Conditions: COPD
Keywords: COPD Bronchodilation FEV1
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 79
Healthy volunteers: no

Brief summary:
The study investigates the effect of 3 days of twice daily treatment of two different doses of RPL554 (a phosphodiesterase \[PDE\]3/4 inhibitor) or placebo, each administered in addition to once daily tiotropium/olodaterol (Respimat) in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Patients will receive each of the three treatment combinations in a randomized sequence using a crossover design

Detailed description:
RPL554 is a dual inhibitor of phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) which are known to have a role in modulating the inflammatory airway response in respiratory diseases, including COPD. PDE3 inhibitors act as bronchodilators 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. The two doses of RPL554 (1.5 mg and 6 mg)have been selected based on the results from prior studies investigating single and multiple ascending doses in healthy subjects, single doses in asthmatics, single/multiple ascending doses in COPD patients, and 3 days of dosing in COPD patients. These doses were demonstrated to be both effective as a bronchodilator and well tolerated.

The purpose of the study is to investigate if RPL554 has an additive bronchodilator effect when administered in combination with a commonly used anticholinergic/β-agonist combination medication, tiotropium/olodaterol (Respimat), in this patient population measured by the peak forced expiratory volume in one second (FEV1), and forced vital capacity (FVC).

Arms:
arm 1: 1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily arm 2: 6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily arm 3: Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily

Interventions: intervention 1: RPL554 Suspension intervention 2: Placebo intervention 3: Tiotropium/olodaterol (Respimat)
Intervention descriptions: intervention 1: A PDE3/4 inhibitor intervention 2: A placebo solution intervention 3: An anticholinergic/β-agonist combination medication

Protocol document:
Prot_000.pdf: 
THIS STUDY WILL BE CONDUCTED IN ACCORDANCE WITH THE 
INTERNATIONAL CONFERENCE ON HARMONISATION GUIDELINES FOR 
GOOD CLINICAL PRACTICE (DIRECTIVE CPMP/ICH/135/95), THE 
DECLARATION OF HELSINKI (1964) AS AMENDED AND APPLICABLE 
REGULATORY REQUIREMENTS 
 
CONFIDENTIAL 
Page 1 of 66 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL    
A PHASE II, RANDOMIZED, DOUBLE BLIND, PLACEBO 
CONTROLLED, THREE WAY CROSSOVER STUDY TO ASSESS THE 
BRONCHODILATOR EFFECT OF RPL554 ADMINISTERED IN 
ADDITION TO OPEN LABEL TIOTROPIUM/OLODATEROL IN 
PATIENTS WITH COPD 
 
STUDY NO. RPL554-CO-204   
 
Version: 
1.0  
Date: 
28 May 2018  
Phase: 
II 
Investigational  
Medicinal Product:  
RPL554 
EudraCT Number: 
2018-001037-41 
IND Number: 
133146 
 
 
 
 
 
 
 




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INVESTIGATOR SIGNATURE PAGE 
I, the undersigned, am responsible for the conduct of the study at my study center and agree to 
the following: 
I understand that this protocol is a confidential document for the use of the Investigator’s team 
and other persons involved in the study only, and for the information of the 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 authorized individuals. 
I have read and understand fully the Investigator Brochure and I am familiar with the study 
medication and its use according to this protocol. 
 
Name and Title 
Signature 
Date 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The contents of this document are the property of Verona Pharma plc and should be regarded 
as confidential.  
It is intended to provide information on the investigational medicinal product for the use of 
clinical Investigators, their research associates, members of 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 
Sponsor 
 
 
 
Verona Pharma plc 
 
 
 
 
 
3 More London Riverside 
London, SE1 2RE 
UK 
+44 (0)203 283 4200 
 
Contract Research 
IQVIA 
Organization 
4820 Emperor Boulevard 
 
Durham, NC 27703 
 
USA 
 
Central Laboratory 
 
 
LGC 
(Pharmacokinetics) 
 
 
Newmarket Road 
Fordham  
Cambridgeshire, CB7 5WW 
UK 
Central Laboratory 
Q2 Solutions 
(Safety Laboratory Tests) 
The Alba Campus/Livingston 
 
West Lothian, EH54 7EG 
 
UK 
 
Central Review of ECGs and  
QECG 
Holter Monitoring 
 
 
502 A, Leela Business Park 
M.V. Road Adheri Mumbai, Maharastra  
 
India 
 
 


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DETAIL OF AMENDMENTS SINCE THE PREVIOUS VERSION 
This is the first version of the protocol. 
 


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SYNOPSIS 
Title of Study:  
A Phase II, randomized, double blind, placebo controlled, three-way crossover study 
to assess the bronchodilator effect of RPL554 administered in addition to open label 
tiotropium/olodaterol in patients with COPD 
Protocol Number: 
RPL554-CO-204 
EudraCT Number: 
2018-001037-41 
IND Number:  
133146 
Phase: 
II 
Sponsor: 
Verona Pharma plc 
Coordinating Investigator:  
Prof S Dave Singh 
Study Centre(s):  
Up to four sites total, in US and UK 
Planned Study Period: 
Estimated: June to December 2018 
Objectives: 
Primary Objective 
To investigate the bronchodilator effect on peak forced expired volume in 1 second 
(FEV1) (measured in the first 4 hours after dosing) of nebulized RPL554 dosed twice 
daily for 3 days, as compared to placebo, when administered in addition to once daily 
tiotropium/olodaterol. The peak FEV1 is measured after the morning dose on Day 3. 
Secondary Objectives 
• 
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 nebulized RPL554 after the first dose on Day 1 as compared 
to placebo, when administered in addition to tiotropium/olodaterol 
• 
To investigate the effect of twice daily nebulized doses of RPL554, as 
compared to placebo, when administered in addition to tiotropium/olodaterol 
on morning trough FEV1 (mean of values 11 and 12 hours after last dose of 
RPL554) on Day 4 
• 
To investigate the effect of twice daily nebulized doses of RPL554, as 
compared to placebo, when administered in addition to tiotropium/olodaterol 
on average (measured as AUC) FEV1 over 4 and 12 hours after the morning 
dose on Day 3 
• 
To assess the bronchodilator effect on peak FEV1 measured within 4 hours after 
the evening dose of RPL554 on Day 3 
• 
To analyze plasma concentrations and assess the steady state pharmacokinetics 
of RPL554 when administered in addition to tiotropium/olodaterol 
• 
To assess the tolerability and safety of twice daily nebulized doses of RPL554 
in addition to tiotropium/olodaterol 
• 
To determine the onset of action of RPL554 when administered with 
tiotropium/olodaterol (after the first 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/olodaterol 
Exploratory Objectives 
• 
To assess the dose response of RPL554 on peak and average (measured as AUC 
over 12 hours) on Day 3, and morning trough FEV1 (mean of values at 11 and 
12 hours after last dose of RPL554) on Day 4, when dosed in addition to 
tiotropium/olodaterol 
• 
To examine the effect of RPL554 on top of tiotropium/olodaterol on average 
(measured as AUC) FEV1 over 24 hours after 3 days of dosing 


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• 
To examine the effect of RPL554 on top of tiotropium/olodaterol on a Likert 
dyspnea scale   
Study Design and Methodology: 
This is a Phase II, randomized, double blind, placebo controlled, complete block 
three-way crossover study to investigate combination treatment with nebulized 
RPL554 and tiotropium/olodaterol Respimat® in patients with moderate to severe 
chronic obstructive pulmonary disease (COPD). It is planned to randomize 
approximately 70 patients at up to four study centers.  
Patients will be screened for eligibility, including a reversibility test with 
salbutamol/albuterol and ipratropium between 7 and 14 days before the first dose of 
study treatment. Eligible patients will then attend three separate treatment periods 
(Treatment Periods 1 to 3), with each lasting 3 days and separated by a 7 to 14-day 
washout period. 
During each treatment period, patients will be present at the study center from the 
morning of Day 1 until the morning of Day 4. Patients will be randomized pre-dose 
on Day 1 of Treatment Period 1.  
At Screening, patients will be assessed for eligibility into the study, including Holter 
monitoring, and reversibility testing with two puffs of salbutamol/albuterol followed 
by two puffs of ipratropium. Eligible patients will have all prior COPD medications 
discontinued, with the exception of inhaled corticosteroids, and placed on 
ipratropium and salbutamol/albuterol to use on a regular or as-needed basis (as per 
Investigator) throughout the study except during the treatment periods. 
During each treatment period, patients will be dosed with tiotropium/olodaterol 
Respimat® once daily each morning (Day 1 to Day 3) and either RPL554 or placebo 
twice daily (in the morning and evening) for total of six doses of RPL554 or placebo 
in 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: 
• 
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 at 2 and 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 and 
1.25 hours post-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 12 hours post-dose 
• 
12-lead ECG pre-dose and at 2 hours post dose and vital sign (supine) 
measurements pre-dose and up to 12 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 measurements pre-dose, 2 hours post-dose and 24 hours 
post- dose. 
• 
Measurement of lung volumes by whole body plethysmography pre-dose and at 
1.25 hours, 8.25 and 12.25 hours post-dose 
• 
Vital signs (supine) done pre-dose, up to 8 hours post dose and 24 hours 
post- dose   
• 
Pharmacokinetic blood sampling pre-dose and up to 12 hours post dose 
• 
24-hour Holter monitor placed 


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Study Procedures: 
• 
Laboratory safety tests (hematology and biochemistry) at 24 hours post-dose 
The final assessments and Holter removal will be performed prior to discharge from 
the study center on Day 4. 
Adverse events and concomitant medications/therapies will be recorded throughout 
the study. 
Number of Patients Planned: 
Approximately 70 evaluable patients 
Main Criteria for Eligibility: 
Inclusion Criteria 
Male and female patients with moderate to severe COPD, with a post-bronchodilator 
FEV1 of 30 to 70% of predicted. They must have a baseline increase in FEV1 of 
>150 mL after use of two puffs each of salbutamol/albuterol and ipratropium. They 
must have at least a 10 pack-year smoking history, and may be a former smoker or 
current smoker.  
Exclusion Criteria  
Patients must be clinically stable without recent COPD exacerbations or 
hospitalizations. They must not have uncontrolled disease or chronic heart failure. 
Study Treatments: 
All study treatments will be administered using the inhaled route. 
Patients will receive the following three dose treatment combinations in a 
randomized sequence during Treatment Periods 1 to 3: 
Tiotropium/olodaterol 5 µg /5 µg once daily + RPL554 6 mg twice daily   
Tiotropium/olodaterol 5 µg /5 µg once daily + Placebo twice daily 
Tiotropium/olodaterol 5 µg /5 µg once daily + RPL554 1.5 mg twice daily 
Each morning during each 3-day period, the tiotropium/olodaterol will be 
administered first followed immediately (starting within 2 minutes) by the nebulized 
study medication (RPL554 or placebo). The study medication only will be repeated 
in the evening on Day 1, Day 2, and 3, 12 hours after the morning dose. 
The tiotropium/olodaterol will be administered open label and the study medication 
will be administered double blind. 
The study medication will be administered using a standard Jet nebulizer and 
compressor.  
The RPL554 formulation is a sterile suspension supplied in a 2.5 mL dose in amber 
glass vials containing sterile micronized RPL554 in pH 7 phosphate buffered saline, 
and 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. 
Duration of Treatment: 
The approximate planned duration of participation for each patient will be up to 
61 days: 7 to 14-day screening period, up to 9 days treatment (three treatment periods 
of 3 days each separated by 7 to 14 days) 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 doses 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, 70 patients will give an 80% power to detect a 
pairwise difference in FEV1 of 50 mL. 


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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 .......................................................................................................... 14 
1.1 
Disease and Study Medication Review ................................................................. 14 
1.2 
Summary of Risks and Benefits ............................................................................ 16 
2 
OBJECTIVES................................................................................................................. 17 
2.1 
Primary Objective ................................................................................................. 17 
2.2 
Secondary Objectives ............................................................................................ 17 
2.3 
Exploratory Objectives ......................................................................................... 17 
3 
INVESTIGATIONAL PLAN ........................................................................................ 18 
3.1 
Overall Study Design and Plan Description ......................................................... 18 
3.2 
Discussion of Study Design, including the Choice of Control Groups ................ 19 
3.3 
Planned Duration of the Study .............................................................................. 19 
3.4 
Definition of the End of the Study ........................................................................ 19 
4 
SELECTION OF STUDY POPULATION .................................................................... 20 
4.1 
Inclusion Criteria................................................................................................... 20 
4.2 
Exclusion Criteria ................................................................................................. 21 
4.3 
Removal of Patients from Therapy or Assessment ............................................... 22 
4.3.1 
Study Treatment Discontinuation ........................................................... 22 
4.3.2 
Patient Withdrawal ................................................................................. 22 
4.3.3 
Study Discontinuation ............................................................................. 23 
4.3.4 
Replacement Policy ................................................................................ 23 
5 
STUDY TREATMENTS ............................................................................................... 24 
5.1 
Study Treatments Administered............................................................................ 24 
5.2 
Identity of Study Treatments................................................................................. 24 
5.2.1 
RPL554 and Placebo ............................................................................... 24 
5.2.2 
Tiotropium/olodaterol Respimat® ........................................................... 24 
5.3 
Preparation and Labelling ..................................................................................... 25 
5.3.1 
Nebulized RPL554 and Placebo ............................................................. 25 
5.3.2 
Tiotropium/olodaterol ............................................................................. 25 


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5.4 
Selection of Doses, Dosing Schedule and Route of Administration..................... 25 
5.4.1 
Selection of Doses in the Study .............................................................. 25 
5.4.2 
Selection and Timing of Dose for each Patient ...................................... 25 
5.4.2.1 
Nebulized RPL554 and Placebo ............................................. 25 
5.4.2.2 
Tiotropium/olodaterol Respimat® .......................................... 26 
5.4.3 
Route of Administration ......................................................................... 26 
5.5 
Storage .................................................................................................................. 26 
5.6 
Accountability ....................................................................................................... 26 
5.7 
Method of Assigning Patients to Treatment Groups ............................................. 27 
5.8 
Blinding ................................................................................................................. 27 
5.9 
Prior and Concomitant Therapies and Medications .............................................. 27 
5.9.1 
Prior and Concomitant COPD Medications ............................................ 27 
5.9.2 
Other (non-COPD) Prior and Concomitant Medications ....................... 29 
5.10 Rescue Medications .............................................................................................. 29 
5.11 Treatment Compliance .......................................................................................... 29 
6 
STUDY PROCEDURES AT EACH VISIT .................................................................. 30 
6.1 
Pre-visit Restrictions ............................................................................................. 35 
6.2 
Screening ............................................................................................................... 35 
6.3 
Treatment Periods 1 through 3 .............................................................................. 36 
6.3.1 
Day 1 ....................................................................................................... 36 
6.3.1.1 
Pre-Dose Assessments ............................................................ 36 
6.3.1.2 
Study Treatment Administration ............................................ 36 
6.3.1.3 
Post-Dose Assessments (after morning doses only) .............. 37 
6.3.2 
Day 2 ....................................................................................................... 37 
6.3.2.1 
Pre-Dose Assessments ............................................................ 37 
6.3.2.2 
Study Treatment Administration ............................................ 37 
6.3.2.3 
Post-Dose Assessments (after morning dose only) ................ 37 
6.3.3 
Days 3 to 4 .............................................................................................. 37 
6.3.3.1 
Pre-Dose Assessments ............................................................ 37 
6.3.3.2 
Study Treatment Administration ............................................ 38 
6.3.3.3 
Post-Dose Assessments .......................................................... 38 
6.4 
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 and Disease History .................................................................. 39 
7.1.3 
Reversibility Test .................................................................................... 39 
7.1.4 
Screening Laboratory Assessments ........................................................ 39 
7.1.5 
Prior and Concomitant Medications and Therapies ................................ 40 
7.1.6 
Eligibility Check ..................................................................................... 40 
7.2 
Efficacy/Pharmacodynamic Assessments ............................................................. 40 


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7.2.1 
Pulmonary Function Tests ...................................................................... 40 
7.2.2 
Whole Body Plethysmography ............................................................... 40 
7.2.3 
Dyspnea Scale ......................................................................................... 40 
7.3 
Pharmacokinetic Assessments .............................................................................. 41 
7.4 
Safety Assessments ............................................................................................... 41 
7.4.1 
Adverse Events ....................................................................................... 41 
7.4.1.1 
Adverse Event Definitions ..................................................... 41 
7.4.1.2 
Recording and Assessing Adverse Events ............................. 42 
7.4.1.2.1 Severity .................................................................. 42 
7.4.1.2.2 Chronicity .............................................................. 42 
7.4.1.2.3 Causality ................................................................ 42 
7.4.1.2.4 Action and Outcome .............................................. 42 
7.4.1.3 
Reporting Procedure for SAEs ............................................... 43 
7.4.2 
Pregnancy ................................................................................................ 43 
7.4.3 
Laboratory Safety Assessments .............................................................. 43 
7.4.3.1 
Hematology ............................................................................ 44 
7.4.3.2 
Biochemistry .......................................................................... 44 
7.4.3.3 
Urinalysis ............................................................................... 44 
7.4.4 
Vital Signs ............................................................................................... 44 
7.4.5 
Physical Examination ............................................................................. 45 
7.4.6 
12-Lead ECG .......................................................................................... 45 
7.4.7 
Holter Monitoring ................................................................................... 45 
8 
QUALITY ASSURANCE AND QUALITY CONTROL ............................................. 46 
8.1 
Audit and Inspection ............................................................................................. 46 
8.2 
Monitoring and Source Document Verification.................................................... 46 
8.3 
Data Management and Coding .............................................................................. 47 
9 
STATISTICAL METHODS .......................................................................................... 49 
9.1 
Statistical and Analytical Plans ............................................................................. 49 
9.2 
Populations to be Analyzed ................................................................................... 49 
9.3 
Study Endpoints .................................................................................................... 49 
9.3.1 
Primary Endpoint .................................................................................... 49 
9.3.2 
Secondary Endpoints .............................................................................. 49 
9.3.3 
Exploratory Endpoints ............................................................................ 50 
9.4 
Statistical Methods ................................................................................................ 50 
9.4.1 
Patient Disposition .................................................................................. 50 
9.4.2 
Protocol Deviations ................................................................................. 50 
9.4.3 
Demographics and Other Baseline Characteristics ................................. 50 
9.4.4 
Extent of Exposure and Treatment Compliance ..................................... 50 
9.4.5 
Efficacy/Pharmacodynamics .................................................................. 51 
9.4.6 
Pharmacokinetics .................................................................................... 51 
9.4.7 
Safety ...................................................................................................... 51 


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9.4.8 
Handling of Withdrawals or Missing Data ............................................. 52 
9.4.9 
Interim Analyses ..................................................................................... 52 
9.5 
Determination of Sample Size .............................................................................. 52 
10 
ETHICAL CONSIDERATIONS ................................................................................... 53 
10.1 Guidelines ............................................................................................................. 53 
10.2 Ethics and Regulatory Approval ........................................................................... 53 
10.3 Informed Consent Process .................................................................................... 53 
10.4 Patient Confidentiality .......................................................................................... 53 
10.5 Record Maintenance/Retention ............................................................................. 54 
11 
FINANCE AND INSURANCE ..................................................................................... 55 
12 
PUBLICATION POLICY .............................................................................................. 56 
13 
REFERENCES ............................................................................................................... 57 
14 
APPENDICES ................................................................................................................ 59 
14.1 Birth Control Methods For Women of Childbearing Potential Which May Be 
Considered As Highly Effective ........................................................................... 59 
14.2 Tiotropium/Olodaterol Prescribing Highlights and Instructions for Use.............. 61 
14.3 Interpreting Adverse Event Causality ................................................................... 66 
 
List of Tables and Figures 
Figure 1 
Study Flow Chart .........................................................................................18 
 
Table 1 
Treatment Combinations in RPL554-CO-204 .............................................24 
Table 2 
Composition of Nebulised RPL554 and Placebo Formulations ..................24 
Table 3 
Overall Schedule of Assessments at Each Visit in RPL554-CO-204 ..........31 
Table 4 
Pre-dose and Post-dose Assessments on Each Day of Treatment Periods 1 to 
3 in RPL554-CO-204 ...................................................................................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 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDTA 
Ethylenediaminetetraacetic acid 
ERS 
European Respiratory Society 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
FEV1 
Forced expired volume in 1 second 
FRC 
Functional residual capacity 
FVC 
Forced vital capacity 
HRT 
Hormone replacement therapy 
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 
NHANES 
National Health and Nutrition Examination Survey 
PC20MCh 
Provocative concentration of methacholine chloride causing a fall in 
FEV1 of 20% from placebo 
PDE 
Phosphodiesterase 
pMDI 
Pressurized metered dose inhaler 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RV 
Residual volume 
SAE 
Serious adverse event 
SAS 
Statistical analysis software 
sGaw 
Specific airway conductance 
SOC 
System organ class 
SOP 
Standard operating procedure 
SUSAR 
Suspected, unexpected serious adverse reaction 
tmax 
Time to maximum concentration 
  


