 
 
 
 
 
 
Medical/surgical and disease history  
X 
 
 
 
 
 
Eligibility criteria  
X 
X[a] 
 
 
 
 
Physical examination 
X (Full) 
X (Brief) 
 
 
X (Brief) 
X (Full) 
Vital signs 
X 
X 
X 
X 
X 
X 
Safety laboratory tests: haematology and biochemistry 
X 
 
 
 
X 
X 
Safety laboratory tests: urinalysis 
X 
 
 
 
 
X 
Viral serology 
X 
 
 
 
 
 
Alcohol breath test 
X 
 
 
 
 
 
Serum pregnancy test (females of childbearing potential) 
X 
 
 
 
 
 
Urine pregnancy test (females of childbearing potential)  
X[b] 
X 
 
 
 
X 
Chest X-ray (or in last 12 months) 
X 
 
 
 
 
 
12-lead ECG  
X 
X 
X 
X 
X 
X 
24-hour Holter monitoring 
X 
 
X 
 
 
 
Spirometry: Reversibility test 
X 
 
 
 
 
 
Spirometry: Study measurements 
 
X 
X 
X 
X 
X 
Whole body plethysmography training 
X 
 
 
 
 
 
Whole body plethysmography  
 
X 
X 
 
 
 
Inhalation training (nebuliser and DPI) 
X 
X 
 
 
 
 
Randomisation 
 
X[a] 
 
 
 
 
Tiotropium and RPL554 or placebo dosing 
 
X 
X 
X 
 
 
Pharmacokinetic sampling  
 
 
 
X 
X 
 
Prior/concomitant medications and therapies 
Throughout the study 
Adverse events 
Throughout the study 
Abbreviations: DPI=dry powder inhaler; ECG=electrocardiogram 
[a] Treatment Period 1 only  
[b] Prior to chest X-ray 


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Table 4 
Pre-dose and Post-dose Assessments on each day of Treatment Periods 1 to 3 in RPL554-CO-202 
Procedures 
Day 1 
Pre- 
0 
5 m 
15m 
30m 
1h 
1.5h 
2h 
4h 
6h 
8h 
12h[a] 
Tiotropium dosing by DPI 
 
X 
 
 
 
 
 
 
 
 
 
 
RPL554 or placebo dosing by nebulisation 
 
X 
 
 
 
 
 
 
 
 
 
X 
Brief physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs  
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Spirometry 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inhalation training 
X 
 
 
 
 
 
 
 
 
 
 
 
Whole body plethysmography 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomisation [b] 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
Throughout 
Abbreviations: DPI=dry powder inhaler; ECG=electrocardiogram; h=hour; m=minutes 
[a] Post-dose samples will be taken in relation to the morning dose of tiotropium DPI and RPL554 or placebo. The 12 hour procedures will therefore be performed pre-dose 
before the evening dose of RPL554 or placebo 
[b] Treatment Period 1 Day 1 only 
 
Procedures 
Day 2 
Pre- 
0 
15m 
30m 
1h 
1.25h 
2h 
3h 
4h 
12h[a] 
Tiotropium dosing by DPI 
 
X 
 
 
 
 
 
 
 
 
RPL554 or placebo dosing by nebulisation 
 
X 
 
 
 
 
 
 
 
X 
Vital signs  
X 
 
 
X 
X 
 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
X 
 
 
 
Spirometry 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Whole body plethysmography 
X 
 
 
 
 
X 
 
 
 
 
Place 24 hour Holter 
X 
 
 
 
 
 
 
 
 
 
Adverse events  
Throughout 
Abbreviations: DPI=dry powder inhaler; ECG=electrocardiogram; h=hour; m=minutes 
[a] 
Post-dose samples will be taken in relation to the morning dose of tiotropium DPI and RPL554 or placebo. The 12 hour procedures will therefore be performed pre-dose before 
the evening dose of RPL554 or placebo. 


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Procedures 
Day 3 
Day 4 
Pre- 
0 
5 m 
15m 
30m 
45m 
1h 
1.5h 
2h 
4h 
6h 
8h 
12h 
15 h 
24 h[a] 
Tiotropium dosing by DPI 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
RPL554 or placebo dosing by nebulisation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief physical examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X[b] 
Vital signs  
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
X 
Remove Holter monitor 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spirometry 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic samples 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Haematology and biochemistry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse events 
Throughout 
Abbreviations: DPI=dry powder inhaler; ECG=electrocardiogram; h=hour; m=minutes 
[a] Procedures performed prior to discharge from the study centre on the morning of Day 4, 24 hours after dosing on Day 3 
[b] Can be performed any time prior to discharge 
 
 


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6.1 
Screening 
Written informed consent will be obtained by the Investigator as specified in Section 11.3 
prior to any study related procedures being performed. Obtaining the informed consent can be 
performed on a separate visit prior to the screening period. Screening procedures may be 
performed over more than one day.  
Patients will be screened to determine eligibility against the inclusion and exclusion criteria 
between 7 and 21 days before the first dose of study treatment. There are no fasting 
requirements for the screening visit. Patients must withhold long acting bronchodilators, 
ipratropium and salbutamol (or Combivent®) prior to screening as defined in Section 5.9.1. 
The following assessments will be performed:  
• 
Recording of demographic information, including height and weight 
• 
Recording of medical/surgical and disease history 
• 
Recording of prior medications and therapies 
• 
Vital signs  
• 
Full physical examination 
• 
Alcohol breath test 
• 
12-lead ECG 
• 
Chest X-ray (unless historical X-ray performed in last 12 months is available) 
• 
Whole body plethysmography training and assessment of capacity to perform 
procedure (may be performed more than once as required) 
• 
Pre-salbutamol spirometry 
• 
Reversibility test (4 puffs salbutamol) 
• 
Post-salbutamol spirometry (starting 20 to 30 minutes after administration) 
• 
Place 24 hour Holter monitor; patients will be instructed to return the next day for 
removal of the Holter monitoring 
• 
Blood and urine samples for laboratory safety tests (haematology, biochemistry, 
urinalysis), pregnancy tests (female patients of childbearing potential only), and viral 
serology. The urine pregnancy test result should be obtained prior to chest X-ray for 
females of childbearing potential. 
• 
Instruct patients to stop all long acting bronchodilators for the duration of the study 
• 
Inhalation training for use of nebuliser and DPI. This will be verbal instruction and 
demonstration of the device 
• 
Questioning for adverse events 
If the patient meets the inclusion and none of the exclusion criteria they will be instructed to 
return in 7 to 21 days for Treatment Period 1, Day 1.  
6.2 
Treatment Period 1; Day 1 
This visit is approximately 72 hours in duration. Patients must withhold long acting 
bronchodilators, ipratropium and salbutamol (or Combivent®) prior to the start of the 
treatment period as defined in Section 5.9.1. Patients will be fasting from 2 hours pre-dose 
until 2 hours post-dose (except for water) and other restrictions defined in Section 5.4.2 
should be adhered to. 


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At the start of Treatment Period 1, patients will be evaluated to ascertain if the inclusion and 
exclusion criteria are still met. If so, patients will receive a randomisation number. The 
following assessments will be performed: 
6.2.1 
Pre-Dose Assessments 
• 
Confirm that respiratory medications were withheld as required. If not reschedule the 
visit for within the permitted windows 
• 
Questioning for adverse events 
• 
Urine pregnancy test (females of childbearing potential only) 
• 
12-lead ECG 
• 
Vital signs  
• 
Brief physical examination 
• 
Spirometry 
• 
Whole body plethysmography 
• 
Inhalation training for use of nebuliser and DPI. This will be verbal instruction and 
demonstration of the device 
6.2.2 
Study Treatment Administration 
Patients will be dosed with open label tiotropium DPI 18 mcg (two inhalations from one 
capsule) followed immediately (within 2 minutes) with either blinded RPL554 or placebo 
using a nebuliser according to randomisation scheme. At 12 hours (±30 minutes) after the 
morning dose, the second dose of RPL554 or placebo will be administered by nebulisation. 
6.2.3 
Post-Dose Assessments (after morning doses only) 
• 
Spirometry at 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8 and 12 hours  
• 
Vital signs at 30 minutes and 1, 2, 4, 6, 8 and 12 hours   
• 
12-lead ECGs at 2 and 4 hours  
• 
Questioning for adverse events 
Patients will stay at the study centre overnight, unless they need to return home overnight and 
this is agreeable to the Investigator.   
6.3 
Treatment Period 1; Day 2 
Patients will be fasting from 2 hours pre-dose until 2 hours post-dose (except for water) and 
other restrictions defined in Section 5.4.2 should be adhered to. The following assessments 
will be performed: 
6.3.1 
Pre-Dose Assessments 
• 
Questioning for adverse events 
• 
Place 24 hour Holter monitor (at least 30 minutes pre-dose) 
• 
12-lead ECG 
• 
Vital signs  
• 
Spirometry 
• 
Whole body plethysmography 


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6.3.2 
Study Treatment Administration 
Patients will be dosed with open label tiotropium DPI 18 mcg (two inhalations from one 
capsule) followed immediately (within 2 minutes) with either blinded RPL554 or placebo 
using a nebuliser according to randomisation scheme. At 12 hours (±30 minutes) after the 
morning dose, the second dose of RPL554 or placebo will be administered by nebulisation. 
6.3.3 
Post-Dose Assessments (after morning doses only) 
• 
12-lead ECGs at 2 hours  
• 
Vital signs at 30 minutes and 1, 2, 3, 4 and 12 hours  
• 
Spirometry at 15 and 30 minutes and 1, 2, 3 and 4 hours  
• 
Whole body plethysmography at 1.25 hours  
• 
Questioning for adverse events 
• 
Continue 24 hour Holter monitoring to at least 24 hours post-dose and prior to Day 3 
dose  
Patients will stay at the study centre overnight, unless they need to return home overnight and 
this is agreeable to the Investigator.   
6.4 
Treatment Period 1; Days 3 to 4 
Patients must remain in the unit for at least 24 hours after morning dosing on Day 3. Patients 
will be fasting from 2 hours pre-dose until 2 hours post-dose (except for water) and other 
restrictions defined in Section 5.4.2 should be adhered to. The following assessments will be 
performed: 
6.4.1 
Pre-Dose Assessments 
• 
Questioning for adverse events 
• 
12-lead ECG 
• 
Vital signs  
• 
Spirometry  
• 
24 hour Holter monitor removed 
• 
Blood sample for pharmacokinetics  
6.4.2 
Study Treatment Administration 
Patients will be dosed with open label tiotropium DPI 18 mcg (two inhalations from one 
capsule) followed immediately (within 2 minutes) with either blinded RPL554 or placebo 
using a nebuliser according to randomisation scheme. There is no evening dose of study 
treatment on Day 3 of each period. 
6.4.3 
Post-Dose Assessments 
Note: 24 hour assessments will be performed in the morning on Day 4 prior to discharge from 
the study centre. 
• 
12-lead ECGs at 2, 4 and 24 hours 
• 
Vital signs at 30 minutes and 1, 2, 4, 6, 8 and 24 hours   
• 
Spirometry at 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8, 12, 15 and 24 hours  
• 
Questioning for adverse events 


