Clinical trial NCT03937479
Conditions: COPD
Sponsor: Verona Pharma plc
Start date: 2019-05-01; Completion date: 2019-11-15
Enrollment: 416 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate the dose response of RPL554 in patients with moderate to severe CHRONIC OBSTRUCTIVE PULMONARY DISEASE that are still symptomatic despite treatment with a stable background of tiotropium over 4 weeks of treatment. This study is intended to support optimal dose selection for a Phase III program evaluating RPL554 as an add-on treatment to standard of care therapy.

Detailed description:
This is a Phase IIb, randomized, double-blind, placebo controlled, multiple dose, parallel group study to investigate the effects of 4 weeks of treatment with nebulized RPL554 (at different dose levels) compared to placebo in patients with moderate to severe CHRONIC OBSTRUCTIVE PULMONARY DISEASE on a stable background therapy of open-label tiotropium. The study comprises seven visits: Pre-screening (Visit 0), Screening (Visit 1) and then a Treatment Period consisting of Randomization (Visit 2), and weekly visits for 4 weeks (Visit 3 to Visit 6).

Arms: arm 1: RPL554 0.375 mg twice daily arm 2: RPL554 0.75 mg twice daily arm 3: RPL554 1.5 mg twice daily arm 4: RPL554 3.0 mg twice daily arm 5: Placebo twice daily
Interventions: intervention 1: Ensifentrine (formerly RPL554) 0.375 mg twice daily plus placebo, in addition to tiotropium intervention 2: Ensifentrine (formerly RPL554) 0.75 mg twice daily plus placebo, in addition to tiotropium intervention 3: Ensifentrine (formerly RPL554) 1.5 mg twice daily plus placebo, in addition to tiotropium intervention 4: Ensifentrine (formerly RPL554) 3.0 mg twice daily plus placebo, in addition to tiotropium intervention 5: Ensifentrine (formerly RPL554) placebo twice daily, in addition to tiotropium
Intervention descriptions: intervention 1: Patients will be randomized to receive one of the following treatment arms plus tiotropiuim:

● RPL554 0.375 mg twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication. intervention 2: Patients will be randomized to receive one of the following treatment arms plus tiotropiuim:

● RPL554 0.75 mg twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication. intervention 3: Patients will be randomized to receive one of the following treatment arms plus tiotropiuim:

● RPL554 1.5 mg twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication. intervention 4: Patients will be randomized to receive one of the following treatment arms plus tiotropiuim:

● RPL554 3.0 mg twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication. intervention 5: Patients will be randomized to receive one of the following treatment arms plus tiotropiuim:

● Placebo twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication.

Protocol documents:
Prot_001.pdf: 
CONFIDENTIAL 
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CLINICAL STUDY PROTOCOL    
A PHASE II, RANDOMIZED, DOUBLE-BLIND, PLACEBO 
CONTROLLED DOSE RANGING STUDY TO ASSESS THE 
EFFECT OF RPL554 ADDED ON TO TIOTROPIUM IN 
PATIENTS WITH COPD 
STUDY NO. RPL554-CO-205  
Version: 
5.0  
Date: 
22 July 2019  
Phase: 
II 
Investigational  
Medicinal Product:  
RPL554 
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 institutional review board. 
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 cooperate 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 institutional review board 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 
 
 
 
 
 
 
 
 
Contract Research 
Organization 
 
 
A full list of all study sites and vendors participating in the study will be maintained in the study 
file. 
 
 
 


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DETAIL OF AMENDMENTS SINCE THE PREVIOUS VERSION 
Section 4.1, Inclusion Criteria 
Inclusion Criterion 4 has been modified to state that ECG tracing must show none of the 
abnormalities that are now listed in Section 14.2. 
Section 4.2, Exclusion Criteria 
Exclusion Criterion 14 has been modified to specify additional clinically significant 
cardiovascular findings that would render patients ineligible for enrollment. 
Exclusion Criterion 19 has been modified to specify additional hepatitis test findings, and their 
respective eligibility characteristics. 
Section 14.2, ECG Requirement for Inclusion 
This section has been added. 
 