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1 
INTRODUCTION 
1.1 
Disease and Study Medication 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 COPD, cystic fibrosis and possibly asthma.  
PDE4 inhibitors (administered orally) have exhibited anti-inflammatory actions; however, they 
have been associated with unfavorable gastrointestinal side effects such as nausea, emesis, 
diarrhea, abdominal pain, loss of appetite and weight loss (Harbinson 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 favorable 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 
βa2-agonists (Calzetta et al, 2013; Calzetta et al, 2015).  
The safety, bronchodilator, bronchoprotective and anti-inflammatory activities of RPL554 
have been evaluated in clinical studies involving over 730 subjects. Initially, five studies were 
done in healthy subjects, patients with mild-moderate persistent asthma and those with allergic 
rhinitis and COPD, using a nebulized solution in citrate/phosphate buffered saline at pH 3.2 
(Franciosi et al, 2013; summarized in the Investigator’s 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 as a nebulized 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 causing a fall in FEV1 of 20% from 
placebo (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, measured in the sputum (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. 
RPL554 has subsequently been re-formulated in a neutral pH phosphate buffered suspension 
formulation for nebulization. This formulation has been tested in seven completed clinical 
studies: 


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1. 
Study RPL554-007-2014 was a Phase I study in which single and multiple ascending 
doses up to 24 mg were administered to healthy subjects and COPD patients (RPL554-
007-2014 Clinical Study Report, 2016). No maximum tolerated dose of RPL554 could 
be determined and there was a large bronchodilator response observed. Pharmacokinetics 
demonstrated a terminal serum half-life of about 10 to 12 hours. 
2. 
Study RPL554-008-2014 was a Phase II crossover study that enrolled patients with mild 
to moderate chronic asthma who received four single doses of RPL554 (0.4 mg, 1.5 mg, 
6 mg and 24 mg), two doses of nebulized salbutamol/albuterol (2.5 mg and 7.5 mg) and 
placebo. RPL554 produced a dose-dependent bronchodilation with a magnitude that was 
comparable to a maximal dose of salbutamol/albuterol, but with fewer of the well 
described salbutamol/albuterol side effects (e.g. hypokalemia, tachycardia, tremor and 
palpitations) (Bjermer et al, 2016).  
3. 
Study RPL554-009-2015 was a Phase II crossover study in moderate to severe COPD 
patients who received salbutamol/albuterol (200 µg), ipratropium (40 µg) or placebo 
using a pressurized metered dose inhaler (pMDI) followed immediately by nebulized 
RPL554 (6 mg) or placebo. RPL554 alone was as effective as standard of care 
bronchodilators, and importantly produced significant additive bronchodilation. Indeed, 
there was an approximately 60% additional increase in peak forced expired volume in 
1 second (FEV1) in COPD patients administered RPPL554 in addition to either 
salbutamol/albuterol or ipratropium (RPL554-009-2015 Clinical Study Report, 2017). 
4. 
Study RPL554-PK-101 was a Phase I study of the oral bioavailability of RPL554 in 
healthy subjects. Subjects were randomized to RPL554 6 mg given with, or without, a 
charcoal block. The study demonstrated a low oral bioavailability of 10.6% and a 
terminal half-life of 11.9 hours (RPL554-PK-101 Clinical Study Report, 2017). 
5. 
Study RPL554-CO-202 was a Phase II crossover study in patients with moderate to 
severe COPD who received tiotropium 18 µg once daily, plus RPL554 1.5 mg, RPL554 
6 mg or placebo twice daily for 3 days. This study demonstrated a significant increase in 
peak FEV1 (103 mL and 127 mL for RPL554 1.5 mg and 6 mg, respectively) as compared 
to tiotropium + placebo. There was also significant improvement in both trough FEV1 
and lung volumes, including residual volume (RV) and functional residual capacity 
(FRC). The time of onset of RPL554 + tiotropium was dramatically faster than with 
tiotropium alone (4.2 versus 37 minutes) (Clinical Study Report pending). 
6. 
Study RPL554-CO-203 was a Phase II parallel group study in 403 patients with COPD 
who were administered either placebo or RPL554 at doses ranging from 0.75 mg to 6 mg 
over 4 weeks. Clinically and statistically significant improvements in peak FEV1 
compared to placebo were observed in all active dose groups at all time points. Secondary 
endpoints of average FEV1, COPD symptoms and quality of life were also met (Clinical 
Study Report pending).   
7. 
Study RPL554-010-2015 was a Phase II crossover study in adult patients with cystic 
fibrosis. Patients received a single dose of RPL554, 1.5 mg, 6 mg, or placebo. This study 
demonstrated a significant increase (6.6%) in peak FEV1, as well as demonstrating 
pharmacokinetic levels that were similar to that seen in patients with COPD. RPL554 
was well tolerated in these patients (Clinical Study Report pending). 
RPL554 was well tolerated in all seven studies, with adverse event rates that were similar to 
the subjects treated with placebo.  
All clinical studies with the solution formulation, and with the first three studies above for the 
suspension, are described in the Investigator’s Brochure.  


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This study is intended to examine the dose ranging effect of RPL554 when dosed on top of the 
combination of a long acting anti-muscarinic receptor antagonist (tiotropium) and a long acting 
β2-agonist (olodaterol) whilst dosing the RPL554 to steady state blood levels. 
1.2 
 Summary of Risks and Benefits 
Data from non-clinical studies suggested a potential for hypotension and tachycardia. However, 
in the clinical studies to date RPL554 has been well tolerated in moderate to severe COPD 
patients, healthy subjects, asthmatics and allergic rhinitics. The most common adverse events 
that have been reported at least twice in subjects who have received single or multiple doses of 
the nebulized suspension of RPL554 were generally mild and in descending order of frequency 
are headache, cough, dizziness, and palpitations. Adverse events for single and multiple dose 
studies are summarized in Investigator’s Brochure Section 6.3.  
The suspension formulation of RPL554 is pH balanced, and has favorable non-clinical 
toxicology and pharmacokinetic data.  
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. In particular, Holter 
findings have indicated no arrhythmogenic potential in the completed studies. 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 planned in this study to be administered for only 6 days (12 doses) over two 
treatment periods (placebo is administered in the third treatment period), 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) 
of nebulized RPL554 dosed twice daily for 3 days, as compared to placebo, when administered 
in addition to once daily tiotropium/olodaterol. The peak FEV1 is measured after the morning 
dose on Day 3. 
2.2 
Secondary Objectives 
• To assess the bronchodilator effect on peak FEV1 (measured in the first 4 hours after 
dosing) and average (measured as the AUC) FEV1 over 12 hours of nebulized RPL554 after 
the first dose (on Day 1) as compared to placebo, when administered in addition to 
tiotropium/olodaterol 
• To investigate the effect of twice daily nebulized doses of RPL554, as compared to placebo, 
when administered in addition to tiotropium/olodaterol on morning trough FEV1 (mean of 
values 11 and 12 hours after last dose of RPL554) on Day 4 
• To investigate the effect of twice daily nebulized doses of RPL554, as compared to placebo, 
when administered in addition to tiotropium/olodaterol on average (measured as AUC) 
FEV1 over 4, 8 and 12 hours after morning dosing on Day 3 
• To assess the bronchodilator effect on peak FEV1 measured within 4 hours after the evening 
dosing of RPL554 on Day 3 
• To analyze plasma concentrations and assess the steady state pharmacokinetics of RPL554 
when administered in addition to tiotropium/olodaterol 
• To assess the tolerability and safety of twice daily nebulized doses of RPL554 in addition 
to tiotropium/olodaterol 
• To determine the onset of action of RPL554 when administered with tiotropium/olodaterol 
(after the first dose) 
• To investigate the effects of RPL554 on specific airway conductance (sGaw) and lung 
volumes (RV, FRC) when administered in addition to tiotropium/olodaterol 
2.3 
Exploratory Objectives 
• To assess the dose response of RPL554 on peak and average (measured as AUC over 
12 hours) after morning dose on Day 3, and morning trough FEV1 (mean of values at 11 
and 12 hours after last dose of RPL554) on Day 4, when dosed in addition to 
tiotropium/olodaterol 
• To examine the effect of RPL554 on top of tiotropium/olodaterol on average (measured as 
AUC) FEV1 over 24 hours after 3 days of dosing 
• To examine the effect of RPL554 on top of tiotropium/olodaterol on a Likert dyspnea scale   


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan Description 
This is a Phase II, randomized, double blind, placebo controlled, complete block three-way 
crossover study to investigate treatment with nebulized RPL554 and tiotropium/olodaterol 
Respimat® in patients with moderate to severe COPD. It is planned to randomize approximately 
70 patients at up to four study centers. The study comprises the following, as 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 summarized in Section 6 and the study assessments are 
described in Section 7. 
Figure 1 
Study Flow Chart 
 
 
 
                      7 to 14 days                                     7 to 14 days                                 7 to 14 days                               4 to 10 days     
 
 
 
 
 
 
 
 
Patients will be screened for eligibility, including a reversibility test with salbutamol (in UK) 
/albuterol (in US) and ipratropium between 7 and 14 days before the first dose of study 
treatment.  
Eligible patients will then attend the clinic for three separate treatment periods (Treatment 
Periods 1 to 3), with each lasting 3 days and separated by a 7 to 14-day washout period (taken 
from last dose of study medication). Patients will be randomized pre-dose on Day 1 of 
Treatment Period 1. During each treatment period, patients will be present at the study center 
from the morning of Day 1 until the morning of Day 4.  
In each treatment period, patients will receive an open label dose of tiotropium/olodaterol from 
a Respimat® device followed immediately (starting within 2 minutes) by a double-blind dose 
of either RPL554 or placebo (depending on treatment sequence) from a nebulizer 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, Day 2 and 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 Days 1 and 2 and up to 24 hours post-morning dose on Day 3 (i.e. Day 4). Whole 
body plethysmography will be performed pre-dose and 1.25 hours post-dose on Day 1, and 
pre-dose and 1.25, 8.25 and 12.25 hours post-dose on Day 3. Vital signs will be measured 
pre-dose and up to 12 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). Electrocardiograms (ECG) assessments will be 
performed pre-dose and up to 4 hours post-dose on Day 1, at 2 hours post-dose on Day 2 and 
RANDOMISATION 
70 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/olodaterol 5 µg /5 µg once daily + RPL554 6 mg twice daily   
Tiotropium/olodaterol 5 µg /5 µg once daily + Placebo twice daily 
Tiotropium/olodaterol 5 µg /5 µg once daily + RPL554 1.5 mg twice daily  


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up to 24 hours post-dose on Day 3 (i.e. Day 4). Adverse events and concomitant medications 
will be recorded throughout the study. 
Patients will be discharged from the study center 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 
The purpose of the study is to investigate if RPL554 has an additive bronchodilator effect when 
administered in combination with a commonly used anticholinergic/β-agonist combination 
medication, tiotropium/olodaterol, in this patient population. 
A total of approximately 70 male or female COPD patients aged 40 to 80 years (inclusive) will 
be randomized. All patients will receive three combinations of study medication (1.5 mg 
RPL554, 6 mg RPL554 and placebo) in a randomized, 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. Study 
medication will be administered double blind to minimize any potential bias in the overall 
assessment of treatment effect and safety.  
The washout period between the three treatment periods has been selected based upon the 
available pharmacokinetics of RPL554 in healthy volunteers, and patients with asthma or 
COPD. Five half-lives is considered as the time for elimination of RPL554t from the body. In 
this study, a washout period of 7 to 14 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 center. This is to ensure standardized 
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 61 days: 7 to 14 days 
screening, up to 9 days treatment (three treatment periods of 3 days each separated by 7 to 
14 days) 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.  
3.4 
Definition of the End of the Study 
The end of the study is defined as the date of the end of study visit of the last patient in the 
study.  
 
 


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4 
SELECTION OF STUDY POPULATION 
The population to be recruited into this study is stable patients with moderate to severe COPD 
and without significant heart disease. Specific criteria are as follows: 
4.1 
Inclusion Criteria 
1. 
Sign an informed consent document indicating they understand the purpose of and 
procedures required for the study and are willing to participate in the study. 
2. 
Male or female aged between 40 and 80 years inclusive, at the time of informed consent. 
3. 
If male: must agree to meet the following from the first dose up to 1 month after the last 
dose of study medication: 
• Not donate sperm  
• Either: be sexually abstinent in accordance with a patient’s usual and preferred 
lifestyle (but agree to abide by the contraception requirements below should their 
circumstances change) 
 
Or: use a condom with all sexual partners. If the partner is of childbearing potential 
the condom must be used with spermicide and a second reliable form of 
contraception must also be used (e.g. diaphragm/cap with spermicide, established 
hormonal contraception, intra-uterine device) 
If female: be of non-childbearing potential or use a highly effective form of contraception 
as defined in Section 14.1.  
4. 
Have a 12-lead ECG recording at Screening and pre-dose in Treatment Period 1 showing 
the following: 
• Heart rate between 45 and 90 beats per minute  
• QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≤450 msec 
for males, and ≤ 470 msec for females 
• QRS interval ≤120 msec 
• No clinically significant abnormality including morphology (e.g. left bundle 
branch block, atrio-ventricular nodal dysfunction, ST segment abnormalities 
consistent with ischemia) 
5. 
Have a Screening Holter report with a minimum of 18 hours recording that is able to be 
evaluated for rhythm analysis showing no abnormality which indicates a significant 
impairment of patient safety or which may significantly impair interpretation, 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  
6. 
Capable of complying with all study restrictions and procedures including ability to use 
the study nebulizer and Respimat® correctly. 
7. 
Body mass index (BMI) between 18 and 36 kg/m2 (inclusive) with a minimum weight of 
45 kg. 
8. 
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. 


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9. 
Post-bronchodilator (two puffs of salbutamol/albuterol followed by two puffs of 
ipratropium) spirometry at Screening: 
• 
Post-bronchodilator FEV1/FVC ratio of ≤0.70 
• 
Post-bronchodilator FEV1 ≥30 % and ≤70% of predicted normal 
• 
Demonstrates ≥150 mL increase from pre-bronchodilator FEV1 
10. 
Clinically stable COPD in the 4 weeks prior to Screening and Randomization (pre-dose 
in Treatment Period 1). 
11. 
A chest X-ray (posterior-anterior) at Screening, or in the 12 months prior to Screening 
showing no abnormalities, which are both clinically significant and unrelated to COPD. 
12. 
Meet the concomitant medication restrictions and be expected to do so for the rest of the 
study.  
13. 
Current and former smokers with smoking history of ≥10 pack years.  
14. 
Capable of withdrawing from long acting bronchodilators for the duration of the study, 
and short acting bronchodilators for 8 hours prior to dosing. 
4.2 
Exclusion Criteria  
1. 
A history of life-threatening COPD including Intensive Care Unit admission and/or 
requiring intubation. 
2. 
COPD exacerbation requiring oral or parenteral steroids, or lower respiratory tract 
infection requiring antibiotics, in the 3 months prior to Screening or Randomization 
(pre-dose in Treatment Period 1). 
3. 
A history of one or more hospitalizations for COPD in the 12 months prior to Screening 
or Randomization (pre-dose in Treatment Period 1). 
4. 
Intolerance or hypersensitivity to tiotropium, olodaterol, ipratropium, or RPL554. 
5. 
Evidence of cor pulmonale or clinically significant pulmonary hypertension. 
6. 
Other respiratory disorders: Patients with a current diagnosis of asthma, active 
tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, interstitial lung 
diseases, sleep apnea, known alpha-1 antitrypsin deficiency or other active pulmonary 
diseases. 
7. 
Previous lung resection or lung reduction surgery. 
8. 
Use of oral COPD medications, except mucolytics, in the 3 months prior to Screening or 
Randomization. 
9. 
Pulmonary rehabilitation, unless such treatment has been stable from 4 weeks prior to 
Screening and remains stable during the study. 
10. 
History of, or reason to believe a patient has, drug or alcohol abuse within the past 
5 years. 
11. 
Inability to perform acceptable spirometry or whole body plethysmography (at Screening 
or pre-dose in Treatment Period 1). 
12. 
Received an experimental drug within 30 days or five half-lives, whichever is longer.  
13. 
Patients with uncontrolled disease including, but not limited to, endocrine, active 
hyperthyroidism, neurological, hepatic, gastrointestinal, renal, hematological, urological, 
immunological, psychiatric, or ophthalmic diseases that the Investigator believes are 
clinically significant. This includes any hepatic disease, or an alanine aminotransferase 
or aspartate aminotransferase>2 x ULN. 


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14. 
Documented cardiovascular disease: arrhythmias, angina, recent (<1 year) or suspected 
myocardial infarction, congestive heart failure, unstable or uncontrolled hypertension, or 
diagnosis of hypertension in the 3 months prior to Screening or Randomization. 
15. 
Use of non-selective oral β-blockers. 
16. 
Major surgery (requiring general anesthesia) in the 6 weeks prior to Screening or 
Randomization (pre-dose in Treatment Period 1), or will not have fully recovered from 
surgery, or planned surgery through the end of the study. 
17. 
A disclosed history or one known to the Investigator, of significant non-compliance in 
previous investigational studies or with prescribed medications. 
18. 
Required use of oxygen therapy, even on an occasional basis. 
19. 
Symptomatic prostatic hyperplasia or bladder-neck obstruction or with narrow-angle 
glaucoma. 
20. 
History of malignancy of any organ system within 5 years, with the exception of localized 
skin cancers (basal or squamous cell). 
21. 
Clinically significant abnormal values for safety laboratory tests (hematology, 
biochemistry, virology or urinalysis) at Screening, as determined by the Investigator (see 
Section 7.1.4).   
22. 
Any other reason that the Investigator considers makes the patient unsuitable to 
participate.  
4.3 
Removal of Patients from Therapy or Assessment 
4.3.1 
Study Treatment Discontinuation 
Study treatment must be discontinued for the following reasons: 
• Unacceptable toxicity related to study treatment 
• Intolerable or persistent adverse events of any severity 
• General or specific changes in the patient's condition rendering the patient unacceptable for 
further treatment in the judgment of the Investigator 
• Clinically significant progression of disease 
• Pregnancy in a female patient 
4.3.2 
Patient Withdrawal 
Investigators have the authority to withdraw a patient at any time for medical or non-
compliance reasons. Should the Investigator decide it is necessary to withdraw any patient for 
specific reasons, this should be recorded in writing and transmitted to the patient in question. 
Such reasons for withdrawal are expected to be medical or related to lack of co-operation by 
the patient. 
The patient has the right to withdraw at any time and for any reason, without explanation and 
without jeopardizing any subsequent treatment by the clinician, if applicable. However, anyone 
withdrawing should be encouraged to offer an explanation for their withdrawal, particularly if 
it relates or is perceived to relate in any way to the study treatment, or to the conduct of the 
study. Patients can also be withdrawn in case of protocol violations and non-compliance. 
If a patient withdraws following Randomization, every attempt should be made to contact the 
patient to determine the reason for withdrawal and to complete the recording of any available 
efficacy data and all adverse event data. The reasons for withdrawal and results of all relevant 


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tests will be recorded in the electronic case report form (eCRF). These patients should have an 
end of study visit unless it is considered by the Investigator that they require greater medical 
supervision and/or investigations and in which case an unscheduled visit prior to and in 
addition to the scheduled follow up visit may be performed.  
If a patient had signed a consent form but withdrew from the study without receiving any study 
treatment, no further follow-up is necessary. 
4.3.3 
Study Discontinuation 
Conditions that may warrant termination of the study include, but are not limited to: 
• The discovery of an unexpected, serious, or unacceptable risk to patients enrolled in the 
study 
• The decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of RPL554 
• Serious failure of the Investigator to comply with the International 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 have 70 evaluable patients (i.e., completing at least two treatment periods). 
Withdrawn patients may need to be replaced to meet this target.  