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• 
Blood samples for pharmacokinetics at 5, 30 and 45 minutes and 1, 1.5, 2, 4, 8, 12, 15 
and 24 hours  
• 
Blood sample for laboratory safety tests (haematology and biochemistry) at 24 hours  
• 
Brief physical examination, can be performed any time prior to discharge (Day 4) 
The procedures listed above for Treatment Period 1 will be repeated for Treatment 
Period 2 and Treatment Period 3. Patients will be instructed to return in 7 to 21 days (taken 
from last dose of study medication on Day 3) for the next visit, or if Treatment Period 3, to 
return in 4 to 10 days (from Day 4) for the end of study visit. 
6.5 
End of Study Visit 
The following will be performed: 
• 
Full physical examination 
• 
Vital signs  
• 
Spirometry (pre-bronchodilator)  
• 
Blood and urine samples for laboratory safety tests (haematology, biochemistry, 
urinalysis) 
• 
Urine pregnancy (females of childbearing potential) 
• 
12-lead ECG 
• 
Questioning for adverse events  


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7 
STUDY METHODOLOGY 
7.1 
Demographics, Baseline Characteristics and Eligibility Assessments  
Safety assessments (laboratory safety assessments, vital signs, 12-lead ECG and physical 
examination) will be performed at screening as part of the eligibility assessment as described 
in Section 7.4.2 to Section 7.4.5. 
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/Surgical and Disease History 
All active medical conditions and all surgeries will be recorded at screening. Disease history, 
including date of diagnosis and prior respiratory therapies 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 mcg) 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: 
• 
Post-bronchodilator FEV1/FVC ratio of ≤0.70 
• 
Post-bronchodilator FEV1 ≥40 % and ≤80% of predicted normal* 
• 
Demonstrates ≥150 mL increase from pre-bronchodilator FEV1  
*NHANES III (Hankinson et al, 1999) will be used as a reference for normal predicted 
values. 
7.1.4 
Screening Laboratory Eligibility Assessments 
At screening, blood samples will be taken and tested at the Local Laboratory for human 
immunodeficiency virus, hepatitis B and hepatitis C serology. All female patients of 
childbearing potential will have a serum pregnancy test. 
A chest X-ray (post-anterior) must be performed at screening or in the 12 months prior to 
screening. 
An alcohol breath test will be performed by the study centre at screening. Urine pregnancy 
tests for female patients of childbearing potential will also be performed by the study centre 
at screening (confirmed to be negative prior to the chest X-ray), on Day 1 of each treatment 
period and at the end of study visit. 
Unscheduled and/or repeat testing may be performed at the discretion of the Investigator. 
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 5.9.1.  


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Other prior medications will be separately recorded at screening and concomitant use during 
the study recorded as described in Section 5.9.2. 
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 Treatment 
Period 1. 
7.2 
Pharmacodynamic Assessments 
7.2.1 
Pulmonary Function Tests 
Spirometry (FEV1 and FVC) will be performed at screening, the end of study visit and the 
following time points in each treatment period: 
• 
Day 1: pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8 and 12 hours  
• 
Day 2: pre-dose; 15 and 30 minutes and 1, 2, 3 and 4 hours 
• 
Day 3: pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8, 12, 15 and 24 hours  
Post-dose measurements will be taken in relation to the morning dose of tiotropium DPI and 
RPL554 or placebo. The 12 hour measurement will therefore be taken pre-dose before the 
evening dose of RPL554 or placebo. The 24 hour measurement on Day 3 will be taken in the 
morning on Day 4 prior to discharge from the study centre. 
Spirometry assessments will be made in accordance with ATS/ERS guidelines 
(Miller et al, 2005). At all timepoints, three technically acceptable measurements should be 
made and recorded. Spirometry assessments may be performed up to eight times to obtain 
three acceptable readings according to ATS guidelines (Miller, 2005). The highest FEV1 and 
FVC readings from each assessment will be used for analysis even if the FEV1 and FVC 
values come from two different forced exhalations. 
7.2.2 
Whole Body Plethysmography 
Whole body plethysmography training and assessment for ability to perform the procedure 
will be conducted at screening. 
Whole body plethysmography will be performed pre-dose on Day 1 and pre-dose and 
1.25 hours post-dose on Day 2 of each treatment period. Assessments will be made in 
accordance with ATS/ERS guidelines (Wanger et al, 2005). 
Patients will be placed on a body box for plethysmographic determination of lung volumes, 
to include RV, FRC and total lung capacity (TLC). Additionally, measurements will be made 
of sGaw and airway resistance (Raw). 
7.3 
Pharmacokinetic Assessments 
Pharmacokinetic analysis will be performed on samples taken from patients on Day 3 of each 
treatment period. Blood samples (4 mL at each time point) will be collected at the following 
timepoints: pre-dose, 5, 30 and 45 minutes and 1, 1.5, 2, 4, 8, 12, 15 and 24 hours post-dose 
(the 24 hour sample will be taken in the morning on Day 4 prior to discharge from the study 
centre). Samples 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 30 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. 


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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 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 
Recording and reporting adverse events is described in detail in Section 8. 
7.4.2 
Laboratory Safety Tests 
In addition to the laboratory tests detailed in Section 7.4.2.1 to Section 7.4.2.3, 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 by 
manually annotating a print out of the results.  
Samples will be taken and handled according to the laboratory manual and analysed at an 
approved Local Laboratory. 
7.4.2.1 
Haematology  
The following will be measured at screening, on Day 4 of each treatment period and at the 
end of study visit: Haemoglobin, haematocrit, total white cell count, leukocyte differential 
count and platelet count.  
At each timepoint, a sample of venous blood will be collected in a collection tube containing 
ethylenediaminetetraacetic acid (EDTA).  
7.4.2.2 
Biochemistry 
The following will be measured at screening, on Day 4 of each treatment period and at the 
end of study visit: creatinine, total bilirubin, alkaline phosphatase, aspartate aminotransferase, 
alanine transaminase, gamma-GT, lactate dehydrogenase, creatine kinase, thyroid stimulating 
hormone, triiodothyronine and thyroxine, glucose, potassium, sodium and calcium.  
At each timepoint, a sample of venous blood will be collected in a vacutainer collection tube.  
7.4.2.3 
Urinalysis 
A midstream urine sample will be collected in a sterile container at screening and at the end 
of study visit. The following will be tested: leukocytes, 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. 
7.4.3 
Vital Signs 
Blood pressure and pulse rate will be measured at screening, the end of study visit and the 
following time points in each treatment period: 


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• 
Day 1: pre-dose; 30 minutes and 1, 2, 4, 6, 8 and 12 hours post-dose  
• 
Day 2: pre-dose; 30 minutes and 1, 2, 3, 4 and 12 hours post-dose 
• 
Day 3; pre-dose; 30 minutes and 1, 2, 4, 6, 8 and 24 hours post-dose 
Post-dose measurements will be taken in relation to the morning dose of tiotropium DPI and 
RPL554 or placebo. The 12 hour measurement will therefore be taken pre-dose before the 
evening dose of RPL554 or placebo. The 24 hour measurement on Day 3 will be taken in the 
morning on Day 4 prior to discharge from the study centre. 
At each timepoint, supine vital signs will be assessed whilst the patient has been at rest for at 
least 5 minutes.  
7.4.4 
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 on Day 1 
and prior to discharge from the study centre on Day 4. 
7.4.5 
12-Lead ECG 
12-lead ECGs will be performed at screening, the end of study visit and the following time 
points in each treatment period: 
• 
Day 1: pre-dose; 2 and 4 hours post-dose 
• 
Day 2: pre-dose; 2 hours post-dose 
• 
Day 3: pre-dose; 2, 4 and 24 hours post-dose 
Post-dose measurements will be taken in relation to the morning dose of tiotropium DPI and 
RPL554 or placebo. The 24 hour measurement on Day 3 will be taken in the morning on 
Day 4 prior to discharge from the study centre. 
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.  
Each 12-lead ECG recording will be sent to a central vendor for interpretation. 
7.4.6 
Holter Monitoring 
12-lead Holter monitors will be used to perform 24 hour Holter monitoring. A Holter monitor 
will be placed at screening, monitoring will be ambulatory and will be recorded as an 
outpatient and the monitor will be removed at the study centre after 24 hours. The screening 
Holter report must have a minimum of 18 hours recording that is evaluable for rhythm 
analysis and the report must be reviewed to assess inclusion criteria prior to randomisation.  
A Holter monitor will also be placed at least 30 minutes pre-dose on Day 2 of each treatment 
period and removed after at least 24 hours post-dose and pre-dose on Day 3. 
Holter readings will be sent to a central vendor for interpretation. 


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7.5 
Appropriateness of Measurements 
The assessments planned in this study are recognised as reliable, accurate and relevant. 
Plasma concentrations of RPL554 will be evaluated using a validated assay and quality 
control samples will be analysed throughout the study. The concentrations will be used to 
determine within run, between run and overall precision and accuracy of the method. The 
procedures, including the limits of quantitation and results will be described in detail in a 
separate bioanalytical protocol and report. The timing of pharmacokinetic samples is deemed 
appropriate to establish the exposure of patients. 
Spirometry is a standard lung function test used to screen for, and monitor, respiratory 
disease. Spirometry will be performed in accordance with ATS/ERS task force 
standardisation guidelines (Miller et al, 2005). Spirometers must be maintained and calibrated 
according to manufacturers’ guidelines. Whole body plethysmography is a further non-
invasive method to obtain information on airway obstruction (airway resistance) and lung 
volumes that is not available through spirometry. This method of assessing the functional 
state of the airways is of value for characterising the multiple, heterogeneous alterations 
occurring in patients with COPD. Whole body plethysmography will be performed in 
accordance with ATS/ERS task force standardisation guidelines (Wanger et al, 2005). Both 
spirometry and whole body plethysmography will be performed using the study centre’s 
standard equipment and standard operating procedures (SOPs).  
Physical examinations, vital signs, 12-lead ECGs, adverse event recording and laboratory 
safety tests are standard assessments of safety and tolerability. The range of assessments to be 
performed is deemed appropriate to detect any safety signals. 
Holter monitoring is a standard method of continuously recording heart activity over periods 
of at least 24 hours. Interpretation will be performed by a specialised central vendor. 
 