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SYNOPSIS 
Title of Study:  
A Phase II, randomized, double-blind, placebo controlled, dose ranging 
study to assess the effect of RPL554 added on to tiotropium in patients with 
COPD 
Protocol Number: 
RPL554-CO-205 
IND Number:  
133146 
Phase: 
II 
Sponsor: 
Verona Pharma plc 
Number of Patients Planned: 
Approximately 400 randomized  
Study Center(s):  
Approximately 50   
Planned Study Period: 
May 2019 to November 2019 
Objectives: 
Primary Objective 
To investigate the bronchodilator effect of different doses of RPL554 
administered by nebulizer on change from baseline in peak forced 
expiratory volume in 1 second (FEV1) (maximum over 3 hours following 
dosing) at the final study visit (i.e., Visit 6, after 4 weeks of treatment) when 
administered twice daily to patients with moderate to severe Chronic 
Obstructive Pulmonary Disease (COPD) on a background of once-daily 
tiotropium. 
Secondary Objectives 
● 
To investigate the bronchodilator effect of RPL554 administered by 
nebulizer on average area under the curve (AUC)0-3h FEV1 at Visit 6  
● 
To investigate the bronchodilator effect of RPL554 administered by 
nebulizer on average AUC0-12h FEV1 at Visit 6 
● 
To investigate the effect of RPL554 administered by nebulizer on 
change from baseline in morning trough FEV1 at Visit 6 
● 
To investigate the effects of RPL554 on COPD symptoms, as measured 
by daily diary (Evaluating Respiratory Symptoms for COPD 
[E-RS™:COPD], St. George’s Respiratory Questionnaire for COPD 
patients (SGRQ-C), Baseline Dyspnea Index (BDI)/Transition 
Dyspnea Index (TDI), and patient global assessment of change (PGAC) 
● 
To investigate the bronchodilator effect of RPL554 administered by 
nebulizer on peak FEV1, trough FEV1 and average AUC0-3h FEV1 at 
Visits 3, 4 and 5 (i.e., after 1, 2 and 3 weeks of treatment) 
● 
To investigate the effect of RPL554 administered by nebulizer on peak 
FEV1, average AUC0-3h FEV1 and AUC0-12h FEV1 at Visit 2 
● 
To investigate the safety of RPL554 when administered for 4 weeks in 
patients with COPD, as measured by adverse events, laboratory tests, 
12-lead electrocardiograms (ECGs) and vital signs 
● 
To investigate the effect of RPL554 on rescue albuterol use 
● 
To investigate the bronchodilator effect of RPL554 administered by 
nebulizer on peak and average AUC0-3h forced vital capacity (FVC) at 
Visits 2 to 6, in average AUC0-12h FVC at Visits 2 and 6 and in morning 
trough FVC at Visits 3 to 6 
● 
To evaluate the steady state exposure of RPL554  
● 
To evaluate the effect of RPL554 on tiotropium steady state exposure 