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5 
STUDY TREATMENTS 
5.1 
Study Treatments Administered 
Patients will receive the three treatment combinations shown in Table 1 in a randomized 
sequence during Treatment Periods 1 to 3. All study treatments will be administered using the 
inhaled route. In each case, the Respimat® medication will be administered first, followed 
immediately (within 2 minutes) by the study medication (RPL554 or placebo). The Respimat® 
medication will be open label and the study medication will be double blind. 
Table 1 
Treatment Combinations in RPL554-CO-204 
Treatment 
Combination 
Respimat® Medication 
Study Medication 
1 
Tiotropium/olodaterol 5 µg /5 µg qd 
RPL554 6 mg bid 
2 
Tiotropium/olodaterol 5 µg /5 µg qd 
Placebo bid 
3 
Tiotropium/olodaterol 5 µg /5 µg qd 
RPL554 1.5 mg bid 
Abbreviation: bid=twice daily; 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 nebulized RPL554 and placebo formulations is shown in Table 2.  
Table 2 
Composition of Nebulized RPL554 and Placebo Formulations 
Constituent 
Concentration (mg/mL) 
RPL554 (micronized) 
 0 (=placebo), 0.6 or 2.4 
Polysorbate 20 (Tween 20) 
0.5 
Sorbitan Monolaurate (Span 20) 
0.05 
Monosodium Phosphate Dihydrate 
7.44 
Disodium Phosphate Dihydrate 
8.53 
Sodium Chloride 
4.80 
Water 
N/A 
RPL554 and placebo are manufactured using aseptic manufacturing techniques in accordance 
with Good Manufacturing Practice (GMP) guidelines.  
RPL554 is supplied as a sterile, micronized suspension in pH 7 phosphate buffered saline with 
surfactants to aid suspension. Two concentrations of RPL554 (0.6 mg/mL and 2.4 mg/mL) and 
a placebo will be provided as a nominal 2.5 mL fill in amber 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. 
5.2.2 
Tiotropium/olodaterol Respimat® 
Tiotropium/olodaterol (Stiolto® in US, Spiolto® in UK) Respimat® (Boehringer Ingelheim 
International GmbH; Anatomic Therapeutic Chemical Code R03BB04) is a marketed 


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anticholinergic and β2-agonist combination for the treatment of COPD (see Section 14.2). This 
medication will be provided by the study center.  
5.3 
Preparation and Labelling 
5.3.1 
Nebulized RPL554 and Placebo 
Vials of RPL554 and placebo will be packed as patient kits, one kit per period, each containing 
six vials, and labelled in compliance with GMP, released by a qualified person, where 
appropriate, and then shipped to the study center. 
RPL554 and placebo are a unit dose 2.5 mL volume and will be prepared (poured into a 
nebulizer cup) by an unblinded individual who will not disclose the nature (appearance) of 
study treatment to the blinded Investigator and study center staff. The dose will be poured into 
a nebulizer cup, with is covered with tape to mask the color of the content. 
5.3.2 
Tiotropium/olodaterol 
Each tiotropium/olodaterol Respimat® will be labelled by the site with the randomization 
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/olodaterol, 5 µg /5 µg once daily (administered as two inhalations of 
2.5 µg /2.5 µg each), is the approved dose for this medication.  
The doses of RPL554 have been selected based on the results from prior studies investigating 
single and multiple ascending doses in healthy subjects, single doses in asthmatics, 
single/multiple ascending doses in COPD patients, and 3 days of dosing in COPD patients. 
These doses were demonstrated to be both effective as a bronchodilator and well tolerated. 
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. The first dose should be given between 7 and 11 am. 
For each morning dose, the tiotropium/olodaterol will be given first, followed immediately 
(starting within 2 minutes) by nebulized RPL554 or placebo. The evening dose (RPL554 or 
placebo only) is given 12 hours (±30 minutes) after the morning dose. 
5.4.2.1 
Nebulized RPL554 and Placebo 
RPL554 and placebo will be administered by inhalation of an aerosol generated by a reusable 
PARI LC Sprint® jet nebulizer, with an exhalation filter, attached to a compressor (PARI 
TurboBOY® SX in the UK or a PARI VIOS Pro® in the US). Wherever possible, the same 
compressor unit should be used for each dose for a given a patient.  
The dosing cup on each nebulizer will be obscured with opaque tape by study center 
personnel to visually blind the study medication.  
The end time of nebulization (sputtering) will be considered Time 0 for the purposes of 
scheduling all post-dose study procedures. Nebulization time should be approximately 
5 minutes and may not exceed 10 minutes. Patients must wear a protective gown on Day 3 


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during the dosing procedure to prevent contamination of the cannula for pharmacokinetic 
samples. Patients should be dosed in a well-ventilated environment, and away from other 
patients. 
The following must be recorded in the eCRF: 
• 
Compressor unit number 
• 
Start and end times of nebulization (times will be rounded down to the nearest minute) 
• 
The volume of residual product at the end of nebulization  
5.4.2.2 
Tiotropium/olodaterol Respimat® 
Prior to use of the Respimat®, patients will be instructed in the proper use of the device, 
including the requirement to inhale slowly through their mouth (see instructions in Section 
14.2). They will be instructed to hold their breath for 10 seconds, or as long as comfortable. A 
second inhalation is required to get the entire dose. The time of dosing will be recorded in the 
eCRF. The tiotropium/olodaterol is administered as two inhalations. 
5.4.3 
Route of Administration 
All study treatments will be dosed via inhalation. RPL554 is administered as a nebulized 
suspension. Tiotropium/olodaterol uses the Respimat® Soft Mist™ inhaler.  
5.5 
Storage 
RPL554 and placebo should be stored below 25°C (77°F) and should not be frozen. The expiry 
date will be indicated on the carton label.  
Tiotropium/olodaterol Respimat® should be at room temperature, 20°C to 25°C (68°F to 77°F) 
(see Section 14.2). 
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 
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 medication (RPL554 and placebo), the Investigator or designee will 
inspect the contents and return the completed acknowledgement of receipt. Copies of all study 
medication inventory records must be retained for accountability of study products and 
supplies. Accountability must be documented from the time of initial receipt at the study center 
to their final removal from the center.  


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Written records must also be maintained to confirm the purpose and reason for any study 
medication disposal, e.g. the amount contaminated, broken, or lost, and the name/signature of 
the personnel responsible for reporting the event.  
At the end of the study, the unused study medication can be destroyed locally after 
accountability has been verified and written authorization has been provided by the Sponsor. 
5.7 
Method of Assigning Patients to Treatment Groups 
All patients consented will be assigned a patient identification number upon signing of the 
informed consent using the following convention: XXX-YYY where XXX is the center 
number and YYY is the patient number (001, 002, etc.). 
Patients will receive three different treatment combinations in the study (See Section 5.1). 
Patients will be equally randomized to one of six treatment sequences (using a Latin Square 
design with the three different potential treatment combinations) before the first study 
treatment administration in Treatment Period 1. 
5.8 
Blinding 
Tiotropium/olodaterol will be used in trade dress and will not be blinded.    
RPL554 and placebo will be administered double blind. The placebo is the same as the active 
medication (RPL554) except for the omission of the active ingredient. Because a visually 
matching placebo could not be developed, the dosing cup on each nebulizer administered at 
the study center will be obscured with opaque tape to visually blind the study medication. 
The study personnel pouring the RPL554 and placebo into the nebulizer will therefore not be 
blinded to the study medication identity. This individual needs to be separate from other study 
center staff participating in the study, and may not reveal the appearance of the nebulizer 
contents to the patient or the blinded study staff. To ensure proper blinding, 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 and the unblinded study staff) 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 
contact the Sponsor as soon as feasible. The Investigator may unblind the investigational 
product immediately if he/she feels it is necessary prior to contacting the Sponsor. However, 
the Investigator should promptly document and explain to the Sponsor any premature 
unblinding. Otherwise, all blinding will be maintained until all queries are resolved and the 
database is locked.   Blind break envelopes will be provided to the site and must be kept in a 
secure access area. 
5.9 
Prior and Concomitant Therapies and Medications 
5.9.1 
Prior and Concomitant COPD Medications 
All prior therapies for COPD taken in the 3 months prior to the first study treatment 
administration and all concomitant COPD therapies will be recorded in the eCRF, with the 
medication, dose, route and start and stop date(s) and time(s) clearly recorded to document all 
required washout periods and compliance with the Inclusion and Exclusion Criteria. 


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The following therapies are restricted or prohibited during the study as indicated: 
• 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 
• Terbutaline is not allowed beginning the day prior to Screening 
• Pulmonary rehabilitation programs should not be started or completed during participation 
in the study, although an ongoing maintenance program is acceptable in accordance with 
Exclusion Criterion #9 
• Oxygen therapy and non-selective oral β-blockers are Exclusion Criteria and are not to be 
used at any time during the study 
• Oral mucolytics and ocular β-blockers are allowed 
• All long acting (once or twice daily) bronchodilators (long acting muscarinic antagonists 
[LAMA], long acting β2-agonists [LABA], or combinations with an inhaled steroid) are to 
be discontinued prior to the Screening visit and are not allowed during the study. The 
withhold period prior to Screening is as follows: 
o Once daily bronchodilators – at least 48 hours prior 
o Twice daily bronchodilators – at least 24 hours prior  
• Patients taking LAMAs and LABAs should be placed on short acting bronchodilators 
(e.g. salbutamol/albuterol, ipratropium or Combivent®) as per the discretion of the 
Investigator. These can be dosed on a regularly scheduled basis or as needed.  
• Patients taking inhaled corticosteroids may continue their medication only if the dose is 
stable from at least 4 weeks prior to Screening and is expected to remain stable.  
• 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. Inhaled steroid medication should be procured via prescription for patients 
requiring its use; it will not be supplied by the Sponsor. 
• No scheduled use of salbutamol/albuterol or ipratropium is allowed during the 3-day 
treatment periods; but may be used as a rescue medication (see Section 5.10). 
Salbutamol/albuterol and ipratropium (or Combivent®) must be withheld for at least 8 hours 
prior to spirometry (per below), and this is to be confirmed in the eCRF at the start of each 
treatment period. If this withhold is not met, the patient should be rescheduled for a repeat 
visit within permitted windows. Short acting bronchodilators should be withheld as 
follows: 
o 8 hours prior to pre-reversibility spirometry for Screening 
o 8 hours prior to pre-dose spirometry for Day 1, Day 2 and Day 3 
o Post dose: 
- Day 1 until after +12 hours spirometry 
- Day 2 until after + 12 hours spirometry 
- Day 3 until after + 24 hours spirometry (Day 4 morning) 
If following the above requirements provide inadequate symptom control, patients should 
contact the Investigator.  


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5.9.2 
Other (non-COPD) Prior and Concomitant Medications  
Patients may continue other prescribed non-respiratory therapies during the study that the 
Investigator considers to neither compromise subject safety nor affect study data. Such 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.  
5.10 
Rescue Medications 
Short acting bronchodilators may be used as rescue medication. Rescue medication will be 
sourced by the study center and dispensed at the Screening visit. 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/albuterol is to be used for primary rescue use.  
5.11 
Treatment Compliance 
Study treatment administration will take place at the study center and will be administered by 
the Investigator or designated and trained study center personnel. The precise date and time of 
administrations shall be documented in the eCRF.  
 


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6 
STUDY PROCEDURES AT EACH VISIT 
The study will consist of the following: 
• Screening will take place in the period between 7 and 14 days prior to the first study 
treatment administration. Screening procedures may be performed as a single visit or more 
than one visit. Since the Holter monitor is to be removed after 24 hours, patients will return 
one day after placement. 
• Three treatment periods, each 3 days in duration and separated by 7 to 14 days (from last 
dose of study medication on Day 3 of each treatment period)  
• An end of study visit between 4 and 10 days after the completion of Treatment Period 3 
Eligible patients may be re-screened at the discretion of the Investigator. 
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 1.1 to Section 6.4 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 (prioritized on the timepoint).  


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Table 3 
Overall Schedule of Assessments at Each Visit in RPL554-CO-204 
Procedures 
Screening 
Treatment Periods 1 to 3 
(7 to 14 days between Treatment Periods) 
End of Study 
14 to 7 days before 
Randomization 
Day 1 
Day 2 
Day 3 
Day 4 
 4 – 10 days after Day 4 of 
Treatment Period 3 
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: hematology 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 
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 (nebulizer and Respimat®) 
X 
X 
 
 
 
 
Randomization 
 
X[a] 
 
 
 
 
Tiotropium/olodaterol and RPL554 or placebo dosing 
 
X 
X 
X 
 
 
Pharmacokinetic sampling  
 
 
 
X 
 
 
Dyspnea scale 
 
X 
 
X 
X 
 
Prior/concomitant medications and therapies 
Throughout the study 
Adverse events 
Throughout the study 
Abbreviations: ECG=electrocardiogram 
[a] Treatment Period 1 only  


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Table 4 
Pre-dose and Post-dose Assessments on Each Day of Treatment Periods 1 to 3 in RPL554-CO-204  
Procedures 
Day 1 
Pre-
dose 
0 
5m 
15m 
30m 
1h 
1.25h 
1.5h 
2h 
4h 
6h 
8h 
12h[a] 
Tiotropium/olodaterol dosing by Respimat® 
 
X 
 
 
 
 
 
 
 
 
 
 
 
RPL554 or placebo dosing by nebulization 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Brief physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs  
X 
 
 
 
X 
X 
 
 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
Spirometry 
X[c] 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Inhalation training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Whole body plethysmography 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Randomization [b] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (females of 
childbearing potential) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dyspnea scale 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Adverse events 
 
Throughout 
Abbreviations: ECG=electrocardiogram; h=hours (post-dose); m=minutes (post-dose) 
[a] Post-dose measurements will be taken in relation to the morning dose of tiotropium/olodaterol 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 only 
[c] Performed at 1 hour and immediately pre-dose 
 
NOTE: Table 4 (Days 2 through 4) continues on next two pages.  
 
 


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Procedures 
Day 2 
Pre- 
0 
15m 
30m 
1h 
1.25h 
2h 
3h 
4h 
12h[a] 
Tiotropium/olodaterol dosing by Respimat® 
 
X 
 
 
 
 
 
 
 
 
RPL554 or placebo dosing by nebulization 
 
X 
 
 
 
 
 
 
 
X 
Vital signs  
X 
 
 
X 
X 
 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
X 
 
 
 
Spirometry 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Adverse events  
Throughout 
Abbreviations: ECG=electrocardiogram; h=hour; m=minutes 
[a] 
Post-dose samples will be taken in relation to the morning dose of tiotropium/olodaterol 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 
[a] 
 
Pre- 
0 
5 m 
15m 
30m 
45m 
1h 
1.25h 
1.5h 
2h 
4h 
6h 
8h 
8.25h 
12h 
12.25h 
13 h 
14h 
16 h 
23 h 
24 h 
Tiotropium/olodaterol dosing 
by Respimat® 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RPL554 or placebo dosing by 
nebulization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Brief physical examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X[b] 
Vital signs  
X 
 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
24-hour Holter monitor placed 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spirometry 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Whole body plethysmography 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
Pharmacokinetic samples 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Xc 
 
 
 
 
 
 
Hematology and biochemistry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Dyspnea scale 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse events 
Throughout 
Abbreviations:  ECG=electrocardiogram; h=hour; m=minutes 
[a] Procedures performed prior to discharge from the study center on the morning of Day 4, 12 hours after final RPL554 dosing on Day 3 
[b] Can be performed any time prior to discharge 
[c] Perform pharmacokinetic sample prior to dosing 


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6.1 
Pre-visit Restrictions 
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 1 hour post-dose  
• Patients should refrain from smoking from 1 hour pre-dose, and at least 1 hour before any 
measurement of lung function 
• Patients should refrain from strenuous exercise for 72 hours prior to all study visits and 
should undertake no unaccustomed strenuous exercise from Screening until the end of 
study visit 
6.2 
Screening 
Written informed consent will be obtained by the Investigator as specified in Section 10.3 prior 
to any study related procedures being performed. This typically will need to be performed prior 
to the Screening visit to allow for discontinuation of any prohibited medications (see 
Section 5.9). Screening procedures may be performed over more than 1 day.  
Patients will be screened to determine eligibility against the Inclusion and Exclusion Criteria 
between 7 and 14 days before the first dose of study treatment. There are no fasting 
requirements for the Screening visit. Patients must observe the medication restrictions 
described in Section 5.9.1, and other restrictions described in Section 1.1To account for diurnal 
variability in pulmonary function, the Screening visit is to take place in the morning. 
The following assessments will be performed, generally in the order indicated (to the extent 
feasible):  
• Obtain informed consent (if not done prior to Screening) 
• Recording of demographic information, including height and weight 
• Recording of medical/surgical and disease history 
• Recording of prior medications and therapies 
• Vital signs  
• Full physical examination (see Section 7.4.5) 
• 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-reversibility spirometry 
• Reversibility test (two puffs salbutamol/albuterol followed by two puffs ipratropium) 
• Post-reversibility spirometry (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 monitor 


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• Blood and urine samples for laboratory safety tests (hematology, 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 nebulizer and Respimat®. This will be verbal instruction and 
demonstration of the device 
• Questioning for adverse events 
If the patient meets all of the Inclusion and none of the Exclusion Criteria, he/she will be 
instructed to return in 7 to 14 days for Treatment Period 1, Day 1.  
6.3 
Treatment Periods 1 through 3  
Each treatment period is approximately 72 hours in duration. Patients will stay at the study 
center for the duration of each treatment period. 
Patients must withhold long acting bronchodilators, ipratropium and salbutamol/albuterol (or 
Combivent®) prior to the start of the treatment period as defined in Section 5.9.1. If not, the 
start of the treatment period must be rescheduled so as to occur within the permitted windows. 
All restrictions defined in Section 1.1 should also be adhered to.  
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 randomization number.  
6.3.1 
Day 1 
6.3.1.1 
Pre-Dose Assessments 
The following assessments will be performed prior to dosing: 
• Confirm that respiratory medications were withheld as required  
• Questioning for adverse events 
• Urine pregnancy test (females of childbearing potential only) 
• 12-lead ECG 
• Dyspnea scale  
• Vital signs  
• Brief physical examination (see Section 7.4.5) 
• Spirometry; 1 hour (±5 minutes) and immediately prior to study treatment administration 
• Whole body plethysmography 
• Inhalation training 
6.3.1.2 
Study Treatment Administration 
Patients will be dosed with open label tiotropium/olodaterol 5/5 µg (two inhalations, each 
containing 2.5 µg /2.5 µg), followed immediately (within 2 minutes) with either blinded 
RPL554 or placebo using a nebulizer according to randomization scheme. At 12 hours (±30 
minutes) after the morning dose, the second dose of RPL554 or placebo will be administered 
by nebulization. 