 
 


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8 
HANDLING OF ADVERSE EVENTS AND PREGNANCIES 
8.1 
Adverse Event Definitions 
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 treatment. 
An adverse event may be any of the following: 
1. 
A new illness 
2. 
An exacerbation of a sign or symptom of the underlying condition under treatment or of 
a concomitant illness 
3. 
Unrelated to participation in the clinical study or an effect of the study treatment 
4. 
A combination of one or more of the above factors 
No causal relationship with the study treatment 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. 
Adverse reaction is defined as all untoward and unintended responses to study treatment 
related to any dose administered. 
Serious adverse event (SAE) is any adverse experience that: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• 
Results in persistent or significant disability/incapacity, OR 
• 
Is a congenital anomaly/birth defect 
• 
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. 
Suspected unexpected serious adverse reactions (SUSAR) is any suspected adverse reaction 
related to the study drug that is both unexpected and serious. 


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8.2 
Recording and Assessing Adverse Events 
All adverse events, whether reported spontaneously by the patient, in response to open 
questioning on treatment days or observed by the Investigator or his/her staff, will be 
recorded from informed consent until the end of study visit. The start and stop time will be 
recorded and adverse events will be assessed by the Investigator for the following: 
8.2.1 
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 
8.2.2 
Chronicity 
Single occasion: 
Single event with limited duration 
Intermittent:  
Several episodes of an event, each of limited duration 
Persistent: 
 
Event which remained indefinitely 
8.2.3 
Causality 
Not related 
This category applies to those adverse events which, after careful 
consideration, are clearly due to extraneous causes (disease, 
environment, etc.)  
Unlikely 
In general, this category can be considered applicable to those adverse 
events which, after careful medical consideration at the time they are 
evaluated, are deemed unlikely to be related to the study treatment but 
cannot be ruled out with certainty. An adverse event may be considered 
unlikely to be related if or when (must have two of the following): 
1. 
It does not follow a reasonable temporal sequence from 
administration of the study treatment. 
2. 
It could readily have been produced by the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy 
administered to the patients. 
3. 
It does not follow a known pattern of response to the study 
treatment. 
4. 
It does not reappear or worsen when the drug is re-administered. 
Possibly  
This category applies to those adverse events for which, after careful 
medical consideration at the time they are evaluated, a plausible 
temporal relationship with the study treatment administration and a 
biological plausibility are present. An adverse event may be considered 
possibly related if or when (must have two of the following): 
1. 
It follows a reasonable temporal sequence from administration of 
the study treatment. 
2. 
It could not readily have been produced by the patient’s clinical 
state, environmental or toxic factors, or other modes of therapy 
administered to the patients. 


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3. 
It follows a known pattern of response to the study treatment. 
Definitely 
This category applies to those adverse events which the Investigator 
feels are incontrovertibly related to study treatment. An adverse event 
may be assigned an attribution of definitely related if or when (must 
have all of the following): 
1. 
It follows a reasonable temporal sequence from administration of 
the study treatment. 
2. 
It could not be reasonably explained by the known characteristics 
of the patient’s clinical state, environmental, or toxic factors, or 
other modes of therapy administered to the patients. 
3. 
It disappears or decreases on cessation or reduction in dose and 
recurs with re-exposure to study treatment. (Note: this is not to be 
construed as requiring re-exposure of the patient; however, a 
category of definitely related can only be used when a recurrence 
is observed.) 
4. 
It follows a known pattern of response to the study treatment. 
8.2.4 
Action and Outcome 
• 
Action taken with study treatment (none, study treatment stopped, study treatment 
temporarily interrupted) 
• 
Other actions (none, concomitant medication, study discontinuation, hospitalisation, 
other) 
• 
The outcome and date of outcome according to the following definitions: 
- 
Recovered or resolved (adverse event disappeared) 
- 
Recovering or resolving (patient is recovering) 
- 
Not recovered or not resolved (adverse event remains without signs of 
improvement) 
- 
Recovered or resolved with sequelae (adverse event has resulted in permanent 
disability or incapacity) 
- 
Fatal 
- 
Unknown (only applicable if patient has been lost to follow-up) 
• 
Seriousness (yes or no) 
8.3 
Reporting Procedure for SAEs 
The Investigator must report all SAEs to the Sponsor in writing using the Sponsor’s reporting 
form and emailed (email address included on Page 2) to as soon as practical, but in no case 
should it be more than 24 hours of awareness. Any SAEs notified in the 30 day period after 
the last dose of study treatment must also be reported 
SUSARs will be determined by the Sponsor’s Medical Monitor. 
SAEs will be reported to the ethics committee(s) 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. 


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It is the responsibility of the Investigator to ensure that any necessary additional therapeutic 
measures and follow-up procedures are performed. 
8.4 
Management of Pregnancies 
Women of childbearing potential (female subjects and partners of male subjects) should use a 
highly effective method of contraception, defined as: 
• 
Combined (oestrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
- 
Oral 
- 
Intravaginal 
- 
Transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation  
- 
Oral 
- 
Injectable 
- 
Implantable 
• 
Intrauterine device  
• 
Intrauterine hormone-releasing system  
• 
Bilateral tubal occlusion  
• 
Vasectomised partner 
• 
Sexual abstinence - 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 preferred and usual lifestyle of the subject. 
Should a female patient become pregnant or a male patient father a child during the study or 
in the 2 months after the last study treatment they must inform the Investigator immediately. 
The Investigator will report this information to the Sponsor within 7 days of awareness using 
an pregnancy reporting form. The Investigator will make all reasonable efforts to ascertain 
the progress and outcome of the pregnancy. If the outcome meets the criteria for immediate 
classification of a SAE (e.g. spontaneous or therapeutic abortion, stillbirth, neonatal death, 
congenital anomaly, birth defect), the Investigator must follow the procedure for reporting 
SAEs. 


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9 
QUALITY ASSURANCE AND QUALITY CONTROL 
The study will be conducted in accordance with the current approved protocol, SOPs and all 
applicable guidelines and requirements (see Section 11). 
9.1 
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. 
9.2 
Monitoring and Source Document Verification 
The Sponsor will arrange for the study to be monitored in accordance with the principles of 
ICH GCP. The frequency of monitoring visits will be determined by the rate of patient 
recruitment. 
The following are examples of items that will be reviewed at these visits: 
• 
Compliance with the protocol 
• 
Consent procedure 
• 
Source documents 
• 
Adverse event procedures 
• 
Storage and accountability of materials 
The monitoring visits also provide the Sponsor with the opportunity to ensure that timely 
patient accrual and the other Investigator’s obligations and all applicable requirements are 
being fulfilled. 
The Investigator must permit the study monitor, the ethics committee, 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. Identifying information (including name) 
will be made known to certain Sponsor personnel or designees (e.g. monitor, auditor) as well 
as regulatory authorities (e.g. inspector) whilst they are on site, but only to the extent 
necessary for review of source documents. 
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: 
• 
Screening/enrolment log 
• 
Medical notes - which should be updated after each visit to include visit dates, medical 
history, diagnosis of COPD, concomitant medication, any clinically relevant findings of 


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clinical examinations or adverse events/medication changes, SAEs and information on 
patient withdrawal 
• 
Informed consent form 
• 
12-lead ECGs 
• 
Laboratory reports 
• 
Visit dates  
• 
Study treatment 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. 
9.3 
Data Management and Coding 
Data for each patient will be recorded on eCRFs. Data collection must be completed for each 
patient who signs an informed consent form and receives at least one dose of study treatment. 
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 (e.g. laboratory 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 
eCRFs to improve data quality. 
Laboratory safety test, Holter, 12-lead ECG and pharmacokinetic data will be transferred 
electronically into the study database. Discrepancies will be queried to the site and/or the 
laboratory until the electronic data and the database are reconciled.  
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. 


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Subsequent changes to the database will then only be made only by written agreement of the 
Sponsor. 
Adverse events will be coded from the verbatim description (Investigator term) using the 
Medical Dictionary for Regulatory Activities (MedDRA) ([specify version] or later). Prior 
and concomitant medications and COPD therapies 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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10 
STATISTICAL METHODS 
10.1 
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 first patient is enrolled 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. 
10.2 
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. 
The full analysis set will consist of all randomised patients with sufficient data collected after 
intake of study treatment to compute the pharmacodynamic parameters on at least two 
treatment periods. A completer analysis set will consist of all randomised patients that 
complete all visits. 
The safety set will consist of all randomised patients who took at least one dose of study 
treatment during at least one visit.  
The pharmacokinetic data set will consist of all randomised patients with blood sampling 
performed after at least one dose of RPL544 and with data sufficient to calculate 
pharmacokinetic parameters. 
10.3 
Study Endpoints 
10.3.1 
Primary Endpoints 
Peak FEV1 (measured in first 4 hours after dosing) and AUC0-12h FEV1. These will be 
measured after dosing on Day 3. 
The primary comparisons are RPL554 6mg + tiotropium vs RPL554 placebo + tiotropium, 
followed by RPL554 1.5 mg + tiotropium vs RPL554 placebo + tiotropium. 
10.3.2 
Secondary Endpoints 
• 
Determination of AUC0-4h FEV1 after morning dosing 
• 
Peak FEV1 (measured in first 4 hours after dosing) and AUC0-12h FEV1. These will be 
measured after dosing on Day 1. 
• 
Determination of onset of action (>10% increase in FEV1, from pre-first dose, censored 
at 120 minutes) on Day 1 
• 
RV, FRC and sGaw at 1.25 hours after dosing on Day 2 
• 
RPL554 steady state pharmacokinetics (AUC, Cmax, time to maximum concentration 
[tmax], half-life) 
• 
Safety and tolerability: 
− 
Continuous monitoring of adverse events 
− 
Laboratory safety tests [haematology, biochemistry and urinalysis] 
− 
12-lead ECG (including QTcF and heart rate), supine vital signs [blood pressure 
and pulse rate] 


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− 
Peak (measured in first 4 hours after dosing) and AUC0-4h pulse rate for each 
treatment period. 
− 
Holter monitor results 
10.3.3 
Exploratory Endpoints 
• 
AUC0-24h FEV1 on Day 3 
• 
Pre-dose FEV1 on Day 3 
10.4 
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. 
10.4.1 
Patient Disposition 
The number of patients enrolled, randomised, completed or withdrawn (with reason for 
withdrawal) will be summarised. 
10.4.2 
Protocol Deviations 
All protocol deviations collected will be divided into 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. 
10.4.3 
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) will be listed 
and summarised appropriately.  
Medical history, prior and concomitant medications, viral serology results, alcohol breath test 
results, pregnancy test results from females and chest X-ray findings will be listed. 
10.4.4 
Extent of Exposure and Treatment Compliance 
All administration of study treatment will be done at the clinic under supervision of the study 
staff; therefore no formal analysis of compliance will be performed. The RPL554 exposure 
will be estimated based on residual volume in the nebuliser cup. 
10.4.5 
Efficacy/Pharmacodynamics  
FEV1 and FVC will be summarised as actual and change from baseline using descriptive 
statistics over time. 
The peak effect on FEV1 during these time intervals will be computed as the maximum value 
in the 4 hours after dosing minus the pre-dose Day 1 baseline value. The average effect will 
be calculated as the AUC divided by the length of the time interval of interest divided by the 
pre-dose Day 1 baseline value.  