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Exploratory Objectives 
● 
To assess peak and average AUC0-12h FEV1 at Visit 6 compared to Visit 
2  
● 
To investigate the effect of RPL554 or placebo on inspiratory capacity 
(IC) at Visits 2 and 6  
● 
To investigate the effects of RPL554 on COPD symptoms, as measured 
by the COPD Assessment Test (CAT) 
● 
To assess the effect of RPL554 on morning symptoms and activity 
limitation 
Study Design and Methodology: 
This is a Phase IIb, randomized, double-blind, placebo controlled, multiple 
dose, parallel group study to investigate the effects of 4 weeks of treatment 
with nebulized RPL554 (at different dose levels) compared to placebo in 
patients with moderate to severe COPD on a stable background therapy of 
open-label tiotropium. The study comprises seven visits: Pre-screening 
(Visit 0), Screening (Visit 1) and then a Treatment Period consisting of 
Randomization (Visit 2), and weekly visits for 4 weeks (Visit 3 to Visit 6).  
Visit 0 will be conducted for the patient to sign the informed consent form 
and receive a patient identification number prior to initiating any study-
related procedures (including medication washout). Patients will be 
screened for eligibility (Visit 1) following at least a 48-hour washout of all 
long-acting bronchodilators, and assessed for reversibility to albuterol. 
Eligible patients will enter a 14-day Run-in taking open-label tiotropium (as 
Spiriva® Respimat®) once daily in the morning, and dispensed an electronic 
diary (e-diary) for recording daily symptoms and activity, rescue medication 
use and confirming proper use of  study treatment. At Visit 1, patients will 
also be instructed on the use of tiotropium. 
Patients will be dispensed rescue medication to be used as needed for 
increased pulmonary symptoms during the screening, run-in and treatment 
periods.  
Study Procedures: 
At Visit 2, patients will be re-assessed for eligibility, including the 
assessment of the Randomization Criteria. Eligible patients will be stratified 
1:1 based on reversibility to albuterol as determined at Screening 
(“reversible” defined as ≥12% and ≥200 mL increase in FEV1, and 
“non-reversible” defined as <12% or <200 mL)). Each reversibility stratum 
will be capped at 50% of patients. Patients will then be randomized equally 
across the five possible treatment arms (four doses of RPL554 and placebo) 
within each reversibility stratum. Following randomization, patients will be 
dispensed double-blind study medication and instructed on the use of the 
nebulizer. Patients will first receive their tiotropium dose followed within 
2 minutes by double-blind study medication. The patient will take the 
second (evening) dose of study medication in the clinic following 
completion of spirometry efforts.  
Between clinic visits, patients will self-administer both tiotropium and study 
medication every morning at home, while only study medication will be 
taken in the evening. Patients will be instructed to withhold all study 
treatments (including tiotropium) and rescue albuterol prior to all study 
visits, and to bring their e-diary, open-label tiotropium and nebulized study 
medication to all study visits. 
Assessments performed at Visit 2 will include: 
● 
Randomization criteria 
● 
SGRQ-C, BDI and CAT questionnaires 


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● 
Pre-dose pharmacokinetic sampling 
● 
Pre- and 2-hours post-dose IC (via slow maneuver) 
● 
Spirometry pre-dose and up to 12 hours post-dose 
● 
12-lead ECG pre-dose and 2 hours post dose 
Assessments performed at Visits 3 through 5 will include: 
● 
Visit 3 only: 12-lead ECG pre-dose and 2 hours post-dose  
● 
Visit 4 only: pre-dose pharmacokinetic sampling, SGRQ-C, TDI, CAT 
and PGAC questionnaires 
● 
Spirometry pre-dose and up to 3 hours post-dose 
Assessments performed at Visit 6 will include: 
● 
SGRQ-C, TDI, CAT and PGAC questionnaires 
● 
Pre- and 2-hours post-dose IC (via slow maneuver) 
● 
Spirometry pre-dose and up to 12 hours post-dose 
● 
12-lead ECG at pre-dose and 2 hours post dose 
A follow-up telephone contact will be made approximately 1 week after 
Visit 6. Adverse events will be recorded from the time informed consent is 
provided until the telephone call. 
Main Criteria for Eligibility: 
Male and female patients 40 to 80 years old with moderate to severe COPD, 
with a post-bronchodilator FEV1 of 30 to 70% of predicted and FEV1/FVC 
ratio of ≤0.70. Patients must have a minimum score of 2 on the modified 
Medical Research Council (mMRC) dyspnea scale. They must have at least 
a 10 pack-year smoking history, and may be a former smoker or current 
smoker. At randomization, patients must continue to have a minimum score 
of 2 on the mMRC, demonstrate pre-dose FEV1 of 30 to 70% of predicted 
and be compliant with e-diary and tiotropium use during the 14 days 
between Visits 1 and 2. 
Patients must be clinically stable without recent COPD exacerbations or 
hospitalizations. They must not have uncontrolled disease or chronic heart 
failure. 
Study Treatments: 
Patients will be randomized to one of the following treatment arms: 
● 
RPL554 0.375 mg twice daily 
● 
RPL554 0.75 mg twice daily 
● 
RPL554 1.5 mg twice daily 
● 
RPL554 3.0 mg twice daily 
● 
Placebo twice daily 
All eligible patients will take open-label tiotropium provided by the study 
centers during the run-in and treatment periods.  
Duration of Treatment: 
The approximate planned duration for each completed patient will be 
14 days of run-in and 28 days of treatment with study medication. 
Statistical Methods: 
Treatments will be compared using mixed model for repeated measures 
(MMRM) adjusting for treatment, visit and treatment by visit interaction. 
Each RPL554 nebulized formulation treatment will first be compared to 
placebo using a closed test procedure starting with the highest dose of 
RPL554. With an FEV1 standard deviation estimated at 200 mL, a 2-sided 
test at a 5% significance and 73 evaluable patients per group, there will be 
an 80% power to detect a true difference of 93 mL between treatments. 
Assuming approximately a 10% early withdrawal rate, 80 patients per group 
are planned to be randomized. 