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6.3.1.3 
Post-Dose Assessments (after morning doses only) 
The following assessments will be performed, at the times indicated relative to dosing: 
• Spirometry at 5 (±1) minutes, 15 (±5) minutes, 30 minutes and 1, 1.5, 2, 4, 6, 8 and 12 hours 
(the latter assessments all ±10 minutes) 
• Whole body plethysmography at 1.25 hours (±10 minutes) 
• Vital signs at 30 minutes and 1, 2, 4, 6, 8 and 12 hours (±10 minutes)  
• 12-lead ECGs at 2 and 4 hours (±10 minutes) 
• Dyspnea scale administered at 5 (±1), 15 (±5), and 30 (±10) minutes  
• Questioning for adverse events 
6.3.2 
Day 2 
6.3.2.1 
Pre-Dose Assessments 
The following assessments will be performed prior to dosing: 
• Questioning for adverse events 
• 12-lead ECG 
• Vital signs  
• Spirometry 
6.3.2.2 
Study Treatment Administration 
Patients will be dosed with open label tiotropium/olodaterol 5 µg /5 µg (two inhalations, each 
containing 2.5 µg /2.5 µg) followed immediately (within 2 minutes) with either blinded 
RPL554 or placebo using a nebulizer according to the randomization scheme. At 12 hours (±30 
minutes) after the morning dose, the second dose of RPL554 or placebo will be administered 
by nebulization. 
6.3.2.3 
Post-Dose Assessments (after morning dose only) 
The following assessments will be performed, at the times indicated relative to dosing: 
• 12-lead ECGs at 2 hours (±10 minutes) 
• Vital signs at 30 minutes and 1, 2, 3, 4, 8 and 12 hours (±10 minutes) 
• Spirometry at 15 (±5) and 30 minutes and 1, 2, 3, 4 and 12 hours (the latter assessments all 
±10 minutes) 
• Questioning for adverse events 
6.3.3 
Days 3 to 4 
6.3.3.1 
Pre-Dose Assessments 
The following assessments will be performed prior to dosing: 
• Questioning for adverse events 
• 12-lead ECG 
• Vital signs  


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• Spirometry  
• Whole body plethysmography  
• 24-hour Holter monitor placed 
• Dyspnea scale 
• Blood sample for pharmacokinetics  
6.3.3.2 
Study Treatment Administration 
Patients will be dosed with open label tiotropium/olodaterol 5 µg /5 µg (two inhalations, each 
containing 2.5 µg /2.5 µg) followed immediately (within 2 minutes) with either blinded 
RPL554 or placebo using a nebulizer according to the randomization scheme. At 12 hours (±30 
minutes) after the morning dose, the second dose of RPL554 or placebo will be administered 
by nebulization. 
6.3.3.3 
Post-Dose Assessments 
• 12-lead ECGs at 2 and 24 hours (±10 minutes) 
• Vital signs at 30 minutes and 1, 2, 4, 6, 8 and 24 hours (±10 minutes)   
• Spirometry at 5 (±1), 15 (±5) and 30 minutes and 1, 1.5, 2, 4, 6, 8, 12, 13, 14, 16, 23 and 
24 hours after the morning dose (the latter assessments all ±10 minutes)  
• Whole body plethysmography at 1.25, 8.25 and 12.25 hours (±10 minutes) 
• Dyspnea scale at 5 (±1), 15 (±5), and 30 (±10) minutes and 24 hours (±10 minutes) 
• Questioning for adverse events 
• Blood samples for pharmacokinetics at 5 (±1), 30 and 45 minutes and 1, 1.5, 2, 4, 8 and 12 
hours (the latter assessments all ±10 minutes) 
• Blood sample for laboratory safety tests (hematology and biochemistry) at 24 hours (±10 
minutes) 
• Brief physical examination prior to discharge (Day 4) 
The 24-hour assessments will be performed in the morning on Day 4 prior to discharge from 
the study center. 
Patients will be instructed to return in 7 to 14 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. Early terminated patients should have an End of Study Visit.  
6.4 
End of Study Visit 
The following will be performed: 
• Full physical examination 
• Vital signs  
• Spirometry  
• Blood and urine samples for laboratory safety tests (hematology, biochemistry, urinalysis) 
• Urine pregnancy test (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  7.1.1 to Section 7.4.6. 
7.1.1 
Demographic Variables 
Demographic 
variables, 
including 
date 
of 
birth, 
sex, 
height, 
weight, 
BMI 
(weight [kg]/height [m]2), race and smoking status will be collected at Screening. 
7.1.2 
Medical and Disease History 
All active medical conditions and all surgeries will be recorded at Screening. Disease history, 
including date of diagnosis will also be recorded.  
7.1.3 
Reversibility Test 
Reversibility in response to salbutamol/albuterol will be assessed at Screening as an eligibility 
measure. Spirometry (FEV1 and FVC) assessment before and after two puffs (200 µg) of 
salbutamol/albuterol and two puffs (40 µg) of ipratropium, each 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 ≥30 % and ≤70% of predicted normal* 
• Demonstrates ≥150 mL increase from pre-bronchodilator FEV1  
*National Health and Nutrition Examination Survey (NHANES) III (Hankinson et al, 1999) 
will be used as a reference for normal predicted values. 
7.1.4 
Screening Laboratory Assessments 
At Screening, blood samples will be taken and tested at the laboratory for human 
immunodeficiency virus, hepatitis B and hepatitis C serology. Note: Patients who received a 
hepatitis B vaccination and are positive for hepatitis B surface antibody, but are negative for 
both hepatitis B surface antigen and hepatitis B core antibody, do not need to be excluded from 
the study. 
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 center at Screening.  
Unscheduled and/or repeat testing may be performed at the discretion of the Investigator. 


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7.1.5 
Prior and Concomitant Medications and Therapies 
Prior COPD therapies and medications will be recorded at Screening and concomitant use 
during the study recorded as described in Section 5.9.1.  
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 
Efficacy/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: 1 hour and immediately pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8 and 12 
hours post-dose 
• Day 2: pre-dose; 15 and 30 minutes and 1, 2, 3 4 hours and 12 hours post-dose 
• Day 3: pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8, 12, 13, 14, 16, 23 and 24 hours 
post-dose. 
Post-dose measurements will be taken in relation to the morning dose of tiotropium/olodaterol 
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 center. 
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. 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 and 1.25 hours post-dose on Day 1, 
and pre-dose and 1.25, 8.25 and 12.25 hours post-dose on Day 3 of each treatment period. 
Assessments will be made in accordance with ATS/ERS guidelines, including the use of 
appropriate quality control measures to minimize data variability and error (Wanger et al, 2005; 
see Quality Control section for plethysmography on pp. 514-515). 
Patients will be placed on a body box for plethysmographic determination of lung volumes, to 
include RV and FRC. Additionally, measurements will be made of sGaw. 
 
7.2.3 
Dyspnea Scale 
An 11-point Likert scale will be utilized, which will be anchored from 0: “no shortness of 
breath” to 10: “the worst shortness of breath that you can imagine” (Davis et al., 2006). This 


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scale will be an instantaneous measurement of their dyspnea at that moment, and not reflective.  
It will be administered on Day 1 pre-dose and 5, 15, and 30 minutes post-dose; and on Day 3 
pre-dose and 5, 15, 30 minutes and 24 hours post-dose. 
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, and 12 hours post-dose.  
Samples will be collected by venipuncture or via indwelling cannula in the forearm into lithium 
heparin tubes and will be immediately chilled (ice bath). The blood will be centrifuged within 
15 minutes of collection. The plasma will be separated in a refrigerated centrifuge (about 4°C) 
at 1100g for 15 minutes and transferred into polypropylene tubes. After each blood collection, 
the plasma will be dispensed into two aliquots. After appropriate labelling, the plasma samples 
will be stored at, or below -20°C. The 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  
7.4.1.1 
Adverse Event Definitions 
An adverse event is defined as any undesirable experience occurring to a patient, or worsening 
in a patient, during a clinical study, whether or not considered related to the study medication. 
An adverse event may be any of the following: 
• A new illness 
• An exacerbation of a sign or symptom of the underlying condition under treatment or of a 
concomitant illness 
• Unrelated to participation in the clinical study or an effect of the study medication 
• A combination of one or more of the above factors 
No causal relationship with the study medication is implied by the use of the term “adverse 
event.” An exacerbation of a pre-existing condition or illness is defined as a more frequent 
occurrence or as an increase in the severity of the pre-existing condition or illness during the 
study. Planned or elective surgical or invasive procedures for pre-existing conditions that have 
not worsened are not adverse events. However, any complication that occurs during a planned 
or elective surgery is an adverse event (if the event fits the serious criteria, such as an extended 
hospitalization, it will be considered to be serious). Conditions leading to unplanned surgical 
procedures may be adverse events. 
An adverse reaction is defined as all untoward and unintended responses to study medication 
related to any dose administered. 
A serious adverse event (SAE) is any adverse experience that: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity, OR 


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• Is a congenital anomaly/birth defect 
• Other medical events* 
*Important medical events that may not be immediately life-threatening or result in death or 
hospitalization may be considered a SAE when, based on appropriate medical judgement, they 
may jeopardize the patient or may require medical or surgical intervention to prevent one of 
the outcomes listed above. 
An unexpected adverse reaction is an adverse reaction in which the nature or severity of which 
is not consistent with the Investigator Brochure. 
A suspected unexpected serious adverse reactions (SUSAR) is any suspected adverse reaction 
related to the study medication that is both unexpected and serious. 
Standard procedures for emergency care should be followed for any individual adverse event, 
whenever clinically needed (decision to be taken by the Investigator). 
7.4.1.2 
Recording and Assessing Adverse Events 
All adverse events, whether reported spontaneously by the patient, in response to open 
questioning on treatment days or observed by the Investigator or his/her staff, will be recorded 
from informed consent until the end of study visit. The start and stop time will be recorded and 
adverse events will be assessed by the Investigator for the following: 
7.4.1.2.1 
Severity 
Mild:  
Resolved without treatment 
Moderate: 
Resolved or was tolerated with specific treatment without affecting study 
activities 
Severe: 
Did not resolve or was not tolerated with treatment 
7.4.1.2.2 
Chronicity 
Single occasion: 
Single event with limited duration 
Intermittent:  
Several episodes of an event, each of limited duration 
Persistent: 
 
Event which remained indefinitely 
7.4.1.2.3 
Causality 
The Investigator will assess causal relationship between the study medication and each adverse 
event, and answer "yes" or "no" to the question, "Do you consider that there is a reasonable 
possibility that the event may have been caused by the study medication?" 
For SAEs, causal relationship will also be assessed for study procedures, additional study 
medication, and other medication. Note that for SAEs that could be associated with any study 
procedure, the causal relationship is implied as "yes". 
A guide to the interpretation of the causality question is found in Section 14.3. 
7.4.1.2.4 
Action and Outcome 
• Action taken with study medication (none, study medication stopped, study medication 
temporarily interrupted) 


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• Other actions (none, concomitant medication, study discontinuation, hospitalization, other) 
• The outcome and date of outcome according to the following definitions: 
- 
Recovered or resolved (adverse event disappeared) 
- 
Recovering or resolving (patient is recovering) 
- 
Not recovered or not resolved (adverse event remains without signs of 
improvement) 
- 
Recovered or resolved with sequelae (adverse event has resulted in permanent 
disability or incapacity) 
- 
Fatal 
- 
Unknown (only applicable if patient has been lost to follow-up) 
• Seriousness (yes or no) 
7.4.1.3 
Reporting Procedure for SAEs 
The Investigator must report all SAEs to the Sponsor as soon as practical, but in call cases 
within 24 hours of awareness. Any fatal SAEs notified in the 28-day period after the last dose 
of study drug must also be reported 
SUSARs will be determined by the Sponsor’s Medical Monitor. 
SAEs will be reported to the ethics committee(s)/institutional review board(s) and regulatory 
authority(is) according to local requirements. 
All adverse events will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical procedures 
as indicated, and/or referral to the patient’s general physician or a medical specialist. 
It is the responsibility of the Investigator to ensure that any necessary additional therapeutic 
measures and follow-up procedures are performed. 
7.4.2 
Pregnancy 
All female patients of childbearing potential will have a serum pregnancy test at Screening. 
Samples will be taken and handled according to the laboratory manual and analyzed at an 
approved central laboratory. 
Urine pregnancy tests will also be performed by the study center 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. 
Should a female patient become pregnant, or if a male patient fathers a child during the study 
or in the 30 days after the end of the study, the Investigator must be informed immediately. 
The Investigator will report this information to the Sponsor within 7 days of awareness. The 
Investigator will make all reasonable efforts to ascertain the progress and outcome of the 
pregnancy. If the outcome meets the criteria for immediate classification of a SAE 
(e.g. spontaneous or therapeutic abortion, stillbirth, neonatal death, congenital anomaly, birth 
defect), the Investigator must follow the procedure for reporting SAEs. 
7.4.3 
Laboratory Safety Assessments 
In addition to the laboratory tests detailed in Section 7.4.3.1 to Section 7.4.3.3, 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 


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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 analyzed at an 
approved central laboratory. 
7.4.3.1 
Hematology  
The following will be measured at Screening, on Day 4 of each treatment period and at the end 
of study visit: Hemoglobin, hematocrit, 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).  
7.4.3.2 
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.  
Additionally, follicle-stimulating hormone (FSH) will be measured at Screening, where 
appropriate, to confirm post-menopausal status.  
At each timepoint, a sample of venous blood will be collected in a vacutainer collection tube.  
7.4.3.3 
Urinalysis 
A midstream urine sample will be collected in a sterile container at Screening and at the end of 
study visit. The following will be tested: leucocytes, blood, ketones, bilirubin, urobilinogen, 
protein and glucose.  
If urinalysis on Dipstick is positive for leucocytes and/or blood/hemoglobin, a microscopic 
examination including erythrocytes, leucocytes, bacteria, casts, epithelial cells and crystals will 
be performed. 
7.4.4 
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: 
• 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/olodaterol 
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 center. 
At each timepoint, supine vital signs will be assessed whilst the patient has been at rest for at 
least 5 minutes. 


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7.4.5 
Physical Examination 
A full physical examination, covering major body systems (assessments of the nose, throat, 
skin, thyroid gland, neurological system, respiratory system, cardiovascular system, abdomen 
[liver and spleen], lymph nodes and extremities) will be performed at Screening. Results will 
be recorded in the eCRF as normal, abnormal not clinically significant or abnormal clinically 
significant and abnormal results described. The full physical examination will be repeated at 
the end of study visit, and any changes only recorded. 
A brief physical examination, including assessments of the skin, respiratory system, 
cardiovascular system, and abdomen (liver and spleen). will be performed pre-dose on Day 1 
and prior to discharge from the study center on Day 4. 
7.4.6 
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 and 2 and 4 hours post-dose 
• Day 2: pre-dose and 2 hours post-dose 
• Day 3: pre-dose and 2 and 24 hours post-morning dose 
Post-dose measurements will be taken in relation to the morning dose of tiotropium/olodaterol 
and RPL554 or placebo. The 24-hour measurement at the end of each treatment period will be 
taken in the morning on Day 4 prior to discharge from the study center. 
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.  
7.4.7 
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 center 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 Randomization.  
A Holter monitor will also be placed at least 30 minutes pre-dose on Day 3 of each treatment 
period and removed on Day 4. 
Holter readings will be sent to a central vendor for interpretation. 
 
 
 


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8 
QUALITY ASSURANCE AND QUALITY CONTROL 
The study will be conducted in accordance with the current approved protocol, standard 
operating procedures (SOPs) and all applicable guidelines and requirements (see Section 10). 
8.1 
Audit and Inspection  
The Sponsor, or its designee may conduct a quality assurance audit. An inspection of this study 
may also be carried out by regulatory authorities at their discretion. Such audits or inspections 
can occur at any time during or after completion of the study. If an audit or inspection occurs, 
the Investigator and institution agree to allow the auditor/inspector direct access to all relevant 
documents and to allocate his time and the time of his staff to the auditor or inspector to discuss 
findings and any relevant issues. 
8.2 
Monitoring and Source Document Verification 
The study will be monitored by a monitor approved by the Sponsor. During these visits, all 
procedures will be monitored for compliance with the protocol. Source documents will be 
reviewed and compared with the data entries in the eCRFs to ensure consistency.  The Sponsor 
will ensure that the study is monitored in accordance with the principles of ICH GCP. The 
frequency of monitoring visits will be determined, in part, by the rate of patient recruitment. 
The following are examples of items that will be reviewed at these visits: 
• Compliance with the protocol 
• Consent procedure 
• Source documents 
• Adverse event procedures 
• Storage and accountability of materials 
The monitoring visits also provide the Sponsor with the opportunity to ensure that timely 
patient accrual and the other Investigator’s obligations and all applicable requirements are 
being fulfilled. 
The Investigator must permit the study monitor, the 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. 
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 
clinical examinations or clinically relevant adverse events/medication changes, SAEs and 
information on patient withdrawal 


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


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concomitant medications will be coded according to the World Health Organisation drug code. 
An independent coding review will be performed by the Sponsor. 
The clinical database (in Statistical Analysis System [SAS] format) will be transferred to the 
Sponsor at the end of the study.  
 
 


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9 
STATISTICAL METHODS 
9.1 
Statistical and Analytical Plans 
This section presents a summary of the planned statistical analyses. A detailed plan describing 
the analyses to be conducted will be defined before the 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. 
9.2 
Populations to be Analyzed 
Allocation of patients to the analysis populations (and whether any patients or specific data 
from a patient will be excluded) will be determined at the pre-database lock meeting. 
The full analysis set will consist of all randomized 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 randomized patients that 
complete all treatment periods. 
The safety set will consist of all randomized patients who took at least one dose of study 
treatment during at least one visit.  
The pharmacokinetic data set will consist of all randomized patients with blood sampling 
performed after at least one dose of RPL544 and with data sufficient to calculate 
pharmacokinetic parameters. 
9.3 
Study Endpoints  
9.3.1 
Primary Endpoint 
The primary endpoint is peak FEV1 (measured in first 4 hours after morning dosing). This will 
be measured after dosing on Day 3. 
The primary comparisons are RPL554 6mg + tiotropium/olodaterol vs RPL554 placebo + 
tiotropium/olodaterol, followed by RPL554 1.5 mg + tiotropium/olodaterol vs RPL554 placebo 
+ tiotropium/olodaterol. 
9.3.2 
Secondary Endpoints 
• 
Change from baseline in trough FEV1 on Day 4 (mean of -1 and 0 time prior to dosing) 
• 
Determination of AUC0-4h FEV1 after morning dosing on Day 3 
• 
Peak FEV1 (measured in first 4 hours after dosing) and AUC0-12h FEV1. These will be 
measured after dosing on Day 1 
• 
Change from baseline in AUC0-12h FEV1 measured on Day 3 
• 
Change from pre-evening dose FEV1 on Day 3 (peak over 4 hours) 
• 
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 on Day 1 and 1.25, 8.25 and 12.25 hours after dosing 
on Day 3 
• 
RPL554 steady state pharmacokinetics (AUC, Cmax, time to maximum concentration 
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• 
Safety and tolerability: 
− 
Continuous monitoring of adverse events 
− 
Laboratory safety tests [hematology, biochemistry and urinalysis] 
− 
12-lead ECG (including 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 
9.3.3 
Exploratory Endpoints 
• 
AUC0-24h FEV1 on Day 3 
• 
Change from baseline in Likert dyspnea scale 
9.4 
Statistical Methods 
In general, unless stated otherwise, continuous variables will be summarized using descriptive 
statistics (number of patients, mean, standard deviation, median, minimum and maximum 
values) and for categorical (nominal) variables, the number and percentage of patients will be 
used.  
All hypothesis testing will be done using two-sided alternative hypotheses. P-values less than 
5% will be considered statistically significant.  
9.4.1 
Patient Disposition 
The number of patients enrolled, randomized, completed or withdrawn (with reason for 
withdrawal) will be summarized. 
9.4.2 
Protocol Deviations 
All protocol deviations collected will be divided into critical, major or minor categories. Prior 
to database lock protocol deviations will be reviewed and consequences for inclusion of 
patients in various analysis population sets determined and documented. 
9.4.3 
Demographics and Other Baseline Characteristics 
Demographics and baseline characteristics (including pre- and post-bronchodilator FEV1 [both 
in liters and in percentage of predicted normal], post-bronchodilator FEV1/FVC, FEV1 
reversibility, duration of COPD [time since diagnosis], smoking habits including number of 
pack years, number of patients taking COPD medications by therapeutic class) will be listed 
and summarized 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. 
9.4.4 
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 nebulizer cup. 


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9.4.5 
Efficacy/Pharmacodynamics  
FEV1 and FVC will be summarized 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. The average effect will be calculated as the AUC divided by the 
length of the time interval of interest. For analysis, the peak, average and trough FEV1 will be 
divided by the pre-dose Day 1 baseline value.  
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 pre-dose Day 1 baseline value as a covariate. FEV1 will be 
analyzed using multiplicative models, which means that data (dependent and baseline) are 
logged prior to analysis and the result then transformed back to the linear scale giving treatment 
differences as ratios of geometric means.  
Primarily the combination RPL554+tiotropium/olodaterol will be compared to tiotropium/ 
olodaterol 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 summarized 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 1 and 1.25, 
8.25 and 12.25 hours post-dose on Day 3 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 summarized by treatment, and, if 
appropriate, a Kaplan-Meier plot illustrating time to first use of rescue constructed. 
9.4.6 
Pharmacokinetics 
The following steady state pharmacokinetic parameters will be calculated from plasma 
concentrations of RPL554 using standard non-compartmental methods. 
• AUC0-12h represents the area under the plasma concentration curve from time 0 to 12 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 
Pharmacokinetic parameters will be summarized by dose level using descriptive statistics (n, 
geometric mean, coefficient of variation (CV), minimum, maximum and median for AUC 
parameters, Cmax, n, arithmetic mean, standard deviation, minimum, maximum and median for 
tmax).  
9.4.7 
Safety  
Safety data including safety laboratory tests, 12-lead ECG and Holter parameters, vital signs 
and physical examinations, will be summarized by treatment group and time point of collection, 
when appropriate. For continuous variables, the change from baseline (pre-dose at each 
treatment period) to each post-dose time point will also be calculated and summarized. Data 
will further be illustrated by shift tables (showing changes from low/normal/high) and shift 


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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 summarized 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 
summarized by SOC and preferred term.   
9.4.8 
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 
summarized. Any unscheduled or unplanned readings will be presented within the patient 
listings, but only the scheduled readings will be used in any summaries. If a visit is rescheduled 
due to variability in FEV1 or other reason, the rescheduled visit will be listed and summarized 
as the valid visit. 
9.4.9 
Interim Analyses 
No formal interim analysis is planned for the study. 
9.5 
Determination of Sample Size 
This is a complete block three-way crossover study. Assuming a residual CV of 6% for peak 
FEV1, 70 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 liters this will correspond to a difference of about 
50 mL.  
 