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Computed pharmacodynamic parameters for FEV1 will be compared between the three study 
treatments using analysis of covariance (ANCOVA) models with fixed factors for treatment, 
period and patient, and using the baseline of the visit (pre-first dose in a treatment period) as 
a covariate. FEV1 will be analysed using multiplicative models, which means that data 
(dependent and baseline) is logged prior to analysis and the result then transformed back to 
the linear scale giving treatment differences as ratios of geometric means.  
Primarily the combination RPL554+tiotropium will be compared to tiotropium alone for each 
of the two doses of RPL554. 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 summarised by treatment and a Kaplan-Meier plot illustrating time to 
onset constructed. 
Outcomes from the whole body plethysmography at 1.25 hours post-dose on Day 2 will be 
compared in the same way as FEV1 using multiplicative ANOVA models. The baseline of 
the visit (pre-first dose in a treatment period) will be used as covariate in these models. 
The use of rescue medication during the study visits will be summarised by treatment, and, if 
appropriate, a Kaplan-Meier plot illustrating time to first use of rescue constructed. 
10.4.6 
Pharmacokinetics 
The following steady state pharmacokinetic parameters will be calculated from plasma 
concentrations of RPL554 using standard non-compartmental methods. 
• 
AUC0-12h and AUC0-24h represent the area under the plasma concentration curve from 
time 0 to either 12 or 24 hours after dose on Day 3. The AUC0-12h value in indicative of 
the steady state AUCƬ for a twice daily dosage regimen of RPL554 for the study cohort 
• 
Cmax denotes the highest plasma concentration measured 
• 
tmax denotes the time point corresponding to Cmax 
• 
t1/2 denotes the estimated half-life and is computed as ln(2)/λz 
Pharmacokinetic 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, half-life; and n, arithmetic mean, standard deviation, minimum, maximum 
and median for tmax).  
10.4.7 
Safety  
Safety data including safety laboratory tests, 12-lead ECG and Holter parameters, vital signs 
and physical examinations, will be summarised by treatment group and time point of 
collection, when appropriate. For continuous variables, the change from baseline (pre-dose at 
each treatment visit) 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 treatment. 
Coded adverse event terms will be presented by system organ class (SOC) and preferred term 
and summarised by treatment group. A summary table 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 event of each intensity 
will be summarised by SOC and preferred term.   


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10.4.8 
Handling of Withdrawals or Missing Data 
Patients withdrawn after only one treatment period will not be included in the efficacy 
analyses. 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. 
10.4.9 
Interim Analyses 
No formal interim analysis is planned for the study. 
10.5 
Determination of Sample Size 
This is a complete block three way crossover study. Assuming a residual CV of 6% for peak 
FEV1, 24 patients will give an 80% power to detect a pairwise difference in peak FEV1 of 
5.1%. Assuming a mean baseline FEV1 of 1.3 litres this will correspond to a difference of 
about 66 mL. The detectable difference for FEV1 AUC0-12h is expected to be similar as for the 
peak. 


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11 
ETHICAL CONSIDERATIONS 
11.1 
Guidelines 
The study will be performed in accordance with the ICH GCP guidelines, the principles 
outlined in the Declaration of Helsinki (1996), the protocol and applicable regulatory 
requirements. 
11.2 
Ethics and Regulatory Approval 
The Sponsor will supply all background data necessary to enable submission to the 
appropriate ethics committee and regulatory authority. 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. 
11.3 
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 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. 
11.4 
Patient Confidentiality 
Data collected during this study may be used to support the development, registration or 
marketing of the study treatment. 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 ethics committee 
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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11.5 
Record Maintenance/Retention 
The Investigator will retain the originals of all source documents generated at his hospital 
unit office, either: 1) until after regulatory agency approval is obtained for the study drug 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 GCP regulations. 
11.6 
Availability of Study Results 
A summary of the study results will be made available via press release and posted at 
clinicaltrials.gov. Study patients inquiring about the results will be provided with instructions 
to access these references. 
 


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12 
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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13 
PUBLICATION POLICY 
The publication policy is detailed in the Investigator Agreement between the Sponsor and 
Investigator. 
 
 


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14 
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):365-76. Doi: 10.1111/bcpt.12209. Epub 2014 Mar 6. 
Bjermer L, Stewart J, Abbott-Banner KH et al. RPL554, a first-in-class dual PDE3/4 inhibitor 
is equi-effective as a bronchodilator to maximal doses of salbutamol in asthmatics but with 
fewer adverse events. Am J Resp Crit Care Med 2016;193:A7770. 
Calverley PM, Sanchez-Toril F, McIvor A et al. Effect of 1-year treatment with roflumilast in 
severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 
176(2):154-161. 
Calzetta L, Page CP, Spina D, et al. The effect of the mixed phosphodiesterase 3/4 inhibitor 
RPL554 on human isolated bronchial smooth muscle tone. J Pharmacol Exp Ther 2013; 346: 
414–423. 
Calzetta L, Cazzola M, Page CP, et al. Pharmacological characterization of the interaction 
between the dual phosphodiesterase (PDE) 3/4 inhibitor RPL554 and glycopyrronium on 
human isolated bronchi and small airways. Pulm Pharmacol Ther 2015 Apr 18. pii: 
S1094-5539(15)00042-5.  
Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of 
patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J, 2004; Vol 
2:932–946. 
Compton CH, Gubb J, Nieman R et al. Cilomilast, a selective phosphodiesterase-4 inhibitor 
for treatment ofpatients with chronic obstructive pulmonary disease: a randomised, dose-
ranging study. Lancet 2001; 358(9278):265-270. 
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 Conference on Harmonisation Topic E6. ICH Harmonised Tripartite Guideline. 
Good Clinical Practice. 
Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 
2005;26(2):319-338. 


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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. 
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. 
Turner MJ, Matthes E, Billet A, et al. The dual phosphodiesterase 3 and 4 inhibitor RPL554 
stimulates CFTR in ciliary beating in primary cultures of bronchial epithelia. Am J Physiol 
Lung Cell Mol Physiol 2016;310:L59-L70. 
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 10/2016.  
Verona Pharma plc RPL554 Investigational Medicinal Product Dossier current version 
Verona Pharma plc.  RPL554-007-2014 Clinical Study Report, August 2016. 
Verona Pharma plc.  RPL554-009-2015 Clinical Study Report (in preparation). 
Wanger J, Clausen JL, Coates A et al. Standardisation of the measurement of lung volumes. 
Eur Respir J 2005;26:511–522 
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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15 
APPENDICES 
15.1 
Instructions for Tiotropium Use 
 


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SAP_001.pdf: 
Syne qua non study no: VMA16001 
 
Verona Pharma Plc study no: RPL554-CO-202 
 
Date: 19SEP2017 
Page 1 of 23 
Version: Final 1.0 Amendment 2.0 
ST/form/010/9 
 
 
 
 
A Phase II, Randomised, Double Blind, Placebo  
Controlled, Three Way Crossover Study to Assess the 
Bronchodilator Effect of RPL554 Administered in Addition 
to Open Label Tiotropium in Patients with COPD 
 
Verona Pharma Plc Study No: RPL554-CO-202 
Syne qua non Ltd Study No: VMA16001 
 
 
Statistical Analysis Plan  
 
 
Version: Final 1.0 Amendment 2.0 
 
Date: 19 September 2017 
 
 
For Syne qua non Ltd – Lead Statistician 
Sig1sig 
 
For Verona Pharma Plc 
If Signing manually, please include: Signature + Date + Full Name + Position 
 
 
Sig2sig 
 


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Verona Pharma Plc study no: RPL554-CO-202 
 
Date: 19SEP2017 
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Version: Final 1.0 Amendment 2.0 
ST/form/010/9 
 
 
Contents 
 
1 
INTRODUCTION ............................................................................................................................. 5 
2 
STUDY OBJECTIVES AND DESIGN ............................................................................................. 5 
2.1 
Study Objectives ......................................................................................................................... 5 
2.2 
Study Endpoints .......................................................................................................................... 6 
2.3 
Study Design ............................................................................................................................... 6 
2.4 
Visit Structure .............................................................................................................................. 7 
3 
Sample Size .................................................................................................................................... 7 
4 
Randomisation ................................................................................................................................ 7 
5 
Interim analysis ............................................................................................................................... 8 
6 
Analysis Plan ................................................................................................................................... 8 
6.1 
General ....................................................................................................................................... 8 
6.2 
Derived data ................................................................................................................................ 8 
6.3 
Analysis Sets .............................................................................................................................. 9 
6.4 
Data presentations ...................................................................................................................... 9 
6.5 
Disposition of patients ............................................................................................................... 10 
6.6 
Protocol Deviations ................................................................................................................... 10 
6.7 
Background and Demographic Characteristics ........................................................................ 10 
6.7.1 
Demography .......................................................................................................................... 10 
6.7.2 
Medical History ...................................................................................................................... 11 
6.7.3 
Diagnosis of COPD ................................................................................................................ 11 
6.7.4 
Pregnancy test ....................................................................................................................... 11 
6.7.5 
Alcohol breath test ................................................................................................................. 11 
6.7.6 
Serology ................................................................................................................................. 11 
6.7.7 
Chest X-Ray .......................................................................................................................... 11 
6.7.8 
Training .................................................................................................................................. 11 
6.7.9 
Spirometry: Reversibility Test ................................................................................................ 11 
6.8 
Prior, Rescue and Concomitant Medications and COPD Therapies ........................................ 12 
6.9 
Lifestyle Restrictions ................................................................................................................. 13 
6.10 
Administration of Study treatment and Exposure ..................................................................... 13 
6.11 
Primary Endpoints .................................................................................................................... 13 
6.11.1 
Primary Analysis .................................................................................................................... 14 
6.12 
Secondary Endpoints ................................................................................................................ 15 
6.12.1 
Secondary Analysis ............................................................................................................... 16 
6.13 
Exploratory Endpoints ............................................................................................................... 17 
6.13.1 
Exploratory Analysis .............................................................................................................. 17 
6.14 
Summary of AUC Data ............................................................................................................. 17 
6.15 
Multiplicity ................................................................................................................................. 17 
6.16 
Spirometry: Pulmonary Function Tests .................................................................................... 18 
6.17 
Pharmacokinetics ..................................................................................................................... 19 
6.18 
SAFETY EVALUATION ............................................................................................................ 19 
6.18.1 
Adverse Events ...................................................................................................................... 20 
6.18.2 
Clinical Laboratory Evaluation ............................................................................................... 21 
6.18.3 
Vital Signs .............................................................................................................................. 21 
6.18.4 
Electrocardiography ............................................................................................................... 22 
6.18.5 
24-Hour Holter Monitoring ..................................................................................................... 22 
6.18.6 
Physical Examination ............................................................................................................. 22 
6.18.7 
Safety Analyses ..................................................................................................................... 22 
6.19 
Changes from the Protocol Planned Analysis .......................................................................... 23 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AUC 
Area under the curve 
AUC0-t  
Area Under the Plasma Drug Concentration Versus Time Curve 
(AUC) up to the Last Measurable Time Point 
AUC0-12h 
Area Under the Plasma Drug Concentration Versus Time Curve 
(AUC) up to 12 Hours 
AUC0-24h 
Area Under the Plasma Drug Concentration Versus Time Curve 
(AUC) up to 24 Hours 
AUC0-4h FEV 
Area Under the FEV Curve (AUC) up to 4 Hours 
AUC0-12h FEV 
Area Under the FEV Curve (AUC) up to 12 Hours 
AUC0-24h FEV 
Area Under the FEV Curve (AUC) up to 24 Hours 
AUC0-4h Heart 
Rate 
Area Under the Heart Rate Curve (AUC) up to 4 Hours 
AUC0-4h Pulse 
Rate 
Area Under the Pulse Rate Curve (AUC) up to 4 Hours 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CAS 
Completer Analysis Set 
Cmax 
Maximum Observed Plasma Drug Concentration 
CI 
Confidence Interval 
CL/F 
The apparent clearance 
COPD 
Chronic Obstructive Pulmonary Disease 
CV 
Coefficient of Variation 
DPI 
Dry Powder Inhaler 
DRM 
Data Review Meeting 
ECG 
Electrocardiogram 
FAS 
Full Analysis Set 
FEV1 
Forced Expiratory Volume in One Second  
FRC 
Functional Residual Capacity 
HIV 
Human Immunodeficiency Virus 
Kel 
The First Order Apparent Elimination Rate Constant 
KG 
Kilogram 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 