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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 ......................................................................................................... 13 
LIST OF ABBREVIATIONS ....................................................................................................... 14 
1 
INTRODUCTION ............................................................................................................... 16 
1.1 
Disease and Study Medication Review ......................................................................... 16 
1.2 
Summary of Risks and Benefits .................................................................................... 18 
2 
OBJECTIVES...................................................................................................................... 19 
2.1 
Primary Objective ......................................................................................................... 19 
2.2 
Secondary Objectives.................................................................................................... 19 
2.3 
Exploratory Objectives ................................................................................................. 19 
3 
INVESTIGATIONAL PLAN ............................................................................................. 20 
3.1 
Overall Study Design and Plan Description ................................................................. 20 
3.2 
Discussion of Study Design, including the Choice of Control Groups ........................ 22 
3.3 
Planned Duration of the Study ...................................................................................... 22 
3.4 
Definition of the End of the Study ................................................................................ 22 
4 
SELECTION OF STUDY POPULATION ......................................................................... 22 
4.1 
Inclusion Criteria at Screening...................................................................................... 22 
4.2 
Exclusion Criteria ......................................................................................................... 24 
4.3 
Randomization Criteria (i.e. Additional Inclusion Criteria at Randomization) ............ 25 
4.4 
Removal of Patients from the Study ............................................................................. 26 
4.4.1 
Screen Failures ........................................................................................................ 26 
4.4.2 
Study Treatment Discontinuation ........................................................................... 26 
4.4.3 
Patient Withdrawal.................................................................................................. 27 


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4.4.4 
Study Discontinuation ............................................................................................. 27 
4.4.5 
Replacement Policy ................................................................................................ 28 
5 
STUDY TREATMENTS .................................................................................................... 29 
5.1 
Study Treatments Administered ................................................................................... 29 
5.2 
Identity of Study Treatments ........................................................................................ 29 
5.2.1 
Study Medication .................................................................................................... 29 
5.2.2 
Tiotropium .............................................................................................................. 30 
5.3 
Study Medication Preparation and Labelling ............................................................... 30 
5.4 
Selection of Doses and Dosing Schedule...................................................................... 30 
5.4.1 
Selection of Doses in the Study .............................................................................. 30 
5.4.2 
Timing of Dose for Each Patient ............................................................................ 31 
5.5 
Storage .......................................................................................................................... 31 
5.6 
Accountability ............................................................................................................... 31 
5.7 
Method of Assigning Patients to Treatment Groups..................................................... 32 
5.8 
Blinding......................................................................................................................... 32 
5.9 
Prior and Concomitant Therapies and Medications ...................................................... 32 
5.9.1 
Prior and Concomitant COPD Medications ............................................................ 32 
5.9.2 
Other (non-COPD) Prior and Concomitant Medications ........................................ 34 
5.10 
Rescue Medication ........................................................................................................ 34 
5.11 
Treatment after the End of Study .................................................................................. 34 
6 
STUDY PROCEDURES AT EACH VISIT ....................................................................... 35 
6.1 
Pre-visit Restrictions ..................................................................................................... 39 
6.2 
Visit 0 (Pre-screening) .................................................................................................. 39 
6.3 
Visit 1 (Screening) ........................................................................................................ 39 
6.4 
Treatment Period: Visit 2 (Randomization) .................................................................. 40 
6.4.1 
Pre-dose Assessments ............................................................................................. 40 
6.4.2 
Study Medication Administration ........................................................................... 41 
6.4.3 
Post-dose Assessments............................................................................................ 41 
6.5 
Treatment Period: Visits 3 through 5 (Interim Treatment Visits) ................................. 41 
6.5.1 
Pre-dose Assessments ............................................................................................. 41 
6.5.2 
Study Medication Administration ........................................................................... 42 
6.5.3 
Post-dose Assessments............................................................................................ 42 
6.6 
Treatment Period: Visit 6 (End of Study [or Early Termination]) ................................ 42 