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10 
ETHICAL CONSIDERATIONS 
10.1 
Guidelines 
The study will be performed in accordance with ICH GCP guidelines, the principles outlined 
in the Declaration of Helsinki (1996), the protocol and applicable regulatory requirements. 
10.2 
Ethics and Regulatory Approval 
The Sponsor will supply all background data necessary to enable submission to the appropriate 
ethics committees and regulatory authorities. The study will not commence before formal 
ethical and regulatory approvals have been granted. 
All changes or revisions of this protocol will be documented. The reason for the amendment 
will be stated. The Sponsor will ensure ethical and regulatory approval is obtained for all 
substantial amendments to the original approved documents. 
10.3 
Informed Consent Process 
It is the responsibility of the Investigator to obtain written informed consent from patients. All 
consent documentation must be in accordance with applicable regulations and GCP. Each 
patient is requested to sign and date the informed consent form after (s)he has received and 
read the patient information sheet and received an explanation of what the study involves, 
including but not limited to: the objectives, potential benefits and risk, inconveniences and the 
patient’s rights and responsibilities. Patients will be given adequate time to evaluate the 
information given to them before signing the informed consent form. 
One original of the signed informed consent form must remain on file and must be available 
for verification by the study monitor at any time. A second original of the informed consent 
form plus the patient information sheet must be given to the patient or the patient’s legally 
authorized representative. 
10.4 
Patient Confidentiality 
Data collected during this study may be used to support the development, registration or 
marketing of the study medication. The Sponsor will control all data collected during the study 
and will abide by the European Union Directive on Data Privacy concerning the processing 
and use of patient’s personal data. For the purpose of data privacy legislation, the Sponsor will 
be the data controller. 
After patients have consented to take part in the study, their medical records and the data 
collected during the study will be reviewed by the Sponsor and/or its representatives. These 
records and data may, in addition, be reviewed by the following: independent auditors who 
validate the data on behalf of the Sponsor; regulatory authorities and the 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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10.5 
Record Maintenance/Retention 
The Investigator will retain the originals of all source documents generated at the location 
where the study is being conducted, either: 1) until after regulatory agency approval is obtained 
for the study medication in the country/countries in which the results of this study comprise 
the submission dossier, or 2) for a period of 2 years after the report of the study has been 
finalized, in the absence of a regulatory approval. After that time, all study-related documents 
will be archived according to GCP regulations. 
 
 


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


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


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13 
REFERENCES 
Abbott-Banner KH, Page CP. Dual PDE3/4 and PDE4 inhibitors: novel treatments for COPD 
and other inflammatory airway diseases. Basic Clin Pharmacol Toxicol. 2014 
May;114(5):365-376. Doi: 10.1111/bcpt.12209. Epub 2014 Mar 6. 
Bjermer L, Stewart J, Abbott-Banner KH et al. RPL554, a first-in-class dual PDE3/4 inhibitor 
is equi-effective as a bronchodilator to maximal doses of salbutamol in asthmatics but with 
fewer adverse events. Am J Resp Crit Care Med 2016;193:A7770. 
Calverley PM, Sanchez-Toril F, McIvor A et al. Effect of 1-year treatment with roflumilast in 
severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 
176(2):154-161. 
Calzetta L, Page CP, Spina D, et al. The effect of the mixed phosphodiesterase 3/4 inhibitor 
RPL554 on human isolated bronchial smooth muscle tone. J Pharmacol Exp Ther 2013; 346: 
414–423. 
Calzetta L, Cazzola M, Page CP, et al. Pharmacological characterization of the interaction 
between the dual phosphodiesterase (PDE) 3/4 inhibitor RPL554 and glycopyrronium on 
human isolated bronchi and small airways. Pulm Pharmacol Ther 2015 Apr 18. pii: 
S1094-5539(15)00042-5.  
Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of 
patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J, 2004; 
2:932-946. 
Compton CH, Gubb J, Nieman R et al. Cilomilast, a selective phosphodiesterase-4 inhibitor 
for treatment of patients with chronic obstructive pulmonary disease: a randomized, 
dose-ranging study. Lancet 2001; 358(9278):265-270. 
Davis AH, Carrieri-Kohlman V, Janson SL et al. Effects of treatment on two types of 
self-efficacy in people with chronic obstructive pulmonary disease. J Pain Symptom Manage 
2006; 32(1):60-70. 
EU Directive 95/46/EC: The Data Protection Directive. 
Franciosi LG, Diamant Z, Banner KH, et al. Efficacy and safety of RPL554, a dual PDE3 and 
PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive 
pulmonary disease: findings from four clinical trials. Lancet Respiratory Medicine 2013; 
1(9):714-727. 
Gamble E, Grootendorst DC, Brightling CE et al. Anti-inflammatory effects of the 
phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am 
J Respir Crit Care Med 2003; 168(8):976-982. 
Grootendorst D, Gauw SA, Verhoosel RM, et al. Reduction in sputum neutrophil and 
eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007; 
62(12); 1081-1087. 
Hankinson JL, Odencrantz JR, Fedan KB. Spirometry reference values from a sample of the 
general U.S. Population. Am J Respir Crit Care 1999;159:179-187. 
Harbinson PL, MacLeod D, Hawksworth R et al. The effect of a novel orally active selective 
PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects. Eur 
Respir J 1997;10(5):1008-1014. 


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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. 
Rabe KF, Bateman ED, O'Donnell D, et al. Roflumilast--an oral anti-inflammatory treatment 
for chronic obstructive pulmonary disease: a randomized controlled trial. Lancet 2005; 
366(9485):563-571. 
Recommendations related to contraception and pregnancy testing in clinical trials.  Clinical 
Trial Facilitation Group, Heads of Medicines Agencies, 2014. Downloaded from: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
Rennard SI, Schachter N, Strek M, et al. Cilomilast for COPD: results of a 6-month placebo 
controlled study of a potent, selective inhibitor of phosphodiesterase 4. Chest 
2006;129(1):56-66. 
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, February 2017.  
Verona Pharma plc RPL554 Investigational Medicinal Product Dossier current version. 
Verona Pharma plc.  RPL554-007-2014 Clinical Study Report, August 2016. 
Verona Pharma plc.  RPL554-009-2015 Clinical Study Report (February 2017). 
Verona Pharma plc.  RPL554-010-2015 Clinical Study Report (in preparation). 
Verona Pharma plc.  RPL554-PK-101 Clinical Study Report (December 2017). 
Verona Pharma plc.  RPL554-CO-202 Clinical Study Report (in preparation). 
Verona Pharma plc.  RPL554-CO-203 Clinical Study Report (in preparation). 
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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14 
APPENDICES 
14.1 
Birth Control Methods For Women of Childbearing Potential Which May 
Be Considered As Highly Effective 
(Adapted from the Clinical Trial Facilitation Group, Heads of Medicines Agencies, 2014)  
 
I. 
Definitions 
Woman of Childbearing Potential  
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered women of childbearing potential: 
1. 
Premenopausal female with one of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note: Documentation can come from the study center staff’s: review of participant’s 
medical records, medical examination, or medical history interview. 
2. 
Premenarchal 
3. 
Postmenopausal female 
Females who are postmenopausal (age-related amenorrhea ≥ 12 consecutive months and 
increased FSH >40 mIU/mL), or who have undergone hysterectomy or bilateral 
oophorectomy are exempt from pregnancy testing. If necessary to confirm 
postmenopausal status, an FSH will be drawn at Screening. 
Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the non-hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
II. 
Methods 
For the purpose of this guidance, methods that can achieve a failure rate of less than 1% per 
year when used consistently and correctly are considered as highly effective birth control 
methods. Such methods include: 
• Combined (oestrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
- 
Oral 
- 
Intravaginal 
- 
Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation1: 
- 
Oral 


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


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14.2 
Tiotropium/Olodaterol Prescribing Highlights and Instructions for Use 
Note: The information below is excerpted from the US package insert for tiotropium/ 
olodaterol. Full prescribing information in the US is available at:  
http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Stiolto%20Respimat/stiolto.pdf 
Full prescribing information in the UK is available at: 
http://www.spioltorespimatpi.uk 
 
 
 
 


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Instructions for Use 
Tiotropium bromide and olodaterol inhalation spray 
In the US:  STIOLTO® RESPIMAT®  (sti-OL-to-RES peh mat)   
(default name used below) 
In the UK:  SPIOLTO® RESPIMAT®  (spi-OL-to-RES peh mat) 
 
For Oral Inhalation Only 
Do not spray STIOLTO RESPIMAT into your eyes. 
 
Read these Instructions for Use before you start using STIOLTO RESPIMAT and each time you 
get a refill. There may be new information. This leaflet does not take the place of talking to your 
doctor about your medical condition or your treatment. 
You will need to use this inhaler ONCE A DAY, at the same time each day. Each time you use it 
take TWO PUFFS. 
 
Do not turn the clear base before inserting the cartridge. 
 
How to store your STIOLTO RESPIMAT inhaler 
• Store STIOLTO RESPIMAT at room temperature 68°F to 77°F (20°C to 25°C). 
• Do not freeze your STIOLTO RESPIMAT cartridge and inhaler. 
• If STIOLTO RESPIMAT has not been used for more than 3 days, release 1 puff towards 
the ground. 
• If STIOLTO RESPIMAT has not been used for more than 21 days, repeat steps 4 to 6 under 
the “Prepare for first use” until a mist is visible. Then repeat steps 4 to 6 three more times. 
• Keep your STIOLTO RESPIMAT cartridge and inhaler out of the reach of children. 
How to care for your STIOLTO RESPIMAT inhaler 
• Clean the mouthpiece, including the metal part inside the mouthpiece, with a damp cloth or 
tissue only, at least once a week. Any minor discoloration in the mouthpiece does not affect 
your STIOLTO RESPIMAT inhaler. 
When to get a new STIOLTO RESPIMAT inhaler 
• Your inhaler contains 60 puffs (30 doses) if used as indicated (2 puffs once daily). If you have 
a sample, your inhaler contains 28 puffs (14 doses) if used as indicated (2 puffs once daily). 


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• The dose indicator shows approximately how much medicine is left. 
• When the dose indicator enters the red area of the scale you need to get a refill; there is 
approximately medicine for 7 days left (if you have a sample, there is approximately 
medicine for 3 days left). 
• When the dose indicator reaches the end of the red scale, your STIOLTO RESPIMAT is 
empty and automatically locks. At this point, the clear base cannot be turned any 
further. 
• Three months after insertion of cartridge, throw away the STIOLTO RESPIMAT even if it has not 
been used, or when the inhaler is locked, or when it expires, whichever comes first. 
 
Prepare for first use  
1.  Remove clear base 
• 
Keep the cap closed. 
• 
Press the safety catch while firmly 
pulling off the clear base with your other 
hand. Be careful not to touch the 
piercing element. 
• 
Write the discard by date on the label 
(3 months from the date the cartridge 
is inserted). 
 
 
2.  Insert cartridge 
• 
Insert the narrow end of the 
cartridge into the inhaler. 
• 
Place the inhaler on a firm surface and 
push down firmly until it clicks into place. 
 
 
3.  Replace clear base 
• 
Put the clear base back into place until it 
clicks. 
• 
Do not remove the clear base or the 
cartridge after it has been put 
together. 
 
4. Turn 
• 
Keep the cap closed. 
• 
Turn the clear base in the direction of 
the arrows on the label until it clicks 
(half a turn). 
 
5. Open 
• 
Open the cap until it snaps fully open. 
 


R P L 5 5 4 -C O -2 0 4  
Ve rsi o n 1. 0  
 
 
2 8 M a y 2 0 1 8  
Ve r o n a P h ar m a plc  
C O N FI D E N TI A L  
P a ge 6 4  of 6 6  
6.  P r e s s  
•  
P oi nt t h e i n h al er t o w ar d t h e gr o u n d. 
•  
Pr e s s t h e d o s e - r el e a s e b utt o n. 
•  
Cl o s e t h e c a p.  
•  
If y o u d o n ot s e e a mi st, r e p e at st e p s 4 
t o 6 u ntil a mi st i s s e e n. 
•  
Aft er a mi st i s s e e n, r e p e at st e p s 
4 t o 6 t hr e e m or e ti m e s.  
•  
Aft er c o m pl et e pr e p ar ati o n of y o ur 
i n h al er, it will b e r e a d y t o d eli v er t h e 
n u m b er of p uff s o n t h e l a b el.  
 
 
 
 
 
D ail y u s e ( T O P ) 
 
T u r n  
•  
K e e p t h e c a p  cl o s e d.  
•  
T u r n t h e cl e ar b a s e i n t h e dir e cti o n of t h e 
arr o w s o n t h e l a b el u ntil it cli c k s ( h alf a  
t ur n). 
 
O p e n  
•  
O p e n t h e c a p u ntil it s n a p s f ull y o p e n. 
 
P r e s s  
 
Br e at h e o ut sl o wl y a n d  f ull y. 
 
Cl o s e y o ur li p s ar o u n d t h e m o ut h pi e c e 
wit h o ut c o v eri n g t h e air v e nt s.  
 
P oi nt t h e i n h al er t o t h e b a c k of y o ur 
t hr o at. 
 
W hil e t a ki n g a sl o w, d e e p br e at h t hr o u g h 
y o ur m o ut h, P r e s s t h e d o s e- r el e a s e 
b utt o n a n d c o nti n u e t o br e at h e  i n. 
 
H ol d y o ur br e at h f or 1 0 s e c o n d s  or f or a s 
l o n g a s c o mf ort a bl e.  
 
R e p e at T u r n, O p e n, P r e s s  ( T O P )  
f or a t ot al of 2 p uff s. 
 
Cl o s e t h e c a p u ntil y o u u s e y o ur 
i n h al er a g ai n.  
 
 
  
 
A n s w e r s t o C o m m o n Q u e s ti o n s  
I t i s diffi c ul t t o i n s e r t t h e c a r t ri d g e d e e p e n o u g h:  
Di d  y o u  a c ci d e n t all y  t u r n  t h e  cl e a r  b a s e  b ef o r e  i n s e r ti n g  t h e  c a r t ri d g e ? O p e n t h e c a p, 
pr e s s t h e d o s e - r el e a s e b utt o n, t h e n i n s ert t h e c artri d g e.  


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Did you insert the cartridge with the wide end first? Insert the cartridge with the narrow end 
first. 
I cannot press the dose-release button: 
Did you turn the clear base? If not, turn the clear base in a continuous movement until it clicks 
(half a turn). 
Is the dose indicator on the STIOLTO RESPIMAT pointing to zero? The STIOLTO RESPIMAT 
inhaler is locked after 60 puffs (30 doses). If you have a sample, the STIOLTO RESPIMAT inhaler is 
locked after 28 puffs (14 doses). Prepare and use your new STIOLTO RESPIMAT inhaler. 
I cannot turn the clear base: 
Did you turn the clear base already? If the clear base has already been turned, follow steps 
“Open” and “Press” under “Daily use” to get your medicine. 
Is the dose indicator on the STIOLTO RESPIMAT pointing to zero? The STIOLTO 
RESPIMAT inhaler is locked after 60 puffs (30 doses). If you have a sample, the STIOLTO 
RESPIMAT inhaler is locked after 28 puffs (14 doses). Prepare and use your new STIOLTO 
RESPIMAT inhaler. 
 
The dose indicator on the STIOLTO RESPIMAT reaches zero too soon: 
Did you use STIOLTO RESPIMAT as indicated (2 puffs once daily)? STIOLTO RESPIMAT 
will deliver 60 puffs and last 30 days if used at 2 puffs once daily. If you have a sample, STIOLTO 
RESPIMAT will deliver 28 puffs and last 14 days if used at 2 puffs once daily. 
Did you turn the clear base before you inserted the cartridge? The dose indicator counts 
each turn of the clear base regardless whether a cartridge has been inserted or not. 
Did you spray in the air often to check whether the STIOLTO RESPIMAT is working? 
Once you have prepared STIOLTO RESPIMAT, no test-spraying is required if used daily. 
Did you insert the cartridge into a used STIOLTO RESPIMAT? Always insert a new cartridge 
into a NEW STIOLTO RESPIMAT. 
My STIOLTO RESPIMAT sprays automatically: 
Was the cap open when you turned the clear base? Close the cap, then turn the clear base. 
Did you press the dose-release button when turning the clear base? Close the cap, so 
the dose-release button is covered, then turn the clear base. 
Did you stop when turning the clear base before it clicked? Turn the clear base in a 
continuous movement until it clicks (half a turn). 
My STIOLTO RESPIMAT doesn’t spray: 
Did you insert a cartridge? If not, insert a cartridge. 
Did you repeat Turn, Open, Press (TOP) less than three times after inserting the 
cartridge? Repeat Turn, Open, Press (TOP) three times after inserting the cartridge as shown in 
steps 4 to 6 under “Prepare for first use”. 
Is the dose indicator on the STIOLTO RESPIMAT pointing to 0? You have used up all your 
medicine and the inhaler is locked. 
For more information about STIOLTO RESPIMAT or a video demonstration on how to use STIOLTO RESPIMAT, go to 
www.stiolto.com. You may also call 1-800- 542-6257 or (TTY) 1-800-459-9906 for further information about STIOLTO  RESPIMAT. 
This Medication Guide and Instructions for Use has been approved by the U.S. Food and Drug Administration. 
Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877 USA 
SPIRIVA
®
, HANDIHALER
®
, STIOLTO
® and RESPIMAT
® are registered trademarks and are used under license from Boehringer 
Ingelheim International GmbH. 
Copyright © 2016 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED.  Revised: June 2016 


RPL554-CO-204 
Version 1.0 
 
 
28 May 2018 
Verona Pharma plc 
CONFIDENTIAL  
Page 66 of 66 
14.3 
Interpreting Adverse Event Causality  
The following factors should be considered when deciding if there is a “reasonable possibility” 
that an adverse event may have been caused by the study medication. 
• Time Course. Exposure to suspect study medication. Has the subject actually received the 
suspect study medication? Did the adverse event occur in a reasonable temporal 
relationship to the administration of the suspect study medication? 
• Consistency with known study medication profile. Was the adverse event consistent with 
the previous knowledge of the suspect study medication (pharmacology and toxicology) or 
drugs of the same pharmacological class? OR Could the adverse event be anticipated from 
its pharmacological properties? 
• Dechallenge experience. Did the adverse event resolve or improve on stopping or reducing 
the dose of the suspect study medication? 
• No alternative cause. The adverse event cannot be reasonably explained by another etiology 
such as the underlying disease, other drugs, other host or environmental factors 
• Rechallenge experience. Did the adverse event reoccur if the suspected study medication 
was reintroduced after having been stopped Laboratory tests. A specific laboratory 
investigation (if performed) has confirmed the relationship? 
A "reasonable possibility" could be considered to exist for an adverse event where one or more 
of these factors exist. 
In contrast, there would not be a "reasonable possibility" of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course, but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause of 
the adverse events. 
In difficult cases, other factors could be considered such as: 
• Is this a recognized feature of overdose of the study medication? 
• Is there a known mechanism? 
Ambiguous cases should be considered as being a "reasonable possibility" of a causal 
relationship unless further evidence becomes available to refute this. Causal relationship in 
cases where the disease under study has deteriorated due to lack of effect should be classified 
as no reasonable possibility. 
 

SAP_001.pdf: 
 
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STATISTICAL ANALYSIS PLAN 
 
 
RPL554-CO-204 
A Phase II, Randomized, Double Blind, Placebo Controlled, Three Way 
Crossover Study to Assess the Bronchodilator Effect of RPL554 
Administered in Addition to Open Label Tiotropium/Olodaterol in 
Patients with COPD 
 
 
 
 
 
AUTHOR: NICHOLAS ROUBINIS 
VERSION NUMBER AND DATE: V1.0, 18OCT2018 
 


 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V1.0 (Dated 18OCT2018) for Protocol RPL554-CO-204. 
 