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PK 
Pharmacokinetic 
PT 
Preferred Term 
QTcF 
QT interval corrected using Fridericia’s formula  
Raw 
Airway Resistance 
RV 
Residual Volume 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SEM 
Standard Error of Mean 
sGaw 
Specific Airway Conductance 
SOC 
System Organ Class 
t1/2 
Terminal Elimination Half-Life 
TEAE 
Treatment Emergent Adverse Event 
TLC 
Total Lung Capacity 
tmax 
Time of the Maximum Observed Plasma Drug Concentration 
Vz/F 
The (Apparent) Volume of Distribution 
WHO Drug 
World Health Organization Drug Dictionary 
 
 


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1 INTRODUCTION 
This document details the statistical analysis of the data that will be performed for 
the Verona Pharma Plc study: A Phase II, Randomised, Double Blind, Placebo 
Controlled, Three way Crossover Study to Assess the Bronchodilator Effect of 
RLP554 Administered in Addition to Open Label Tiotropium in Patients with Chronic 
Obstructive Pulmonary Disease (COPD). 
The proposed analysis is based on the contents of the Final Version of the protocol, 
Version 2.0 (dated 26 April 2017). In the event of future amendments to the protocol, 
this statistical analysis plan (SAP) may be modified to account for changes relevant 
to the statistical analysis.  
The table, listing and figure shells are supplied in a separate document. 
2 STUDY OBJECTIVES AND DESIGN 
2.1 Study Objectives 
The primary objective of the study is to investigate the bronchodilator effect on peak 
forced expiratory volume in one second (FEV1) (measured in first 4 hours after 
dosing) and average (measured as the area under the curve (AUC)) FEV1 over 12 
hours of nebulised RPL554 dosed twice daily for 3 days (five total doses), as 
compared to placebo, when administered in addition to once daily tiotropium. 
The secondary objectives of the study are: 
• To investigate the effect of twice daily nebulised doses of RPL554, as 
compared to placebo, when administered in addition to tiotropium on lung 
volumes 
• To assess the bronchodilator effect on peak FEV1 (measured in first 4 hours 
after dosing) and average (measured as the AUC) FEV1 over 12 hours of 
nebulised RPL554 after the first dose as compared to placebo, when 
administered in addition to tiotropium 
• To 
analyse 
plasma 
concentrations 
and 
assess 
the 
steady 
state 
pharmacokinetics of RPL554 when administered in addition to tiotropium 
• To assess the tolerability and safety of twice daily nebulised doses of RPL554 
in addition to tiotropium  
• To assess the dose response of two different doses of RPL554 on peak, 
average (0 to 12 hours), and morning trough FEV1 on Day 3 when dosed in 
addition to tiotropium 
• To determine the onset of action of RPL554 when administered with 
tiotropium (after the first dose) 
• To investigate the bronchodilator effect on nebulised RPL554, or placebo, 
administered in addition to tiotropium on average FEV1 over 4 hours after 
each morning dose 


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• To investigate the effects of RPL554 on specific airway conductance (sGaw) 
and lung volumes (residual volume [RV], functional residual capacity [FRC]) 
when administered in addition to tiotropium. 
The exploratory objectives are: 
• To examine the effect of RPL554 on top of tiotropium on average FEV1 over 
24 hours after 3 days of dosing 
• To assess morning trough FEV1 prior to the final dose of study treatment. 
2.2 Study Endpoints 
The primary endpoints of the study are: 
• Peak FEV1 (measured in first 4 hours after dosing) and AUC0-12h FEV1. These 
will be measured after dosing on Day 3. 
The secondary endpoints are: 
• Determination of AUC0-4h FEV1 after morning dosing 
• Peak FEV1 (measured in first 4 hours after dosing) and AUC0-12h FEV1. These 
will be measured after dosing on Day 1 
• Determination of onset of action (>10% increase in FEV1, from pre-first dose, 
censored at 120 minutes) on Day 1 
• RV, FRC, and sGaw at 1.25 hours after dosing on Day 2 
• RPL554 steady state pharmacokinetics (AUC, maximum observed 
concentration (Cmax), time to maximum concentration (tmax), half-life) 
• Safety and tolerability: 
- 
Continuous monitoring of adverse events 
- 
Laboratory safety tests [haematology, biochemistry and urinalysis] 
- 
12-lead electrocardiogram (ECG) (including QT interval corrected using 
Fridericia’s formula (QTcF) and heart rate), supine vital signs [blood 
pressure and pulse rate] 
- 
Peak (measured in first 4 hours after dosing) and AUC0-4h
 pulse rate for 
each treatment period 
- 
Holter monitor results 
The exploratory endpoints are: 
- 
Pre-dose FEV1 on Day 3 
2.3 Study Design 
This is a phase IIb, randomised, double blind, placebo controlled, complete block 
three-way crossover study to investigate treatment with nebulised RPL554 and 
tiotropium together in patients with moderate to severe COPD. It is planned to 
randomise up to 30 patients to have 24 evaluable patients at one study centre. The 
study comprises the following: screening, three treatment periods each lasting 3 
days and an end of study visit.  


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2.4 Visit Structure 
The visit structure and scheduled assessments are detailed in the study protocol 
section 6. 
3 SAMPLE SIZE 
This is a complete block three-way crossover study. Assuming a residual coefficient 
of variation (CV) of 6% for peak FEV1, 24 patients will give an 80% power to detect a 
pairwise difference in peak FEV1 of 5.1%. Assuming a mean baseline FEV1 of 1.3 
litres this will correspond to a difference of about 66mL. The detectable difference for 
FEV1 AUC0-12h is expected to be similar as for the peak. 
4 RANDOMISATION 
All patients consented will be assigned a screening number using the study centre’s 
standard convention. 
 
Patients will receive three different treatment combinations (dry powder inhaler (DPI) 
plus nebulised treatment) shown in Table 1 in a randomised sequence during 
Treatment Periods 1 to 3. All study treatments will be administered using the inhaled 
route. In each case, the DPI treatment will be administered first, followed 
immediately (within 2 minutes) by the nebulised RPL554 or placebo using a standard 
Jet nebuliser (PARI LC SPRINT® attached to a PARI TurboBOY® SX compressor 
unit). The DPI treatment will be open label and the nebulised treatment will be 
double blind. 
 
Table 1: Treatment Combinations in RPL554-CO-202 
 
TREATMENT 
COMBINATION 
DPI TREATMENT 
NEBULISED 
TREATMENT 
1 
Tiotropium 18 mcg qd 
RPL554 6 mg bid 
2 
Tiotropium 18 mcg qd 
Placebo bid 
3 
Tiotropium 18 mcg qd 
RPL554 1.5 mg bid 
Abbreviation: bid=twice daily; DPI=dry powder inhaler; qd=once daily 
 
 
Patients will be equally randomised to one of six treatment sequences (using a Latin 
Square design with the three different potential medication combinations) before the 
first study treatment administration in Treatment Period 1. 
 
Tiotropium will be provided in trade dress and will not be blinded. 
 
RPL554 and placebo will be administered double blind. It has not been possible to 
completely match the placebo to RPL554, as the visual appearance is slightly 
different. The study personal preparing the RPL554 and placebo, placing them into 
the nebuliser, and supervising dosing will therefore not to blinded to treatment 
identity. The dosing cup on each nebuliser will be obscured with tape to visually blind 
the study treatment. The sponsor, Investigator (defined as Principal Investigator and 
all study physicians), all patients and all other research personnel (except 


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bioanalytical personnel performing the pharmacokinetic assays) will therefore be 
blinded to the treatment allocation. 
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 discuss it with the Sponsor’s Medical monitor in advance. 
 
Otherwise, all blinding will be maintained until all queries are resolved and the 
database is locked. 
5 INTERIM ANALYSIS 
No formal interim analysis is planned for this study. 
6 ANALYSIS PLAN 
6.1 General 
Summary statistics for continuous variables will consist of number of non-missing 
observations (n), mean, standard deviation (SD), minimum, median and maximum, 
unless specified otherwise.  The precision of these variables is defined in the table, 
figure and listing shells document. 
For categorical variables, the number and percentage of patients in each category 
will be presented, based on the number of non-missing observations apart from 
disposition of patients, protocol deviations, background and demographic 
characteristics, prior and concomitant medications/procedures and adverse events 
where the percentage will be based on the number of patients in the analysis set.   
All statistical tests will be performed using a two-tailed 5% overall significance level, 
unless otherwise stated.  The null hypothesis at all times will be that the treatments 
are equivalent.  All comparisons between the treatments will be reported with 95% 
confidence intervals for the difference.  
6.2 Derived data 
• Definition of baseline 
Baseline is defined as the last non-missing value (including scheduled and 
unscheduled assessments) prior to the patient receiving study treatment for each of 
the respective study treatments. 
For ECG and vital signs, time-matched baselines from Day 1 of each Treatment 
Period will be used for the analysis of data.  
 
• Incomplete dates 
For calculation purposes, incomplete dates will be completed using worst case. 
Further details are detailed in the relevant sections as required. 
 
• Non-numeric values for numeric variables 


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In the case where the result of a variable is recorded as “>x”, “≥x”, “<x” or “≤x”, then 
for analysis purposes a value of x will be taken. Where a range of values is quoted 
the midpoint of the range will be taken. 
 