 
Name 
Signature 
Date 
Author: 
Nicholas Roubinis 
 
 
 
Position: 
Senior Biostatistician 
 
Company: 
IQVIA 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
Ruaan Van Zyl 
 
 
 
Position: 
Manager, Biostatistics 
 
Company: 
IQVIA 
 
Approved By: 
Brian Maurer 
 
 
 
Position: 
Senior Director, Clinical Operations 
 
Company: 
Verona Pharma 


 
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MODIFICATION HISTORY 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
1.0 
18OCT2018 
Nicholas Roubinis 
Not Applicable – First Version 
 
 
 


 
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TABLE OF CONTENTS 
1. 
INTRODUCTION............................................................................................................... 9 
2. 
STUDY OBJECTIVES ....................................................................................................... 9 
2.1. 
Primary Objective ........................................................................................................................................... 9 
2.2. 
Secondary Objectives ...................................................................................................................................... 9 
2.3. 
Exploratory Objectives ................................................................................................................................. 10 
3. 
STUDY DESIGN ............................................................................................................... 10 
3.1. 
General Description ....................................................................................................................................... 10 
3.2. 
Schedule of Events ......................................................................................................................................... 12 
3.3. 
Changes to Analysis from Protocol .............................................................................................................. 12 
4. 
PLANNED ANALYSES ................................................................................................... 12 
4.1. 
Data Monitoring Committee (DMC) ............................................................................................................ 13 
4.2. 
Interim Analysis ............................................................................................................................................. 13 
4.3. 
Final Analysis ................................................................................................................................................. 13 
5. 
ANALYSIS SETS.............................................................................................................. 14 
5.2. 
All Patients Randomized Set [RND] ............................................................................................................ 14 
5.3. 
Safety Analysis Set [SAF] .............................................................................................................................. 14 


 
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5.4. 
Full Analysis Set [FAS] ................................................................................................................................. 14 
5.5. 
Completers Analysis Set [CAS] .................................................................................................................... 15 
5.6. 
Pharmacokinetics [PK] Analysis Set ............................................................................................................ 15 
6. 
GENERAL CONSIDERATIONS ................................................................................... 15 
6.1. 
Reference Start Date and Study Day ........................................................................................................... 15 
6.2. 
Baseline ........................................................................................................................................................... 16 
6.3. 
Repeat/reschedule, Unscheduled Visits and Early Termination Data ...................................................... 16 
6.4. 
Windowing Conventions ............................................................................................................................... 17 
6.5. 
Statistical Tests .............................................................................................................................................. 17 
6.6. 
Common Calculations ................................................................................................................................... 17 
6.7. 
Software Version ............................................................................................................................................ 18 
7. 
STATISTICAL CONSIDERATIONS ............................................................................ 18 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses ....................................................... 18 
7.2. 
Multicenter Studies ........................................................................................................................................ 19 
7.3. 
Missing data ................................................................................................................................................... 19 
7.4. 
Multiple Comparisons/ Multiplicity ............................................................................................................. 19 
7.5. 
Examination of Subgroups ............................................................................................................................ 20 
8. 
OUTPUT PRESENTATIONS ......................................................................................... 20 


 
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9. 
DISPOSITION AND WITHDRAWALS ........................................................................ 20 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 21 
10.1. 
Derivations ................................................................................................................................................. 22 
11. 
SURGICAL, MEDICAL AND COPD/SMOKING HISTORY .................................... 22 
12. 
MEDICATIONS ............................................................................................................... 23 
13. 
STUDY MEDICATION EXPOSURE ............................................................................ 25 
13.1. 
Derivations ................................................................................................................................................. 26 
14. 
STUDY MEDICATION COMPLIANCE ...................................................................... 26 
15. 
EFFICACY OUTCOMES................................................................................................ 26 
15.1. 
Primary Efficacy ........................................................................................................................................ 26 
15.1.1. 
Primary Efficacy Variable(s) & Derivation(s) ......................................................................................... 26 
15.1.2. 
Missing Data Methods for Primary Efficacy Variable(s) ........................................................................ 27 
15.1.3. 
Primary Analysis of Primary Efficacy Variable(s) .................................................................................. 27 
15.2. 
Secondary Efficacy .................................................................................................................................... 29 
15.2.1. 
Secondary Efficacy Variables & Derivations .......................................................................................... 29 
15.2.1.1. 
Change from baseline in trough FEV1 on Day 4 (mean of 11 and 12 hour values after evening dose 
on Day 3) (Secondary variable 1) ........................................................................................................................ 29 
15.2.1.2. 
Determination of AUC0-4h FEV1 (Average FEV1 over 4 hours) after morning dosing on Day 3 
(Secondary variable 2) ......................................................................................................................................... 29 
15.2.1.3. 
Peak FEV1 (measured in first 4 hours after dosing) and AUC0-12h FEV1 after dosing on Day 1 
(Secondary variable 3) ......................................................................................................................................... 30 
15.2.1.4. 
Change from baseline in AUC0-8h, AUC0-12h FEV1 measured on Day 3 (Secondary variable 4) ...... 30 
15.2.1.5. 
Change from baseline in peak FEV1 after evening dose on Day 3 (peak over 4 hours) (Secondary 
variable 5) 30 
15.2.1.6. 
Determination of onset of action (>10% increase in FEV1, from pre-first dose, censored at 120 
minutes) on Day 1 (Secondary variable 6) .......................................................................................................... 31 
15.2.1.7. 
RV (Residual volume), FRC (Functional residual capacity) and sGaw (Specific airway 
conductance) at 1.25 hours on Day 1 and 1.25, 8.25 and 12.25 hours after dosing on Day 3 (Secondary variable 


 
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7) 
31 
15.2.1.8. 
RPL554 steady state pharmacokinetics (AUC0-12h, Cmax, time to maximum concentration [tmax]) 
(Secondary variable 8) ......................................................................................................................................... 32 
15.2.2. 
Missing Data Methods for Secondary Efficacy Variable(s) .................................................................... 32 
15.2.3. 
Analysis of Secondary Efficacy Variables............................................................................................... 32 
15.2.3.1. 
Analysis of Secondary Variables 1, 2, 3, 4, 5 and 7......................................................................... 32 
15.2.3.2. 
Analysis of Secondary Variable 6 .................................................................................................... 32 
15.2.3.3. 
Analysis of Secondary Variable 8 .................................................................................................... 33 
15.3. 
Exploratory Efficacy ................................................................................................................................. 33 
15.3.1. 
Exploratory Efficacy Variables & Derivations ........................................................................................ 33 
15.3.1.1. 
AUC0-24h FEV1 on Day 3 ................................................................................................................. 33 
15.3.1.2. 
Change from baseline in dyspnea scale ........................................................................................... 34 
15.3.2. 
Missing Data Methods for Exploratory Efficacy Variable(s) .................................................................. 34 
15.3.3. 
Analysis of Exploratory Efficacy Variables ............................................................................................ 34 
16. 
SAFETY OUTCOMES .................................................................................................... 35 
16.1. 
Adverse Events ........................................................................................................................................... 35 
16.1.1. 
All TEAEs ............................................................................................................................................... 36 
16.1.1.1. 
Severity ............................................................................................................................................ 36 
16.1.1.2. 
Relationship to Study Medication .................................................................................................... 36 
16.1.2. 
TEAEs Leading to Discontinuation of Study Medication ....................................................................... 36 
16.1.3. 
Serious Adverse Events ........................................................................................................................... 37 
16.1.4. 
Adverse Events Leading to Death............................................................................................................ 37 
16.2. 
Laboratory Evaluations ............................................................................................................................ 37 
16.2.1. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ............................................................ 38 
16.3. 
ECG Evaluations ....................................................................................................................................... 38 
16.4. 
Vital Signs ................................................................................................................................................... 39 
16.5. 
Physical Examination ................................................................................................................................ 39 
16.6. 
Other Safety Assessments ......................................................................................................................... 40 


 
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17. 
REFERENCES .................................................................................................................. 41 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS .............................. 42 
IQVIA Output Conventions...................................................................................................................................... 42 
Table and Listing Output Conventions ................................................................................................................... 42 
Figure Output Conventions ...................................................................................................................................... 44 
Dates & Times ............................................................................................................................................................ 44 
Spelling Format.......................................................................................................................................................... 45 
Presentation of Treatment Groups .......................................................................................................................... 45 
Presentation of Treatment Sequences ...................................................................................................................... 45 
Presentation of Visits ................................................................................................................................................. 46 
Listings ....................................................................................................................................................................... 46 
APPENDIX 2. PARTIAL DATE CONVENTIONS ............................................................. 46 
Algorithm for Treatment Emergence of Adverse Events ....................................................................................... 47 
Algorithm for Prior / Concomitant Medications .................................................................................................... 48 
 
 


 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy and safety 
data for protocol RPL554-CO-204. It describes the data to be summarized and analyzed, including specifics of the 
statistical analyses to be performed. The statistical analysis plan (SAP) is based on the final protocol version 2.0, 
dated 10JUL2018. 
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
The primary objective of this study is to investigate the bronchodilator effect on peak forced expiratory volume in 1 
second (FEV1) (measured in the first 4 hours after dosing) of nebulized RPL554 dosed twice daily for 3 days, as 
compared to placebo, when administered in addition to once daily tiotropium/olodaterol. The peak FEV1 is 
measured after the morning dose on Day 3.  
2.2.  SECONDARY OBJECTIVES 
The secondary objectives are as follows: 
 
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 nebulized RPL554 after the first dose (on 
Day 1) as compared to placebo, when administered in addition to tiotropium/olodaterol  
 
To investigate the effect of twice daily nebulized doses of RPL554, as compared to placebo, when administered 
in addition to tiotropium/olodaterol on morning trough FEV1 (mean of values 11 and 12 hours after last dose of 
RPL554) on Day 4  
 
To investigate the effect of twice daily nebulized doses of RPL554, as compared to placebo, when administered 


 
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in addition to tiotropium/olodaterol on average (measured as AUC) FEV1 over 4, 8 and 12 hours after morning 
dosing on Day 3  
 
To assess the bronchodilator effect on peak FEV1 measured within 4 hours after the evening dosing of RPL554 
on Day 3  
 
To analyze plasma concentrations and assess the steady state pharmacokinetics (PK) of RPL554 when 
administered in addition to tiotropium/olodaterol  
 
To assess the tolerability and safety of twice daily nebulized doses of RPL554 in addition to 
tiotropium/olodaterol  
 
To determine the onset of action of RPL554 when administered with tiotropium/olodaterol (after the first 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/olodaterol  
2.3.  EXPLORATORY OBJECTIVES 
The exploratory objectives are as follows: 
 
To assess the dose response of RPL554 on peak and average (measured as AUC over 12 hours) after morning 
dose on Day 3, and morning trough FEV1 (mean of values at 11 and 12 hours after last dose of RPL554) on Day 
4, when dosed in addition to tiotropium/olodaterol  
 
To examine the effect of RPL554 on top of tiotropium/olodaterol on average (measured as AUC) FEV1 over 24 
hours after 3 days of dosing  
 
To examine the effect of RPL554 on top of tiotropium/olodaterol on a Likert dyspnea scale  
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
This is a Phase II, randomized, double blind, placebo controlled, complete block three-way crossover study to 


 
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investigate treatment with nebulized RPL554 and tiotropium/olodaterol Respimat® in patients with moderate to 
severe chronic obstructive pulmonary disease (COPD).  
 
A total of approximately 70 male or female COPD patients (as defined by the American Thoracic Society 
[ATS]/European Respiratory Society [ERS] guidelines with symptoms compatible with COPD for at least 1 year 
prior to Screening) aged 40 to 80 years (inclusive) will be randomized across up to 4 sites, in the Unites States (US) 
and the United Kingdom (UK). All patients will receive 3 combinations of study treatment (1.5 mg RPL554, 6 mg 
RPL554 and placebo) in a randomized, crossover design; therefore, each patient will act as his or her own control in 
the study. There are 6 possible treatment sequences a patient can be randomized to: a) RPL544 1.5 mg / RPL544 
6.0 mg/Placebo, b) RPL544 1.5 mg / Placebo / RPL544 6.0 mg, c) RPL544 6.0 mg / RPL544 1.5 mg / Placebo, d) 
RPL544 6.0 mg / Placebo / RPL544 1.5 mg, e) Placebo / RPL544 1.5 mg / RPL544 6.0 mg and f) Placebo / RPL544 
6.0 mg / RPL544 1.5 mg, with the ratio of patients to treatment groups / treatment sequences being 1:1:1:1:1:1. 
 
Patients will be screened for eligibility, including a reversibility test with salbutamol (in UK) or albuterol (in US) 
and ipratropium between 7 and 14 days before the first dose of study treatment. Eligible patients will then attend 3 
separate treatment periods (Treatment periods 1 to 3), with each lasting 3 days and separated by a 7 to 14-day 
washout period. Figure 1 below summarizes these details. 


 
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Figure 1 Study Flow Chart 
 
3.2. SCHEDULE OF EVENTS 
Schedule of events can be found in Section 6 of the protocol. 
3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
Not applicable. 
4. PLANNED ANALYSES 
There are no data monitoring committee (DMC) or interim analyses to be performed for this study. Only a final 


 
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analysis will be performed. 
4.1. DATA MONITORING COMMITTEE (DMC)  
There will be no DMC analyses for this study. 
4.2. INTERIM ANALYSIS  
No formal interim analysis is planned for the study. 
4.3. FINAL ANALYSIS  
All final, planned analyses identified in this SAP will be performed by IQVIA Biostatistics following Database Lock 
on a clean database:  
 
All outstanding data issues and queries resolved. 
 
All irresolvable data issues documented in the Data Handling Report (DHR) from Data Management. 
 
All coding of medications and AEs completed. 
 
Serious adverse event (SAE) reconciliation completed. 
 
All reconciliation of vendor data with electronic case report form (eCRF) data completed successfully. 
 
Analysis sets authorized. 
It should be noted that all verbatim text from the eCRF will be presented in outputs “as is” with no “manual hard 
coding” corrections for such data. 
PK analysis will be performed by another party (third party vendor), however details of this analysis will be 
specified in this SAP. 


 
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5. ANALYSIS SETS 
Agreement and authorization of patients included/excluded from each analysis set will be conducted prior to the 
unblinding of the study.  
5.1. ALL SUBJECTS ENROLLED SET [ENR] 
The all subjects enrolled (ENR) set will contain all subjects who provide informed consent for this study. 
5.2. ALL PATIENTS RANDOMIZED SET [RND] 
The all patients randomized (RND) set will contain all patients who provide informed consent and who are 
randomized to study medication. For analyses and displays based on RND, patients will be classified according to 
randomized treatment.  
5.3. SAFETY ANALYSIS SET [SAF] 
The safety analysis set (SAF) will contain all patients in the RND set who receive at least 1 dose of study medication 
and patients will be classified according to treatment received. If there is any doubt whether a patient was treated or 
not, they will be assumed treated for the purposes of analysis.  
5.4. FULL ANALYSIS SET [FAS] 
The full analysis set (FAS) will contain all patients in the RND set with sufficient data collected after intake of study 
medication to compute the pharmacodynamic parameters (FEV1, sGaw, RV, FRC measurements) on at least 2 
treatment periods. For analyses and displays based on FAS, patients will be classified according to actual treatment.  


 
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5.5. COMPLETERS ANALYSIS SET [CAS] 
The completers analysis set (CAS) will contain all patients in the SAF analysis set who complete all treatment 
periods i.e., a patient who receives a first and last dose intake plus 1 day for all 3 treatment periods per schedule of 
events (see section 6 of the protocol for schedule details). 
5.6. PHARMACOKINETICS [PK] ANALYSIS SET 
The PK analysis set will contain all patients in the RND analysis set who have a blood sampling performed after at 
least 1 dose of RPL544 and PK parameter data.  The PK analysis set will be determined by a third-party vendor and 
the data will be provided to IQVIA. 
6. GENERAL CONSIDERATIONS 
6.1. REFERENCE START DATE AND STUDY DAY 
Study day will be calculated from the reference start date, and will be used to show start/stop day of assessments and 
events. Reference start date is defined as the day of the first dose of study medication (e.g., treatment period 1, 
Day 1 is the day of the first dose of study medication in treatment period 1), and will appear in every listing where 
an assessment date or event date appears. 
 
If the date of the event is on or after the reference date then:  
 
Study day = (date of event – reference date) + 1. 
 
If the date of the event is prior to the reference date then:  
 
Study day = (date of event – reference date). 


 
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In the situation where the event date is partial or missing, the date will appear partial or missing in the listings, and 
study day, and any corresponding durations will be presented based on the imputations specified in Appendix 2; 
Partial Date Conventions. 
6.2. BASELINE 
Baseline definitions are related to the treatment period the patient enters. For majority of endpoints (primary 
endpoint, relevant secondary/exploratory endpoints and safety endpoints assessed post-dose in the treatment 
periods), this will be the pre-dose assessment on Day 1 of each treatment period (treatment period 1 to treatment 
period 3). Baseline pre-dose FEV1/FVC will be derived from 3 acceptable readings (performed up to 8 times to 
obtain these), with the highest being used for analysis. For safety laboratory tests (hematology, biochemistry, 
urinalysis) and 24-hour Holter monitoring screening assessment, performed 7 to 14 days before randomization, will 
be considered as baseline. 
6.3. REPEAT/RESCHEDULE, UNSCHEDULED VISITS AND EARLY 
TERMINATION DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. If a visit is 
repeated/rescheduled due to variability in FEV1 or other reason, the repeated/rescheduled visit, will be listed and 
summarized as the valid visit (same visit number assigned), at the discretion of the Investigator. Unscheduled 
measurements will not be included in by-visit summaries, but will contribute to the endpoint value, at the discretion 
of the Investigator. For example, if an unscheduled visit occurred at 10 hours post-dose on Day 3, then this value 
will be considered in the calculation of the average FEV1 over 12 hours (AUC0-12h FEV1) on Day 3. Any 
unscheduled or unplanned readings will be presented within the patient listings. 
 
Early termination data will be mapped according to the visit number the termination occurred for by-visit 
summaries. If early termination occurs pre-first dose (after baseline), then it is summarized at the actual visit. If 


 
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termination is after first dose in period or during the following wash-out period, data collected remains at the visit 
performed. However, if the patient returns for end of study, then this data will be mapped to end of study visit.  
 
If AE data occurs in the 7 to 14-day gap between treatment periods, these will be mapped to the earlier of the two 
treatment periods. Similarly, the AE will be mapped to the last treatment group received. If AE data occurs in the 
post-treatment period, these will be mapped to the last treatment period and last treatment group received.  
 
Listings will include scheduled, unscheduled, repeat/reschedule and early discontinuation data. 
6.4. WINDOWING CONVENTIONS  
No visit windows will be applied in this study and the scheduled assessments will be reported and analyzed as per 
eCRF collection. 
6.5. STATISTICAL TESTS 
The default significant level will be (5%); confidence intervals will be 95% and all tests will be 2-sided, unless 
otherwise specified in the description of the analyses. All significant p-values (i.e. < 0.05) will be flagged by means 
of an “*” for ease of review. 
 
For presentation of summary statistics for quantitative and qualitative variables see Appendix 1; Programming 
conventions for outputs.  
6.6. COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
 
Test value at post-dose time point – pre-dose at each treatment period value. 


 
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Peak effect will be calculated as: 
 
Maximum value in the first 4 hours after dosing. 
Average effect will be calculated as: 
 
FEV1 AUC divided by the length of the time interval of interest. 
Log-transformations will be performed on FEV1 data: 
 
FEV1 will be analyzed using multiplicative models, which means that data will be logged prior to analysis. 
 
The results will then be back-transformed to linear scale (treatment differences will thus be ratios of geometric 
means). 
 
Morning trough FEV1 calculated as mean of the 11 and 12-hour FEV1 measurements following the pre-evening 
dose. 
6.7. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4.  
7. STATISTICAL CONSIDERATIONS 
7.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
The following covariates are used in the analyses. For details of their inclusion in the models, see the specific 
analysis section. 
 
Randomized treatment (fixed). 
o 
RPL554 1.5mg 
o 
RPL554 6.0mg 
o 
Placebo 


 
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 
Treatment period (fixed). 
o 
Treatment period 1 
o 
Treatment period 2 
o 
Treatment period 3 
 
Baseline value of analyzed variable (covariate). 
7.2. MULTICENTER STUDIES 
This study will be conducted by multiple investigators at up to 4 study centers, in US and UK.  Randomization to 
treatment groups is not stratified by country/center.  
7.3. MISSING DATA 
Missing safety data will not be imputed, apart from partial date imputations as specified in Appendix 2.  
Missing efficacy data will be handled as described in section 15.1.2 and section 15.2.2 of this analysis plan. Partial 
date imputations will be handled as specified in Appendix 2. 
7.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
Significance of treatment effect will be tested for the primary and secondary efficacy endpoints and will be done for 
each of the 2 doses of RPL554 against placebo, starting with the highest dose (6 mg). To this end, the 
fixed-sequence testing approach (Maurer et al., 1995; Westfall & Krishen, 2001) will be used. 
Let i = 0, 1 and 2 represent increasing dose levels, 0 denoting placebo. Also, let µi, i = 0, 1 and 2, denote the mean 
change from baseline in peak FEV1 at Day 3 (measured in first 4 hours after morning dosing) for placebo and each 
increasing active dose level, respectively.  The primary null hypotheses are defined as: 
Hi: µj - µ0 = 0 and will be tested against the 2-sided alternative Ki: µj - µ0 ≠ 0, j = 1 and 2 
 


 
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Finally, let p1 and p2 denote the marginal p-values obtained from the statistical tests associated with H1 and H2 
(obtained from the model). 
The fixed-sequence testing will begin with the null hypothesis corresponding to the highest dose versus placebo. If a 
statistically significant difference is found at the 2-sided α level of 5%, the testing will proceed with the next highest 
dose. Otherwise, testing stops and the remaining null hypotheses are accepted without testing. 
This testing strategy can be written as the following stepwise algorithm: 
 
Step 1: If p2 ≤ α reject H2 and go to Step 2. Otherwise, fail to reject H2 and H1 and stop. 
 
Step 2: If p1 ≤ α reject H1. Otherwise, accept H1. 
 
The fixed-sequence procedure controls the family-wise error rate in the strong sense because, for each null 
hypothesis, the testing is conditional upon rejecting all hypotheses earlier in the sequence (Dmitrienko, et al., 2009). 
 
Each secondary endpoint will be tested independently and nominally following a hierarchical testing of doses like 
the one used for the primary.  
7.5. EXAMINATION OF SUBGROUPS 
No subgroup analyses will be performed for this study. 
8. OUTPUT PRESENTATIONS 
Appendix 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP describe the presentations for this study and therefore the format and content 
of the summary tables, figures, and listings to be provided by IQVIA Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
All patients who provide informed consent will be accounted for in this study.  
 


 
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Patient disposition, withdrawals and reasons for exclusion from each analysis set and protocol deviations, 
including inclusion and exclusion criteria will be presented for all patients, including those with screen failures and 
summarized by treatment sequence.  Number of patients treated and discontinued in each treatment period will also 
be presented. Discontinued patients are assigned to treatment period based on the last day of treatment + 1 from 
study start: treatment period 1, treatment period 2 (7 to 14 days after treatment period 1), treatment period 3 (7 to 14 
days after treatment period 2). If the patient discontinued/withdrawn, he/she will be allocated to the last treatment 
period attended and last treatment administered.  
 
All protocol deviations collected will be divided into critical, major or minor categories and will be assigned to the 
treatment group the patient is on according to when the protocol deviation occurred. Critical and/or major protocol 
deviations affect the integrity of the drug activity data and will be obtained by the clinical research associates 
(CRAs) and documented in a log. The deviations will be discussed at monthly calls with the sponsor to determine 
the accuracy of classification and severity and to determine if any changes are needed to the wording of the 
descriptions. Major deviations however, are discussed as soon as they arise. 
 
Preliminary assignment to each analysis population (therefore whether a patient is included/excluded in each 
analysis population [excluding the PK and PK/PD analysis population) will be recorded in an EXCEL sheet by the 
IQVIA Biostatistician, with the reason for exclusion from each population indicated. The EXCEL sheet will be 
reviewed by Verona and assignments/comments will be discussed and an agreement should be reached prior to the 
Database Lock of the study. After agreement is reached, the EXCEL sheet should be authorized by means of a 
customer authorization form (CAF).   
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics (including screening disease characteristics) will be presented 
for the all analysis sets (RND, SAF, FAS, CAS, PK) by the treatment sequences. No statistical testing will be carried 
out for demographic or other baseline characteristics. 


 
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The following demographic and other baseline characteristics will be reported for this study: 
 
Age (years) 
 
Sex 
 
Childbearing potential 
 
Race  
 
Ethnicity 
 
Height (cm) 
 
Weight (kg) 
 
BMI (kg/m2) 
 
Pre (prior to dosing at baseline)/post (post dosing at baseline) bronchodilator FEV1 (both in liters and in 
percentage of predicted normal) 
 
Post-bronchodilator FEV1/ forced vital capacity (FVC) 
 
FEV1 reversibility test (mL and %) 
10.1. DERIVATIONS 
 
Age (years) = (Randomization date – informed consent date) 
 
Height (cm) = height (cm) (if recorded in cm) OR height (inches) x 2.54 (if recorded in inches) 
 
Weight (kg) = weight (kg) (if recorded in kg) OR weight (lbs) x 0.453592 (if recorded in lbs) 
 
BMI (kg/ m2) = weight (kg)/ height (m)2 
 
Demographic and other baseline characteristics without derivations are recorded on the eCRF and used as is on the 
eCRF. 
11. SURGICAL, MEDICAL AND COPD/SMOKING HISTORY 
Surgical and Medical History information will be presented in listings only, for the RND analysis set.  


 
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 
Surgical History will be coded by Medical Dictionary for Regulatory Activities (MedDRA) dictionary using the 
version specified in the data management plan. 
o 
Surgical History conditions are defined as those conditions which stop prior to or at Screening.  
o 
Data captured on the Surgical Procedure History page of the eCRF will be presented by SOC (System 
Organ Class) and PT (Preferred Term).  
 
Medical History will be coded by MedDRA dictionary using the version specified in the data management plan. 
o 
Medical History conditions are defined as those conditions which stop prior to or at Screening.  
o 
Data captured on the Medical History page of the eCRF will be presented by SOC and PT.  
 
COPD/Smoking History data captured on the COPD and Smoking History page of the eCRF will be presented 
for the RND analysis set. 
o 
Duration of COPD – calculated relative to date of first diagnosis (Randomization date – first COPD 
diagnosis date) 
o 
Smoking history (current or former, including pack years). Pack-years = Number of packs per day x 
Number of years smoking 
12. MEDICATIONS 
Medications will be coded using WHO-DD version specified in the data management plan and will be presented by 
Anatomical Therapeutic Chemical (ATC) (the 1st level of the ATC code) and PT for the RND analysis set. 
Medications may be assigned to multiple treatment groups based on their occurrence date, due to the cross-over 
design of the study. Certain medications (or a special grouping of medications) will be classified in a list during the 
study and signed-off prior to lock by a medical advisor. As this list, may change prior to sign-off they will not be 
defined in this section of the SAP. Potential medications include, but are not limited to, inhaled corticosteroids 
(ICS), LAMAs (long-acting muscarinic antagonists), LABAs (long-acting beta2-agonists) etc. 
 
See Appendix 2 for handling of partial dates for medications, in the case where it is not possible to define a 
medication as prior, concomitant, or post treatment, the medication will be classified by the worst case; i.e. 


 
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concomitant.  
 
‘Prior’ medications are medications which started and stopped in the 3 months prior to the first dose of study 
medication and are recorded at Screening.  
 
‘Concomitant’ medications are medications which:  
o Started 3 months prior to first dose of each study medication and on or after the first dose of each study 
medication. 
o AND ended on or after the date of first dose of study medication or were ongoing at the end of the study. 
o A patient can report more than 1 concomitant medication with the same PT, but concomitant medication 
will be counted only once. Similarly, if a patient reported more than 1 concomitant within the same primary 
ATC Level 1, the patient will be counted only once. However, a medication can be counted once per 
treatment period, if it occurs in multiple treatment periods. 
Prior and concomitant medications will be presented in a listing only, by treatment group. 
 
 
Rescue medications will be recorded on the Rescue Medication page of the eCRF. These are short acting 
bronchodilators and will be sourced by the study center and dispensed at the Screening visit. Rescue medication 
used during each treatment period must be separately documented on the eCRF (medication, dose, route, date 
and time of each administration). Protocol procedures must continue even if rescue medication has been taken. 
Salbutamol/albuterol is to be used for primary rescue use. Salbutamol/albuterol and ipratropium (or 
Combivent®) must be withheld for at least 8 hours prior to spirometry (per below), and this is to be confirmed 
in the eCRF at the start of each treatment period. If this withhold is not met, the patient should be rescheduled 
for a repeat visit within permitted windows. Short acting bronchodilators should be withheld as follows:  
o 8 hours prior to pre-reversibility spirometry for Screening  
o 8 hours prior to pre-dose spirometry for Day 1, Day 2 and Day 3  
o Post dose:  
- Day 1 until after +12 hours spirometry. 
- Day 2 until after + 12 hours spirometry. 
- Day 3 until after + 24 hours spirometry (Day 4 morning). 
 
Rescue medications used (during the treatment periods) will be summarized by treatment group and the type of 


 
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rescue medications, presented in a table. Time to first use of rescue medication will also be estimated for each 
treatment group, where start time is considered the time of first dose administration in treatment period 1 and end 
time the time when first rescue medication was used or the time of last spirometry (24 h after evening dose 3) 
performed in the period. Kaplan-Meier estimates, if calculable, for median time to first overall fall with 95% 
confidence interval, minimum, 25th and 75th percentiles and maximum will be presented for each treatment group. 
An accompanying Kaplan-Meier figure will also be presented, including all available rescue medications recoded 
from patients. Patients not experiencing a use of rescue medications will be censored at the time of last spirometry 
within treatment period or premature discontinuation. If rescue medication usage is deemed to be low (number of 
patients using rescue medications < 10%), as expected, the Kaplan-Meier estimates and accompanying figure will 
not be presented. Rescue medications will also be presented in a listing.  
13. STUDY MEDICATION EXPOSURE 
Exposure to study medication in days will be presented by treatment sequence for the RND analysis set. The date of 
first study medication administration (tiotropium/olodaterol dosing) will be taken from the Drug Exposure eCRF 
page for treatment period 1. The date of last study medication will be taken from the Disposition eCRF page based 
on date of completion/discontinuation. Interruptions/washout periods between treatment periods (7 to 14 days) are 
not considered for duration of exposure. The mean duration of exposure in days will also be summarized.  
Total exposure (in mL) will be based on the volume of residual product for AM dose of the first nebulization 
(RPL554 or Placebo dosing), or residual product of first and second nebulization (RPL554 or Placebo dosing), if 
applicable, and will also be summarized. 
 
Drug accountability will also be summarized by treatment sequence for the RND analysis set. The number of vials 
dispensed will be compared to the number of unused vials returned, as measured on the Drug accountability eCRF 
page. 


 
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13.1. DERIVATIONS 
 
Duration of exposure (days) = date of last study medication administration – date of first study medication 
administration – number of washout period days between treatment periods (21 to 42 days) + 1.  
 
Total exposure (mL) = (number of vials dispensed x contents of each vial) – residual product for AM dose of 
first (and second, if applicable) nebulization. 
 
Drug accountability (number of vials) = Number of vials dispensed - number of unused vials returned. 
14. STUDY MEDICATION COMPLIANCE  
All administration of study treatment will be done at the clinic under supervision of the study staff; therefore, no 
formal analysis of compliance will be performed.  
15. EFFICACY OUTCOMES  
15.1. PRIMARY EFFICACY 
15.1.1. PRIMARY EFFICACY VARIABLE(S) & DERIVATION(S) 
The primary efficacy variable is peak FEV1 (measured in first 4 hours after morning dosing). This will be measured 
after dosing on Day 3 and is collected on the Spirometry Study measurements eCRF page. 
 
Three acceptable readings are performed at each of the timepoints in first 4 hours after morning dosing on Day 3 (5, 
15 and 30 minutes and 1, 1.5, 2 and 4 hours) and the highest of the 3 is used for analysis purposes. Hence peak FEV1 
is derived as the highest of all these readings.  
 


 
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Descriptive statistics (see Appendix 1 [Programming conventions for outputs]) for peak FEV1 will be presented for 
all patients assigned to FAS, at each assessment and change from baseline at each assessment and overall (where 
overall is regardless of treatment period, day and timepoint to assess treatment group as a whole) as relevant. All 
summaries will be presented for each treatment group. In addition, a figure (bar graph) representing mean change 
from baseline FEV1 to peak FEV1 by treatment will be presented, including the standard error of the mean.   
 
Change from baseline FEV1 to peak FEV1 (over 4 hours) at Day 3 will be derived to test the hypothesis described in 
section 15.1.3 with baseline defined as the FEV1 pre-dose assessment (-5 minutes) collected on Day 1 of each 
treatment period. Peak FEV1 at Day 3 is defined as the maximum post-dose value among the 5, 15, 30 minutes, 1, 
1.5, 2 and 4-hour assessments collected at after morning dose on Day 3 of each treatment period.  
15.1.2. MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE(S) 
No imputation will be applied. 
15.1.3. PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
The primary efficacy objective of the study is to show that at least 1 RPL554 + tiotropium/olodaterol treatment 
group (RPL554 6mg + tiotropium/olodaterol and/or RPL554 1.5 mg + tiotropium/olodaterol) will increase peak 
FEV1 (change from Baseline) compared to RPL554 placebo + tiotropium/olodaterol at Day 3 (measured in first 4 
hours after morning dosing) by rejecting the null hypothesis described below at significance level α=0.05 level 
(2-sided): 
H0: µj = µ0 versus H1: µj ≠ µ0 
 
where µj and µ0 are the mean change from Baseline in peak FEV1 at Day 3 (measured in first 4 hours after morning 
dosing) for 1 RPL554 + tiotropium/olodaterol treatment group (RPL554 6mg + tiotropium/olodaterol and/or 
RPL554 1.5 mg + tiotropium/olodaterol) and RPL554 placebo + tiotropium/olodaterol respectively.  


 
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An ANCOVA will be used to test the hypothesis with change from baseline FEV1 to peak FEV1 (measured in first 4 
hours after morning dosing) on Day 3 as response variable, and treatment, treatment period and baseline FEV1 as 
covariates. Analyses will be implemented using the SAS® procedure MIXED as follows:  
 
PROC MIXED DATA = …; 
 
CLASS SUBJECT PERIOD TREATMENT; 
 
MODEL CHG = TREATMENT PERIOD BASELINE; 
 
RANDOM USUBJID; 
 
LSMEANS TREATMENT / CL DIFF; 
RUN; 
 
where CHG = difference in log (peak FEV1) – log (baseline FEV1) i.e. log (peak FEV1 / baseline FEV1) 
TREATMENT = treatment group (1.5 mg RPL554, 6 mg RPL554 and placebo) 
PERIOD = treatment period (treatment period 1, 2 and 3) 
BASELINE = log (baseline FEV1) 
USUBJID = subject ID   
 
The primary comparison will be the contrast (difference in least squares mean [LSMEAN]) between 6 mg RPL554 
and placebo on Day 3 (in first 4 hours after morning dosing). 
 
Peak FEV1 and baseline FEV1 will be log-transformed prior to analysis using natural logarithm. The difference 
between the two (log [peak FEV1] – log [baseline FEV1] equals log (peak FEV1 / baseline FEV1). The covariate, 
baseline FEV1, will also be log transformed. Therefore, the LSMEAN statement between treatments in the above 
PROC MIXED will provide the log of the contrasts. Prior to presentations, the antilog of these point estimates and 
associated 95% confidence intervals will be performed, giving ratios of geometric means on the linear scale. The 
2-sided p-value for the exponential (exp) least squares mean, exp(LSM), ratio between each of the 2 treatment 
groups and placebo will be reported. 
 


 
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Summary statistics for FEV1 will be presented for baseline, peak on Day 3 (in first 4 hours after morning dosing) 
and change from baseline to peak by treatment group on patients with both assessments, on the original scale.  
15.2. SECONDARY EFFICACY 
The secondary efficacy analyses will be performed for the FAS.  
15.2.1. SECONDARY EFFICACY VARIABLES & DERIVATIONS 
15.2.1.1. Change from baseline in trough FEV1 on Day 4 (mean of 11 and 12 hour values after 
evening dose on Day 3) (Secondary variable 1) 
 
Morning trough FEV1 is defined as mean of values 11 and 12 hours after the evening dose of RPL554 on Day 3. 
15.2.1.2. Determination of AUC0-4h FEV1 (Average FEV1 over 4 hours) after morning dosing on Day 
3 (Secondary variable 2) 
 
Average FEV1 after morning dosing on Day 3 is defined as the AUC0-4h FEV1 collected during Day 3 under analysis, 
divided by the length of the time (in hours). AUC0-4h FEV1 is derived using the following formula: 
𝐴𝑈𝐶= 1
2 (𝑡1 −𝑡0)(𝑦1 + 𝑦0) + 1
2 (𝑡2 −𝑡1)(𝑦2 + 𝑦1) + ⋯ 
Where i are the number of intervals, ti are the time values or time intervals (in actual hours) between assessments 
and yi the FEV1 values. The AUC result will then be divided by the actual time (the time elapsed since morning 
dosing on Day 3, until the time of assessment) at 4-hour assessment (as this can occur ± 10 minutes) to obtain the 
average FEV1. For analysis purposes, it will be assumed that the pre-dose value occurred at time 0 when computing 
pharmacodynamic parameters. 
 
If a patient misses’ hours 2 and 4 then the AUC0-4 is set to missing.  


 
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15.2.1.3. Peak FEV1 (measured in first 4 hours after dosing) and AUC0-12h FEV1 after dosing on Day 
1 (Secondary variable 3) 
 
Peak FEV1 (after 4 hours of dosing) on Day 1 is defined as the change from baseline to peak FEV1 and derived 
similarly to primary analysis (see section 15.1.3), but instead at Day 1.  
AUC0-12h FEV1 on Day 1 is also defined and derived similarly to secondary endpoint above (see section 15.2.1.2), 
but at Day 1. Parameters will be calculated over 12 hours (on Day 1 of each treatment period). If patient misses 
hours 8 and 12 then the AUC0-12h is set to missing. 
15.2.1.4. Change from baseline in AUC0-8h, AUC0-12h FEV1 measured on Day 3 (Secondary variable 
4) 
 
AUC0-8h and AUC0-12h FEV1 on Day 3 is defined and derived similarly to secondary endpoint in section 15.2.1.2, but 
at Day 3. Parameters will be calculated over 8 and 12 hours (on Day 3 of each treatment period), respectively. If 
patient misses hours 4 and 8 then AUC0-8h is set to missing. Similarly, if 8 and 12 then the AUC0-12h is set to missing. 
15.2.1.5. Change from baseline in peak FEV1 after evening dose on Day 3 (peak over 4 hours) 
(Secondary variable 5) 
 
Peak FEV1 on Day 3 evening is defined as the maximum value among the 13, 14 and 16-hour assessments collected 
after pre-evening dose of each treatment period. 
Change from baseline to peak FEV1 on Day 3 evening (over 4 hours) will be derived to test the hypothesis described 
in section 15.1.3.  
 
 


 
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15.2.1.6. Determination of onset of action (>10% increase in FEV1, from pre-first dose, censored at 
120 minutes) on Day 1 (Secondary variable 6) 
 
Onset of action is defined as a >10% increase in FEV1 from pre-dose on Day 1 over the next 120 minutes (2 hours) 
after morning dosing on Day 1 (5, 15 and 30 minutes and 1, 1.5, 2 hours). Time to onset will be derived as the time 
to onset of action is achieved. For analysis purposes, it will be assumed that the pre-dose value occurred at time 0. 
Patients not experiencing an onset of action will be censored at 120 minutes (2 hours) or at time of premature 
discontinuation (if withdrawn before 120 minutes). If onset of action is deemed to be low (number of patients with 
onset of action < 10%), the Kaplan-Meier estimates and accompanying figure will not be presented, similar to rescue 
medications. 
15.2.1.7. RV (Residual volume), FRC (Functional residual capacity) and sGaw (Specific airway 
conductance) at 1.25 hours on Day 1 and 1.25, 8.25 and 12.25 hours after dosing on Day 3 
(Secondary variable 7) 
 
RV, FRC, sGaw (1.25 hours) on Day 1 are defined as the lung volume/specific airway conductance assessments 
recorded pre-dose and 1.25 hours post-dose (on Day 1 of each treatment period). Similarly, RV, FRC, sGaw (pre-
dose, 1.25, 8.25 and 12.25 hours) on Day 3 are defined as the lung volume/specific airway conductance assessments 
recorded pre-dose and 1.25, 8.25 and 12.25 hours, respectively post-dose (on Day 3 of each treatment period). 
 