 
• Methods for handling withdrawals and missing data 
Patients withdrawn after only one treatment period will not be included in the efficacy 
analyses. If a patient has baseline data missing for a parameter, within a treatment 
period, data for that patient and parameter will not be derived or analysed for that 
treatment period. 
 
No 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 treatment day is rescheduled due to variability in FEV1 or other 
reason, the rescheduled treatment day will be listed and summarised as the valid 
treatment day. 
6.3 Analysis Sets 
The Enrolled Set includes all patients who passed screening irrespective of whether 
they received the study treatment. 
The Completer Analysis Set (CAS) includes all randomised patients who complete 
all treatment periods. 
The Full Analysis Set (FAS) includes all randomised patients with sufficient data 
collected after intake of study treatment to compute the pharmacodynamics 
parameters on at least two treatment periods. Patients will be analysed according to 
the treatment they are assigned to at randomisation, irrespective of what treatment 
they actually received. 
The Safety Analysis Set (SAF) consists of all patients who take at least one 
administration of study treatment.  Patients will be analysed according to the 
treatment actually taken.   
The Pharmacokinetic (PK) Set will consist of those patients in the SAF who have at 
least one pre-dose and one post-dose RPL554 PK concentration and with sufficient 
data to calculate PK parameters. Patients will be analysed according to the 
treatment actually taken. 
The list of patients included in the FAS, CAS, SAF and PK will be agreed prior to 
database lock once all study data are available.  
6.4 Data presentations 
The data will be summarised in tabular form by treatment group apart from 
disposition of patients, background and demographic characteristics which will be 
summarised by treatment sequence and overall patients. 


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Only scheduled post-baseline laboratory, vital signs and ECG values will be 
tabulated. Post-baseline repeat/unscheduled assessments will be disregarded, 
although they will be listed and in particular all clinically significant values will be 
noted. 
All listings apart from eligibility and analysis sets will be based on SAF. Eligibility and 
analysis sets will be listed using the enrolled set. Listings will be sorted by treatment 
sequence, patient number and date/time of assessment.  Treatment sequences will 
be presented in the following order: 
- 
Placebo - RPL554 1.5 mg – RPL554 6 mg 
- 
RPL554 1.5 mg – RPL554 6 mg – Placebo 
- 
RPL554 6 mg – Placebo – RPL554 1.5 mg 
- 
RPL554 6 mg - RPL554 1.5 mg – Placebo 
- 
RPL554 1.5 mg – Placebo – RPL554 6 mg 
- 
Placebo – RPL554 6 mg – RPL554 1.5 mg 
Graphical presentations of the data will also be provided where appropriate. 
Disposition of patients will be summarised using the enrolled set. Background and 
demographic characteristics will be summarised using the SAF. The primary efficacy 
endpoints will be summarised using the FAS and CAS. Secondary endpoints will be 
summarised using the FAS. Protocol deviations, prior/concomitant medications and 
safety will be summarised using the SAF. 
6.5 Disposition of patients 
The number and percentage of all patients enrolled, randomised, included in the 
FAS, CAS, SAF, PK analysis set who completed the study and prematurely 
discontinued study treatment and study duration will be summarised.  The number 
and percentage of patients will be summarised by their reasons for withdrawal where 
applicable.  Eligibility for each of the analysis sets along with reasons for exclusion 
will be listed. Study completion/withdrawal data will be listed. 
6.6 Protocol Deviations 
Prior to database lock, Verona Pharma Plc may review the individual deviations and 
classify them as major (which includes those described in section 6.3 above) or 
minor during a data review meeting (DRM).  
Details of all protocol deviations (date, deviation category, specific details and 
classification of major or minor) and patient eligibility will be listed.   
The number and percentage of patients with protocol deviations will be summarized 
by category. 
6.7 Background and Demographic Characteristics 
6.7.1 Demography 
Demographic characteristics (age, sex, ethnic origin and race), body measurements 
(height, weight and body mass index (BMI)) and smoking status collected at 
Screening will be summarised. 


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Age is calculated in years from the date of first administration of study treatment.   
BMI is calculated as (weight (kilogram(kg))/height (m)²). 
All patient demographic data including informed consent will be listed. 
6.7.2 Medical History 
Medical history events will be coded using the latest Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary version. The number and percentage of 
patients will be presented by system organ class (SOC), and preferred term (PT), 
where SOC and PT will be presented in decreasing frequency of the total number of 
patients with medical history events. All events will be listed, which will include a flag 
for ongoing conditions. 
6.7.3 Diagnosis of COPD 
Details of the diagnosis of COPD including date of diagnosis, date of onset of 
symptoms, any hospitalisations, history of a chronic cough with phlegm for at least 3 
months a year for at least 2 years and number of exacerbations in the prior year 
(defined as needing oral steroids and/or antibiotics) taken at screening will be 
summarised and listed. Where possible, duration of symptoms (years) will be derived 
as (date of enrolment – date of symptom +1). Duration of diagnosis (years) will be 
derived as (date of enrolment – date of diagnosis + 1). Dates will not be imputed, 
instead, where days and months are missing but year known, duration can be 
derived from years, where months and year are known, duration can be derived 
using the month and year. 
6.7.4 
Pregnancy test 
Details of the pregnancy test conducted at Screening, Treatment Period 1 - Day 1, 
Treatment Period 2 - Day 1, Treatment Period 3 - Day 1 and End of Study will be 
listed. 
6.7.5 
Alcohol breath test 
Details of the alcohol breath test conducted at Screening will be listed. 
6.7.6 
Serology 
Details of the screen for human immunodeficiency virus (HIV), hepatitis B and 
hepatitis C conducted at Screening will be listed. 
6.7.7 
Chest X-Ray 
Details of the chest x-ray conducted at Screening will be listed. 
6.7.8 
Training 
Details of the whole-body plethysmography and inhalation training conducted at 
Screening will be listed. 
6.7.9 
Spirometry: 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 mcg) of salbutamol administered using a pMDI will be performed.  
 


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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. The highest reading from each 
assessment will be used for calculation of predicted values and increase from 
baseline.  
 
The following must be confirmed for inclusion:  
• Post-bronchodilator FEV1/FVC ratio of ≤0.70 (derived as the highest of the 3 
post-bronchodilator FEV1 measurements divided by the highest of the 3 
post-bronchodilator FVC measurements) 
• Post-bronchodilator FEV1 ≥40 % and ≤80% of predicted normal*  
• Demonstrates ≥150 mL increase from pre-bronchodilator FEV1 (derived as the 
highest of the 3 post-bronchodilator FEV1 measurements – the highest of the 3 
pre-bronchodilator FEV1 measurements) 
*NHANES III will be used as a reference for normal predicted values. 
These data will be summarised and listed. 
6.8 Prior, Rescue and Concomitant Medications and COPD 
Therapies  
Medications will be coded using the latest World Health Organization Drug dictionary 
(WHO Drug) version.  
Prior therapies and prior medications are defined as those that started and ended 
prior to the first administration of study treatment. Medications that are ongoing at 
the first administration of study treatment or started after time of first administration 
will be deemed to be concomitant medications. If medication dates are incomplete 
and it is not clear whether the medication was concomitant, it will be assumed to be 
concomitant. 
The following rules will be used for defining whether a medication is concomitant and 
which treatment they should be assigned to: 
1. If the start date is after the period first administration of study treatment and 
before the start of the next period, then the study treatment is concomitant 
and assigned to the treatment for that period.  
2. The start date is before the period first administration of study treatment and 
the end date is after the first administration of study treatment of the period, 
then the medication is concomitant and assigned to the treatment for that 
period.  
3. Any medication taken after the end of the final period (i.e. in the follow-up 
period) will be concomitant and will be assigned to the treatment for the final 
period. 
4. Any medication that starts and ends during the washout period counts as part 
of the previous treatment period. 
5. Any medication that starts during the washout period and ends after the start 
of the next treatment period will be assigned to the previous and current 
treatment period, 
The number and percentage of patients taking prior and separately concomitant 
medications will be summarised by medication class and standardised medication 
name, where medication class and standardised medication name will be presented 


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in decreasing frequency of the total number of patients with medications.  In 
summary tables, patients taking multiple medications in the same medication class 
or having the same standardised medication recorded multiple times in the study will 
be counted only once for that specific medication class and standardised medication 
name.  
Medication data will be listed, where concomitant medications will be flagged. 
6.9 Lifestyle Restrictions 
The date and time of the lifestyle restrictions assessments, information regarding 
refrain from xanthine for at least 24 hours prior to visit (yes/no), information regarding 
refrain from alcohol for 24 hours prior to visit (yes/no) and whether the patient 
refrained from strenuous exercise for 72 hours prior to visit will be listed. 
6.10 Administration of Study treatment and Exposure 
Study treatment administration will take place at the study centre and will be 
administered by the investigator or designated and trained study centre personnel.  
Patients will be dosed with open label tiotropium DPI 18 mcg (two inhalations from 
one capsule) followed immediately (within 2 minutes) with either blinded RPL554 or 
placebo using a nebuliser according to the randomisation scheme. At 12 hours (±30 
minutes) after the morning dose, the second dose of RPL554 or placebo will be 
administered by nebulisation. 
A summary of whether treatment was received (yes/no), whether the patient fasted 
from 2 hours pre-dose, and continue until 2 hours post-dose (yes/no) and has the 
patient refrained from smoking within 1 hour of dosing (yes/no) will be presented by 
timepoint and treatment day. 
The number of doses of study treatment administered (0 if no treatment 
administered, 1 if only first or second dose taken and 2 if first and second doses 
taken) during each period and the number of days of exposure to the study treatment 
(last date of dosing minus first day of dosing + 1) during each period will be 
summarised.   
The duration of the first and second nebulisation of RPL554 in minutes will be 
summarised by timepoint and treatment day and listed. Time of tiotropium dosing will 
be included in the listing. 
Details of the first compressor unit number, volume of first residual product (mL), 
second compressor unit number and volume of second residual product (mL) will be 
summarised and listed. 
6.11 Primary Endpoints 
Peak FEV1 (measured in first 4 hours after dosing) and AUC0-12h FEV1. These will be 
measured after dosing on Day 3 
The peak effect on FEV1 during these time intervals will be computed as the 
maximum value within the 4 hours after dosing minus the pre-dose Day 1 baseline 
value.  