 


 
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15.2.1.8. RPL554 steady state pharmacokinetics (AUC0-12h, Cmax, time to maximum concentration 
[tmax]) (Secondary variable 8) 
 
Concentration of RPL554 (AUC0-12h, Cmax [maximum concentration], tmax [time to maximum concentration]) on Day 
3 of each treatment period (pre-dose, 5, 30 and 45 minutes and 1, 1.5, 2, 4, 8 and 12-hours post dose). 
15.2.2. MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLE(S) 
Missing data will not be imputed similarly to primary endpoint, where applicable (see section 15.1.2). 
15.2.3. ANALYSIS OF SECONDARY EFFICACY VARIABLES 
15.2.3.1. Analysis of Secondary Variables 1, 2, 3, 4, 5 and 7 
 
The secondary endpoints listed above will be analyzed in the same way as the primary endpoint. In the analyses 
using AUC of the FEV1, the average FEV1 at the each timepoint of interest will be used. Similarly, to the primary 
analysis, average AUC of the FEV1 and baseline FEV1 will be log-transformed prior to analysis using natural 
logarithm and the difference between the two will be estimated, with log (baseline FEV1), being a covariate.  
 
In the analysis of the RV, FRC and sGaw the pre-dose will be used as baseline in the model and the dependent 
endpoint will be the change at each timepoint of interest (1.25 hours after dosing on Day 1 and 1.25, 8.25 and 12.25 
hours after dosing on Day 3). 
15.2.3.2. Analysis of Secondary Variable 6 
 
Onset of action will be summarized by treatment and a Kaplan-Meier plot illustrating time to onset constructed. The 
SAS® procedure LIFETEST including covariates, if relevant, will be used as follows:  
 


 
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PROC LIFETEST DATA=...  OUTSURV =... CONFTYPE = LINEAR METHOD = 
KM ALPHA = 0.05 ALPHAQT = 0.05 PLOTS = (SURVIVAL (FAILURE NOCENSOR));  
 
TIME ONSET*STATUS (1); 
 
STRATA TRT; 
RUN; 
 
where ONSET = time to onset of action 
TRT = treatment group 
STATUS (1) = indicates an event of onset of action 
 
If a patient does not have onset of action from pre-dose on Day 1 over the next 120 minutes (2 hours) the data will 
be censored at 120 minutes or if a patient prematurely discontinued before 120 minutes, the last available 
assessment time post-dose (1 indicates censored variables). 
15.2.3.3. Analysis of Secondary Variable 8 
 
Summary statistics (number of observations, geometric mean, CV [coefficient of variation], minimum and 
maximum) will be presented for the concentrations of RPL554, specifically AUC0-12h, Cmax and tmax on the PK 
analysis set population. 
15.3. EXPLORATORY EFFICACY  
15.3.1. EXPLORATORY EFFICACY VARIABLES & DERIVATIONS 
15.3.1.1. AUC0-24h FEV1 on Day 3 
 
AUC0-24h FEV1 after evening dose on Day 3 is defined and derived similarly to secondary endpoint in section 
15.2.1.3. Parameters will be calculated over 24 hours (on Day 4 of each treatment period). If patient misses hours 12 
and 24 then the AUC0-24h is set to missing. 


 
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15.3.1.2. Change from baseline in dyspnea scale  
 
An 11-point Likert scale will be utilized, with patients being asked the following question by a blinded member of 
staff: “On a scale of zero to ten, please rate your current shortness of breath, with zero indicating no shortness of 
breath and ten indicating the worst shortness of breath that you can imagine”. This scale will be an instantaneous 
measurement of their dyspnea at that moment, and not reflective. It will be administered on Day 1 pre-dose and 5, 
15, and 30 minutes post-dose; and on Day 3 pre-dose and 5, 15, 30 minutes and 24 hours post-dose. Baseline will be 
considered the pre-dose assessment on Day 1 of each treatment period and change from baseline will be assessed at 
30 min post-dose on Day 1 and Day 3 and 24hours post-dose on Day 3.  
15.3.2. MISSING DATA METHODS FOR EXPLORATORY EFFICACY VARIABLE(S) 
Missing data will not be imputed similarly to primary endpoint, where applicable (see section 15.1.2). 
15.3.3. ANALYSIS OF EXPLORATORY EFFICACY VARIABLES 
The analysis relating the to the average FEV1 on Day 3 over 24 hours will be analyzed in the same way as the 
primary endpoint.  
 
Dyspnea score and the change in dyspnea score will be summarized at each timepoint of interest (30 min post-dose 
on Day 1 and Day 3 and 24hours post-dose on Day 3).  
 
In addition, Wilcoxon signed rank test for pair-wise comparisons between baseline and the relevant post-baseline 
assessment, will be applied to identify differences. 
 
The SAS® procedure NPAR1WAY will be used as follows, to conduct the Wilcoxon rank sum test: 
 
 


 
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PROC NPAR1WAY DATA=… WILCOXON; 
  CLASS TREATMENT; 
  VAR DIFF; 
  EXACT WILCOXON; 
RUN; 
 
where 
DIFF = difference in dyspnea score between baseline and each post-baseline assessment 
TREATMENT = treatment group 
16. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the SAF.  
There will be no statistical comparisons between the treatment groups for safety data, unless otherwise specified 
with the relevant section.  
16.1. ADVERSE EVENTS 
Adverse Events (AEs) will be coded by MedDRA dictionary using the version specified in the data management 
plan.  
 
Treatment emergent adverse events (TEAEs) are defined as AEs that started or worsened in severity on or after the 
first dose of study medication, based on the investigator assessment of severity. TEAEs will be assigned to treatment 
groups based on actual treatment received. TEAEs, like medications, may be assigned to multiple treatment groups 
due to the cross-over design of the study. This will depend on the occurrence date and duration of each TEAE. 
 
See Appendix 2 for handling of partial dates for AEs.  In the case where it is not possible to define an AE as 
treatment emergent or not, the AE will be classified by the worst case; i.e. treatment emergent.  
 


 
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An overall summary of number of patients within each of the categories described in the sub-section below, will be 
provided as specified in the templates.  
 
Listings will include TEAEs and Non-TEAEs. 
16.1.1. ALL TEAES  
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) and broken down 
further by maximum severity and relationship to study medication. 
16.1.1.1. Severity 
Severity is classed as mild/ moderate/ severe (increasing severity). TEAEs starting after the first dose of study 
medication with a missing severity will be classified as severe. If a patient reports a TEAE more than once within 
that SOC/ PT, the AE with the worst-case severity will be used in the corresponding severity summaries. 
16.1.1.2. Relationship to Study Medication 
Relationship, as indicated by the Investigator, is classed as “yes” or “no”. A related TEAE is defined as a TEAE 
with a relationship to study medication as “yes”. TEAEs with a missing relationship to study medication will be 
regarded as relationship = “yes” to study medication. If a patient reports the same AE more than once within that 
SOC/ PT, the AE with the worst-case relationship to study medication will be used in the corresponding relationship 
summaries.  
16.1.2. TEAES LEADING TO DISCONTINUATION OF STUDY MEDICATION 
TEAEs leading to permanent discontinuation of study medication will be identified by using the question “Did the 
AE cause the Patient to discontinue from the study?” from the AE page of the eCRF. 
 
For TEAEs leading to discontinuation of study medication, summaries of incidence rates (frequencies and 


 
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percentages) by SOC and PT will be prepared. 
16.1.3. SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse Events page of the eCRF. A 
summary of serious TEAEs by SOC and PT will be prepared. 
16.1.4. ADVERSE EVENTS LEADING TO DEATH 
TEAEs leading to Death are those events which are recorded as “Death” on the Adverse Events page of the eCRF. A 
summary of TEAEs leading to death by SOC and PT will be prepared. 
16.2. LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this study for hematology, blood chemistry 
and urinalysis. A list of laboratory assessments to be included in the outputs is included in the protocol, Sections 
7.4.3.1, 7.4.3.2 and 7.4.3.3 for hematology, blood chemistry and urinalysis, respectively. Presentations will use SI 
Units.  
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of quantification (BLQ), or 
“> X”, i.e. above the upper limit of quantification (ULQ), will be converted to X for quantitative summaries, but will 
be presented as recorded, i.e. as “< X” or “> X” in the listings. 
The following summaries will be provided for laboratory data: 
 
Actual and change from baseline (pre-dose at each treatment period) to each post-dose time point (for 
quantitative measurements), including overall (where overall is regardless of treatment period, day and 
timepoint to assess treatment group as a whole). 
 
Incidence of abnormal values according to normal range criteria 
 
Shift from baseline according to normal range criteria (for quantitative measurements and categorical 


 
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measurements) 
 
Listing of abnormal values occurring after the first dose of study treatment. 
16.2.1. LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges in SI units and 
categorized as: 
 
Low: Below the lower limit of the laboratory reference range.  
 
Normal: Within the laboratory reference range (upper and lower limit included). 
 
High: Above the upper limit of the laboratory reference range. 
 
In addition to the high and low quantitative laboratory assignments (as identified by means of the laboratory 
reference ranges), markedly abnormal quantitative safety (and other) laboratory assessments will also be identified 
by the Investigator by manually annotating a print out of the results. 
16.3. ECG EVALUATIONS 
Overall results from the central ECG (Electrocardiogram) Reading Center will be included in the reporting of this 
study. The overall assessment of ECG parameters will be reported for this study: 
 
Normal 
 
Abnormal not Clinically Significant (ANCS) 
 
Abnormal Clinically Significant (ACS) 
 
The following summaries will be provided for ECG data: 
 
Actual assessments at baseline (pre-dose at each treatment period) and each post-dose time points, including 
end of study visit and overall (where overall is regardless of treatment period, day and timepoint to assess 
treatment group as a whole). 


 
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 
Shift of overall assessment baseline to post-dose time points according to markedly abnormal criteria 
 
Incidence of markedly abnormal criteria 
 
Listing of patients meeting markedly abnormal criteria 
16.4. VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
 
Supine Systolic Blood Pressure (mmHg) 
 
Supine Diastolic Blood Pressure (mmHg) 
 
Supine Pulse Rate (bpm) 
 
The following summaries will be provided for vital signs data: 
 
Actual assessments at screening, baseline (pre-dose at each treatment period) and each post-dose time points, 
including end of study visit and overall (where overall is regardless of treatment period, day and timepoint to 
assess treatment group as a whole). 
16.5. PHYSICAL EXAMINATION 
The following summaries will be provided for the full physical examination data, covering major body systems 
(nose, throat, skin, thyroid gland, neurological system, respiratory system, cardiovascular system, abdomen [liver 
and spleen], lymph nodes and extremities): 
 
Incidence of abnormalities at screening 
 
Incidence of abnormalities at end of study 
 
Changes in abnormalities between screening and end of study 
The following summaries will be provided for a brief physical examination to be also performed, on skin, 
respiratory system, cardiovascular system, and abdomen (liver and spleen): 
 
Incidence of abnormalities pre-dose on Day 1 


 
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Version Number: 
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Version Date:  
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Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
 
Incidence of abnormalities prior to discharge from the study center on Day 4 
 
Changes in abnormalities between pre-dose on Day 1 and prior to discharge from the study center on Day 4 
16.6. OTHER SAFETY ASSESSMENTS 
24-hour Holter monitoring screening assessment, performed 7 to 14 days before randomization (with patients 
returning the next day for the removal of the Holter monitor), and on Day 3 pre-dose will be performed. The results 
of these assessments will be summarized by treatment group and time point of collection.  
 
The Screening Holter report must have a minimum of 18 hours recording that is evaluable for rhythm analysis and 
the report must be reviewed as part of the inclusion criteria prior to randomization. 
Alcohol breath test and trainings (including whole body plethysmography training and inhalation training) results 
will be presented in a listing only. 
 


 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
17. REFERENCES  
Dobson, A. J. (2002). An introduction to generalized linear models, 2nd ed. Chapman & Hall/CRC. 
Dmitrienko, A., Bretz, F., Westfall, P. H., Troendle, J., Wiens, B. L., Tamhane, A. C., & Hsu, J. C. (2009). Multiple 
testing methodology. Multiple Testing Problems in Pharmaceutical Statistics. Chapman and Hall/CRC Press, 
New York. 
Maurer, W., Hothorn, L. A., & Lehmacher, W. (1995). Multiple Comparisons in Drug Clinical Trials and Preclinical 
Assays: A-priori ordered Hypotheses. Testing Principles in Clinical and Preclinical Trials (J. Vollmar, 
editor) STuttgart, Gustav Fisher Verlag, 3-18. 
SAS Institute, Inc. (1999). SAS Procedures Guide, version 8. Cary, NC: SAS Institute. 
 
 
 
 
 
 


 
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Version Date:  
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
IQVIA OUTPUT CONVENTIONS 
Outputs will be presented according to the following: 
TABLE AND LISTING OUTPUT CONVENTIONS 
General: 
• The first row in the body of the table or listing should be blank 
• The left-hand column should start in column 1. No indenting or centering of the output should occur. 
• Rounding should be done with the SAS function ROUND. 
• Numbers in tables should be rounded, not truncated. 
• Alphanumeric output should be left aligned. 
• Numbers should be decimal point aligned. 
• Whole numbers should be right aligned. 
• Text values should be left aligned. 
• The first letter of a text entry should be capitalized 
• Listings of adverse events, concomitant medications, medical histories etc. should be sorted in chronological order, 
with earliest adverse event, medication or history coming first. 
• The study drug should appear first in tables with treatments as columns 
• In general, only present totals (across treatment groups) at baseline/randomization, and do not present them post 
randomization, unless the customer specifically requests it. 
• If possible, include 100% frequencies in the table shell, so that it is clear what the denominator is for percentage 
calculations. 
• All listing outputs should be sorted (preferably by Treatment, Site Number and Subject Number). 
• Exponentiation will be expressed using a double asterisk, i.e., mm3 will be written as mm**3. 
• All variables that are output in the CRF (which have data present) should appear in the listings, along with all 
derived data appearing in the corresponding tables 
• The width of the entire output should match the linesize. 
 
Univariate Statistics: 
• Statistics should be presented in the same order across tables (i.e., n, Mean, SD, Median, Minimum, Maximum) 


 
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• Table statistics should line up under the N part of the (N=XXX) in the table header. All decimal points should line 
up. If the minimum and maximum are output on 1 line as Minimum, Maximum then the comma should line up 
with the decimal point. 
• If the original data has N decimal places, then the summary statistics should have the following decimal places: 
Minimum and maximum: N 
Mean, median and CV%: N + 1 
SD: N + 2 
 
Frequencies and percentages (n and %): 
• Percent values should be reported inside parentheses, with 1 space between the count and the left parenthesis of the 
percentage. Parentheses should be justified to accept a maximum of 100.0 as a value and padded with blank space 
if the percent is less than 100.0. An example is given below: 
77 (100.0%) 
50 ( 64.9%) 
0 ( 0.0%) 
• Percentages will be reported to 1 decimal place, except percentages <100.0% but >99.9% will be presented as 
‘>99.9%’ (e.g., 99.99% is presented as >99.9%); and percentages < 0.1% will be presented as ‘<0.1%’ (e.g., 
0.08% is presented as <0.1%). Rounding will be applied after the <0.1% and >99.9% rule. 
e.g. ( <0.1%) 
( 6.8%) 
(>99.9%) 
Percentages may be reported to 0 decimal places as appropriate (for example, where the denominator is 
relatively small). 
• Where counts are zero, percentages of 0.0% should appear in the output. 
 
Confidence Intervals: 
• As a rule, confidence intervals are output to 1 place more than the raw data, and standard deviations and standard 
errors to 2 places more than the raw data 
• Confidence intervals should be justified so that parentheses displayed on consecutive lines of a table “line up”. 
• Boundary values of confidence intervals should be separated by a comma. 
• Boundary values should be padded as necessary to accept negative values and to allow alignment of the decimal 
place. 
• An example is given below: 
(-0.12, -0.10) 
( 9.54, 12.91) 
 
P-values: 


 
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• P-values should be reported to 3 decimal places, except values <1.000 but >0.999 will be presented as ‘>0.999’ 
(e.g., 0.9998 is presented as >0.999); and values <0.001 will be presented as ‘<0.001’ (e.g., 0.0009 is presented as 
<0.001). Rounding will be applied after the <0.001 and >0.999 rule 
 
Ratios: 
• Ratios should be reported to 1 more decimal place than the original data. 
 
Spacing: 
• There must be a minimum of 1 blank space between columns (preferably 2) 
 
Denominators: 
• If a different count other than the population count is used for a denominator (within the table) to calculate 
percentages, there should be a row in the table that identifies that number “n”. 
• Alternatively, a footnote should be included in each table with percentages to indicate the denominator for 
percentages. 
 
Missing values 
• A “0” should be used to indicate a zero frequency. 
• A blank will be used to indicate missing data in an end-of-text table or subject listing. 
FIGURE OUTPUT CONVENTIONS 
• Figures should be provided in RTF files using the SAS Output Delivery System (ODS), as Computer Graphics 
Metafile (CGM) formatted graphical output generated by SAS. 
• The CGM file itself should contain the title or footer. 
• The image should be clear and of high quality when viewed in the Word document, and when printed. 
• In general, boxes around the figures should be used. 
DATES & TIMES 
Depending on data available, dates and times will take the form DDMMMYYY THH:MM:SS. 


 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
SPELLING FORMAT 
English US.  
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in that order: 
Treatment Group 
For Tables, Graphs and Listings 
Tiotropium/olodaterol 5 μg /5 μg once daily + 
RPL554 1.5 mg 
RPL554 1.5 mg 
 
Tiotropium/olodaterol 5 μg /5 μg once daily + 
RPL554 6.0 mg 
RPL554 6.0 mg 
 
Tiotropium/olodaterol 5 μg /5 μg once daily + 
Placebo twice daily 
Placebo 
Non-randomized (where applicable) 
Non-randomized  
PRESENTATION OF TREATMENT SEQUENCES 
For outputs, treatment sequences will be represented as follows and in that order: 
Treatment Group 
For Tables, Graphs and Listings 
RPL544 1.5 mg / RPL544 6.0 mg / Placebo  
Seq 1 
RPL544 1.5 mg / Placebo / RPL544 6.0 mg  
Seq 2 
RPL544 6.0 mg / RPL544 1.5 mg / Placebo  
Seq 3 
RPL544 6.0 mg / Placebo / RPL544 1.5 mg  
Seq 4 
Placebo / RPL544 1.5 mg / RPL544 6.0 mg 
Seq 5 
Placebo / RPL544 6.0 mg / RPL544 1.5 mg 
Seq 6 
Non-randomized (where applicable) 
Non-randomized  


 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
PRESENTATION OF VISITS 
For outputs, visits will be represented as follows and in that order, considering there will be 3 treatment periods (1 to 
3): 
Long Name (default) 
Short Name  
Screening 
Scr 
Day 1 
Day 1 
Day 2 
Day 2 
Day 3 
Day 3 
End of Study 
EOS 
Overall (where applicable) 
Overall 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
 
Randomized treatment group (or treatment received if it’s a safety output), first by active dose [by ascending 
dose group] and then placebo.  
 
Center-patient ID,  
 
Date (where applicable), 
 
For listings where non-randomized patients are included, these will appear in a category after the randomized 
treatment groups labeled ‘Non-randomized’. 
APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 


 
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ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Partial 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Missing 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
 
 
Partial, but known 
components show that it 
cannot be on or after study 
med start date 
Known 
Not TEAE 
 
Partial 
Not TEAE 
 
Missing 
Not TEAE 
 
 
 
Partial, could be on or after 
study med start date 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month 
if day unknown or 31st December if day and month are 
unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < study med start date, then not TEAE 


 
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START DATE 
STOP DATE 
ACTION 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month 
if day unknown or 31st December if day and month are 
unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS  
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior  
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant  
If stop date >= study med start date and start date > end of treatment, assign 
as post study  
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, assign 
as post treatment 
 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 


 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
START DATE 
STOP DATE 
ACTION 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, assign 
as post treatment 
 
Partial 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown) and impute stop 
date as latest possible date (i.e. last day of month if day unknown or 31st 
December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, assign 
as post treatment 
 
Missing 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Missing 
Known 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 


 
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START DATE 
STOP DATE 
ACTION 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Missing 
Assign as concomitant