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The average effect will be calculated as the AUC divided by the length of the time 
interval of interest. The AUC parameters will be calculated using the linear 
trapezoidal rule. 
Pre-dose treatment day 1 value for each treatment period will be used as the 
baseline value. 
Changes from baseline in AUC average effect parameters will be derived by 
deducting the pre-dose treatment day 1 value from the average effect. 
Peak effect and average effect will be loge transformed in order to perform a 
multiplicative (Analysis of Covariance) ANCOVA as follows: 
Loge (Max FEV1) 
Loge (AUC0-12h FEV1 /12) 
Spirometry performed within 8 hours after the use of a rescue bronchodilator 
(salbutamol) will not be utilized in calculations of peak or AUC FEV1. 
Observed FEV1 data will be summarised as actual and change from baseline using 
descriptive statistics over time.  
Hypothesis to be tested: 
H0 = tiotropium + RPL554 in patients with COPD has the same effect on FEV1(first 4 
hours)/ AUC0-12h FEV1 as tiotropium + Placebo 
The primary comparisons are tiotropium + RPL554 6mg vs tiotropium + RPL554 
placebo, followed by tiotropium + RPL554 1.5mg vs tiotropium + RPL554 placebo. 
All hypothesis testing will be done using two-sided alternative hypotheses. P-values 
less than 5% will be considered statistically significant. 
6.11.1 Primary Analysis 
The primary analysis will be based on the FAS and CAS. Peak FEV1 and AUC0-12h 
FEV1 measured after dosing on Day 3 will be analysed. 
Loge (Max FEV1) and loge (AUC0-12h FEV1/12) will be compared between the three 
study treatments using ANCOVA models with fixed factors for treatment, period and 
patient, and using the loge baseline FEV1 of the treatment period (pre-first dose in a 
treatment period) as a covariate. FEV1 will be analysed using multiplicative models, 
and the result then transformed back to the linear scale giving treatment differences 
as ratios of geometric means. Primarily the combination tiotropium + RPL554 will be 
compared to tiotropium + Placebo RPL554 for each of the two doses of RPL554. 
Results of the comparisons will be expressed as the mean geometric ratio with 95% 
confidence intervals and associated, 2-sided, p-value. 
Derived FEV1 data will be summarised and listed.  
Example SAS code for Peak FEV1 analysis is as follows: 
PROC GLM DATA=dataset; 
   CLASS TREATMENT PATIENT PERIOD; 
   MODEL LOGE(MAX 4HRS POSTDOSE VALUE) = TREATMENT PATIENT PERIOD 
LOGE(BASELINE);  
   LSMEANS TREATMENT / DIFF PDIFF CL; 
RUN; 
Example SAS code for AUC0-12h FEV1 analysis is as follows: 


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PROC GLM DATA=dataset; 
   CLASS TREATMENT PATIENT PERIOD; 
   MODEL LOGE(AUC/12) = TREATMENT PATIENT PERIOD LOGE(BASELINE);  
   LSMEANS TREATMENT / DIFF PDIFF CL; 
RUN; 
6.12 Secondary Endpoints 
The following endpoints will be analysed based on the FAS: 
AUC0-4h FEV1 after morning dosing on Day 1, Day 2 and Day 3 
Loge (AUC0-4h FEV1/4) 
 
 
Peak FEV1 (measured in first 4 hours after dosing) and AUC0-12h FEV1 Day 1  
Peak effect and average effect will be loge transformed in order to perform a 
multiplicative ANCOVA as follows: 
Loge (Max FEV1) 
Loge (AUC0-12h FEV1/12) 
Onset of action  
Time to onset of action will be determined for each patient on Day 1 of each 
treatment period. The scheduled timepoint at which ≥10% increase from baseline 
was achieved and the scheduled timepoint before that will be interpolated to 
determine the time relative to dosing at which 10% increase occurred for that patient 
on that treatment day. Subjects who do not achieve a 10% increase from baseline by 
120 minutes (2 hours postdose) on Day 1 will be censored.  
 
The following formulae will be used to derive the time to onset: 
 
Time to Onset = Time A + (FEV1 target - FEV1 A)/ (FEV1 B - FEV1 A) * (Time B - Time A)  
 
Where: 
- 
Time A is the scheduled timepoint before 10% increase is met 
- 
Time B is the scheduled timepoint at which 10% increase is met 
- 
FEV1 target is the FEV1 value corresponding to a 10% increase or, if FEV1 
is expressed as percentage increases from baseline, it is the value 10 
itself 
- 
FEV1 A is the maximum FEV1 measurement at the timepoint before 10% 
increase is met 
- 
FEV1 B is the maximum FEV1 measurement at the timepoint at which 
10% increase is met 
RV, FRC, sGaw and Raw at 1.25 hours after dosing on Day 2  
Ability to adequately perform whole body plethysmography will be conducted at 
screening. Whole body plethysmography assessments will be conducted at pre-dose 
Day 1, pre-dose and 1.25 hours post-dose on Day 2 of each treatment period. 
Patients will be placed on a body box for plethysmographic determination of lung 
volumes, to include RV, FRC and total lung capacity (TLC). Additionally, 


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measurements will be made of airway conductance (sGaw) and airway resistance 
(Raw).  
Plethysmographic endpoints will be calculated on Day 2, at both pre-dose and 1.25 
hours post dose of each treatment period. The change from pre-dose Day 1 will be 
calculated for RV, FRC, sGaw and Raw at 1.25 hours post-dose on Day 2 of each 
treatment period. 
AUC, Cmax, tmax and half-life 
RPL554 steady state pharmacokinetics (AUC, maximum observed concentration 
(Cmax), time to maximum concentration (tmax) and half-life) will be determined. 
Analysis of PK data is detailed in section 6.16.  
Rescue Medication 
The use of rescue medication during the study will documented. Short acting 
bronchodilators (e.g. salbutamol, ipratropium or Combivent) may be used as rescue 
medication. Salbutamol should be considered the primary rescue medication and 
ipratropium secondary. The time to the first rescue medication use is defined as the 
duration from the date of first dose of study treatment to the date of the first 
administration of a rescue medication for each study period calculated in hours. 
Subjects who do not use rescue medication will be right-censored at the date of the 
last timepoint of the last treatment day of each study period. 
Tolerability and Safety 
Assessment of safety and tolerability of twice daily nebulised doses of RPL554 in 
addition to tiotropium is detailed in section 6.17. 
6.12.1 Secondary Analysis 
Continuous variables will be compared between the three study treatments using 
analysis of covariance (ANCOVA) models with fixed factors for treatment, period and 
patient, and using the loge baseline measurement of the treatment day (pre-first dose 
in a treatment period) as a covariate. The analysis uses multiplicative models.  
The combination of tiotropium + RPL554 will be compared to tiotropium alone for 
each of the two doses of RPL554. Results of the comparisons will be expressed as 
the mean geometric ratio with 95% confidence intervals and associated, 2-sided, 
p-value.   
AUC0-4h FEV1 after morning dosing will be determined separately for Day 1, Day 2 
and Day 3 and analysed as above, as average effect (AUC0-4h /4 FEV1). 
Median time to onset of action for each study treatment will be calculated. The 
median time to onset across all patients will only be reported if at least 50% of 
patients achieve a 10% increase from baseline in FEV1 from pre-first dose within 
120 minutes on Day 1. 95% CI of the median time to onset will also be presented. 
Kaplan-Meier plot illustrating time to onset will also be constructed. Where possible, 
the median time to onset of action data will be compared using a Wilcoxon signed 
rank test. P-values will be generated for comparisons of the median time to onset of 
the two tiotropium + RPL554 doses against tiotropium + Placebo. 
 
Loge transformed Plethysmographic endpoints will be compared in the same way as 
FEV1. The loge baseline of the treatment day (pre-first dose in a treatment period) 
will be used as covariate in these models. Results of the comparisons will be back 


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transformed and expressed as the mean geometric ratio with 95% confidence 
intervals and associated, 2-sided, p-value.   
 
All plethysmography data will be listed and summarised where applicable. A 
histogram of change from baseline (pre-dose day 2 to pre-dose day 1) and 
(post-dose day 2 to pre-dose day 1) mean plethysmography data will be presented 
for actual values and percent predicted values of RV, FRC and actual values for 
sGaw and Raw for each study treatment. All treatments will be presented on the 
same figure. 
The use of rescue medication during the study timepoints will be summarised by 
treatment, as the number and percentage of patients who used rescue medication, 
and, if appropriate, a Kaplan-Meier plot illustrating time to first use of rescue 
constructed. Rescue medication data will also be listed. 
6.13 Exploratory Endpoints 
The following endpoint will be analysed based on the FAS: 
- 
Pre-dose FEV1 on Day 3 
6.13.1 Exploratory Analysis 
Loge (pre-dose FEV1) on Day 3 will be compared between the three study treatments 
using analysis of covariance (ANCOVA) models with fixed factors for treatment, 
period and patient, and using the baseline measurement of the treatment day (pre-
first dose in a treatment period) as a covariate. The analysis uses multiplicative 
models and the result will be transformed back to the linear scale giving treatment 
differences as ratios of geometric means.  
The combination of tiotropium + RPL554 will be compared to Placebo tiotropium + 
RPL554 for each of the two doses of RPL554. Results of the comparisons will be 
expressed as the mean geometric ratio with 95% confidence intervals and 
associated, 2-sided, p-value.   
6.14 Summary of AUC Data 
Changes from baseline in AUC parameters will be derived using the following 
definitions for baseline: 
- 
AUC0-4h: 4 * pre-dose treatment day 1 value 
- 
AUC0-12h: 12 * pre-dose treatment day 1 value 
- 
AUC0-24h: 24 * pre-dose treatment day 1 value 
6.15  Multiplicity 
For the primary endpoints analyses, a closed test procedure will be used to maintain 
the overall type 1 error rate starting with the highest dose of RPL554. The method is 
illustrated in Figure 1 below. 
 
FIGURE 1: CLOSED TESTING PROCEDURE 
 


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For the RPL554 6mg dose compared to RPL554 Placebo for each of peak and AUC 
FEV1, a significant result will be required for both variables to proceed to testing the 
lower dose. 
 
 
 
 
 
 
where p1 < p2 
p12 = 2*min (p1/1, p2/2) 
           P1 = a                                                                                      P2 = b     
           adj P1 = Max (P12, P1)                                                             adj P2 = Max (P12, P2) 
If H1 and H2 are rejected, then analysis of the primary endpoints will stop here. 
However, if both H1 and H2 are accepted then the above closed test procedures will 
be repeated for the lower dose of RPL554 compared to placebo RPL554.  If either 
H1 or H2 are accepted, testing will continue for the hypothesis that was accepted for 
the lower dose of RPL554 compared to placebo RPL554. 
The adjusted p-value of the relevant endpoint from above, will be used to assess 
significance. 
All secondary endpoints and the supportive analyses will be considered as 
descriptive evidence of efficacy and will be analysed without any procedures to 
account for multiple comparisons. 
6.16 Spirometry: Pulmonary Function Tests 
Spirometry (FEV1 and FVC) will be performed at screening, the end of study visit and 
the following time points in each treatment period:  
• Day 1: pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8 and 12 hours  
• Day 2: pre-dose; 15 and 30 minutes and 1, 2, 3 and 4 hours  
• Day 3: pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8, 12, 15 and 24 hours  
Post-dose measurements will be taken in relation to the morning dose of tiotropium 
DPI and RPL554 or placebo. The 12-hour measurement will therefore be taken pre-
dose before the evening dose of RPL554 or placebo. The 24-hour measurement on 
Day 3 will be taken in the morning on Day 4 prior to discharge from the study centre.  
Spirometry assessments will be made in accordance with ATS/ERS guidelines 
(Miller et al, 2005). At all timepoints, three technically acceptable measurements 
should be made and recorded. Spirometry assessments may be performed up to 
eight times to obtain three acceptable readings according to ATS guidelines (Miller, 
2005). 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.  
Pulmonary function tests data (FEV1 and FVC) including change from baseline will 
be listed and summarised. 
H12 
H1= Endpoint 1, p1 = a 
H2= Endpoint 2, p2 = b 
H1 
H2 


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Mean (±Standard error of mean (SEM)) figures will be presented for FEV1 and FVC 
data separately using change from baseline data where baseline is the pre-dose Day 
1 value. Separate figures will be generated for FEV1 and FVC data collected from 
Day 1 to Day 3. The three treatments will be represented on the figures using 
different colours. 
6.17 Pharmacokinetics 
Plasma concentrations of RPL554 will be listed and summarised over time. Values 
below the lower limit of quantification (LLOQ) of 5 pg/mL will be set to 0.5 *LLOQ for 
calculation of summary plasma concentration statistics. Individual plasma 
concentration profiles will be plotted both on the original scale and on the log scale 
separately.  Mean (±SD) and median plasma concentration profiles will be plotted on 
the original scale and on the log scale. 
The following steady state pharmacokinetic parameters will be calculated from 
plasma concentrations of RPL554 using standard non-compartmental methods by 
LGC Ltd and transferred to SQN for analysis. 
- 
Area under the plasma drug concentration versus time curve (AUC) up to 
12 hours (AUC0-12h (pg.h/mL)) 
- 
Area under the plasma drug concentration versus time curve (AUC) up to 
24 hours (AUC0-24h (pg.h/mL)) 
- 
Area under the plasma drug concentration versus time curve (AUC) up to 
the last measurable time point (AUC0-t (pg.h/mL)) 
- 
Maximum plasma drug concentration (Cmax (pg/mL))  
- 
Time of observed maximum plasma drug concentrations (tmax (h)) 
- 
The first-order apparent elimination rate constant (Kel (hr-1)) 
- 
Half-life (t1/2(h)) The apparent clearance (CL/F (mL/min)) 
- 
The (apparent) volume of distribution (Vz/F (L)) 
These PK parameters will be summarised by treatment using descriptive statistics 
(n, geometric mean, coefficient of variation (CV), minimum, maximum and median 
for AUC parameters, Cmax, half-life, and n, arithmetic mean, standard deviation, 
minimum, maximum and median for.: t1/2, tmax, Cmax, AUC0-12h, AUC0-24h and AUC0-t, 
CL/F, Vz/F. Kel. 
The PK parameters will be listed. 
6.18 SAFETY EVALUATION 
Safety and tolerability will be assessed by assessments including physical 
examinations, vital signs, 12-lead ECGs, 24-Hour Holter monitoring, adverse event 
recording and laboratory safety tests. 
 
Safety data will be summarised by treatment group and time point of collection when 
appropriate. For continuous variables, the change from baseline (pre-dose at each 
treatment day) 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) 


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and shift plots for selected time points. Separate listings will be generated of 
abnormal values occurring after the first dose of study treatment. 
6.18.1 Adverse Events 
Adverse events (AEs) will be coded using the latest MedDRA dictionary version.  
A treatment-emergent adverse event (TEAE) is defined as an AE that started on or 
after the start of the administration study treatment. If adverse event dates or times 
are incomplete and it is not clear whether the adverse event was treatment-
emergent, it will be assumed to be treatment-emergent. 
 
Where there are partial dates, if the start date and other data mean that the event 
could have occurred during more than one treatment, then the event will be recorded 
under the lowest possible active study treatment excluding placebo that the TEAE 
could be assigned to. 
 
Adverse events are treatment emergent and accountable to period x treatment if 
they started on or after the start of the administration study treatment in period x up 
to the first administration of study treatment in period x+1.  However, for treatment 
period 3, adverse events are treatment emergent and accountable to the last 
treatment period if they started on or after the start of the administration study 
treatment in the last period up to the end of the follow-up period.   
 
If an adverse event starts in period x and continues on till after period x+1, the 
adverse event will be counted in period x, i.e. the period where it first occurred. If the 
start time of adverse event is missing, the adverse event will be taken to have 
started post dose. 
 
A treatment-related TEAE is defined as a TEAE that is definitely, possibly and 
unlikely related to the study treatment. If the TEAE has a missing relationship it is 
assumed to be related to the study treatment for analysis purposes. 
System organ class and preferred term will be ordered by decreasing frequency of 
the total number of patients with TEAEs. 
A summary table will present the following:  
• TEAEs (events and patients).  
• Serious TEAEs (events and patients).  
• Serious study treatment related TEAEs (events and patients). 
• TEAEs by severity (mild/moderate/severe) (events and patients). 
• TEAEs by relationship (definitely/probable/possible/unrelated) to study 
treatment, the pooled study treatment related category and the pooled study 
unrelated category (events and patients). 
• TEAEs leading to withdrawal from study (patients only).  
• TEAEs leading to discontinuation of study treatment (patients only). 
• Study treatment related TEAEs leading to discontinuation of study treatment 
(patients only). 
• TEAEs leading to death (patients only). 


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In the above summaries, if a patient experienced more than one TEAE, the patient 
will be counted once using the most related event for the “by relationship to study 
treatment” and “related to study treatment” summaries and at the worst severity for 
the “by severity” summary. 
The following tables will be presented: 
• TEAEs by system Organ Class (SOC) and Preferred Term (PT) and by 
treatment group. 
• TEAEs by PT. 
• TEAEs by SOC, PT and severity. 
• TEAEs by SOC, PT and relation to study treatment. 
For all of the above, SOC and PT will be presented in decreasing frequency of the 
total number of patients with TEAEs. 
Further details of the above four tables are given below: 
1. If a patient experienced more than one TEAE, the patient will be counted once 
for each SOC and once for each PT. 
2. If a patient experienced more than one TEAE, the patient will be counted once 
for each PT.  
3. If a patient experienced more than one TEAE, the patient will be counted once 
for each SOC and once for each PT at the worst severity. 
4. If a patient experienced more than one TEAE, the patient will be counted once 
for each SOC and once for each PT using the most related event. 
Adverse event data will be listed in full and this will also include a treatment 
emergent flag, the time of onset and cessation of event relative to first dosing of 
study treatment and duration of AE. All SAEs, AEs leading to withdrawal and AEs 
leading to study treatment discontinuation will be listed separately. 
6.18.2 Clinical Laboratory Evaluation 
Observed values of haematology and biochemistry assessments will be summarised 
over time. If the test results are reported in categorical format, the results will be 
summarised by patient counts and percentage for each category. 
Haematology, biochemistry and urinalysis data will be listed separately and clinical 
significance will be flagged. 
6.18.3 Vital Signs 
The AUC parameters will be calculated using the linear trapezoidal rule. The peak 
pulse rate will be computed as the maximum value in the 4 hours after dosing minus 
the pre-dose Day 1 baseline value.  
Peak (measured in first 4 hours after dosing) and AUC0-4h pulse rate will be derived. 
Vital sign observed values and change from baseline by parameter (unit) will be 
summarised over time. 
In addition, ‘substantial’ changes from baseline will be categorised as follows: 
change from baseline in systolic/diastolic blood pressure (BP) (systolic BP 
[>±40 mmHg], diastolic BP [>±20 mmHg]) and pulse rate [>±30 bpm]). The number 


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and percentage of patients with changes from baseline as categorised above will be 
summarised separately for positive and negative changes over time and at any post-
baseline time point.    
All vital sign data will be listed including change from baseline and flags for 
substantial changes from baseline.,  
A listing of clinically significant vital signs recorded throughout the study will be 
provided.  
Mean (±SEM) figures will be presented for changes from baseline blood pressure 
and pulse rate data for each treatment day. The three study treatments will be 
represented by different colours on the figures at each postdose timepoint.  
6.18.4 Electrocardiography 
The AUC parameters will be calculated using the linear trapezoidal rule. The peak 
heart rate will be computed as the maximum value in the 4 hours after dosing.   
Peak (measured in first 4 hours after dosing) and AUC0-4h heart rate will be derived. 
ECG data including QTcF and heart rate data will be summarised and listed. 
Shift table in relation to the normal range from baseline over time for the absolute 
values will be presented for ECG data. Number and percentage of subjects will be 
presented for the change from baseline values. The absolute values will be 
categorised as: ≤450 msec, >450 msec, >480 msec and >500 msec. The change 
from baseline values will be categorised as: increase >30 msec and increase >60 
msec. 
Mean (±SEM) figures will be presented for changes from baseline QTcF and heart 
rate data for Day 1 and Day 3 separately. The three study treatments will be 
represented by different colours on the figures at each postdose timepoint.  
All ECG overall interpretation data will be listed. Abnormal ECG data will be listed 
separately. 
6.18.5 24-Hour Holter Monitoring 
All 24-hour Holter monitoring and parameter data will be listed. Data for time in AFIB 
percentage, supraventricular runs, total QRS complexes, ventricular runs, ventricular 
singles and RR > 2 seconds will be summarised. 
6.18.6 Physical Examination 
The number and percentage of patients with physical examination findings will be 
presented for each body system over time in the form of a shift table. The shift table 
will show change from normal to abnormal across body systems. Data will be 
classed as normal, abnormal and missing.   
Individual patient physical examination data will be listed. 
6.18.7 Safety Analyses 
Peak (measured in first 4 hours after dosing) and AUC0-4h pulse rate and heart rate 
will be analysed. 
Peak and AUC0-4h for the pulse rate and heart rate will be analysed by comparing 
between the three study treatments using ANCOVA models with fixed factors for 


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treatment, period and patient, and using the baseline measurement of the treatment 
day (pre-first dose in a treatment period) as a covariate. The combination of 
tiotropium + RPL554 will be compared to tiotropium alone for each of the two doses 
of RPL554. Results of the comparisons will be expressed as the least squared 
means with 95% confidence interval (CI) and associated, 2-sided p-value. 
6.19 Changes from the Protocol Planned Analysis 
The definition of the PK analysis set has been edited to clarify that patients are 
required to have at least one pre-dose and one post-dose PK concentration to be 
part of the PK analysis set. 
 
It was clarified that the Peak parameters will be derived for inclusion in analysis 
models as the loge (maximum value measured within the first 4 hours) as they are 
assumed not to be normally distributed. 
 
AUC0-24h Day 3 will not be analysed. 
 
An additional plethysmography endpoint, Raw will now be analysed. 
Details of derivation of time to first use of rescue medication was added.