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6.6.1 
Pre-dose Assessments ............................................................................................. 42 
6.6.2 
Study Medication Administration ........................................................................... 43 
6.6.3 
Post-dose Assessments............................................................................................ 43 
7 
STUDY METHODOLOGY ................................................................................................ 44 
7.1 
Demographics, Baseline Characteristics and Eligibility Assessments ......................... 44 
7.1.1 
Demographic Variables .......................................................................................... 44 
7.1.2 
Medical and Disease History .................................................................................. 44 
7.1.3 
Reversibility Test .................................................................................................... 44 
7.1.4 
Modified Medical Research Council (mMRC) Questionnaire ............................... 44 
7.1.5 
Screening Laboratory Assessments and Chest X-ray ............................................. 44 
7.1.6 
Prior and Concomitant Medications and Therapies ................................................ 45 
7.2 
Efficacy/Pharmacodynamic Assessments ..................................................................... 45 
7.2.1 
Pulmonary Function Tests ...................................................................................... 45 
7.2.2 
Electronic Diary ...................................................................................................... 45 
7.2.3 
St. George’s Respiratory Questionnaire – COPD specific (SGRQ-C) ................... 46 
7.2.4 
Baseline and Transition Dyspnea Indexes (BDI and TDI) ..................................... 46 
7.2.5 
COPD Assessment Test (CAT) .............................................................................. 47 
7.2.6 
Patient Global Assessment of Change (PGAC) ...................................................... 47 
7.2.7 
Diary Compliance ................................................................................................... 47 
7.2.8 
Tiotropium and Study Medication Compliance ...................................................... 47 
7.3 
Pharmacokinetic Assessments ...................................................................................... 47 
7.4 
Safety Assessments ....................................................................................................... 48 
7.4.1 
Adverse Events ....................................................................................................... 48 
7.4.1.1 
Adverse Event Definitions............................................................................... 48 
7.4.1.2 
Recording and Assessing Adverse Events ....................................................... 49 
7.4.1.2.1 Severity........................................................................................................ 49 
7.4.1.2.2 Chronicity .................................................................................................... 49 
7.4.1.2.3 Causality ...................................................................................................... 49 
7.4.1.2.4 Action and Outcome.................................................................................... 49 
7.4.1.3 
Reporting Procedure for SAEs ........................................................................ 50 
7.4.2 
Pregnancy ................................................................................................................ 50 
7.4.3 
Laboratory Safety Assessments .............................................................................. 50 
7.4.3.1 
Hematology ..................................................................................................... 50 


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7.4.3.2 
Blood Chemistry .............................................................................................. 51 
7.4.3.3 
Urinalysis ......................................................................................................... 51 
7.4.4 
Vital Signs ............................................................................................................... 51 
7.4.5 
Physical Examination.............................................................................................. 51 
7.4.6 
12-Lead ECG .......................................................................................................... 51 
8 
QUALITY ASSURANCE AND QUALITY CONTROL .................................................. 52 
8.1 
Audit and Inspection ..................................................................................................... 52 
8.2 
Monitoring and Source Document Verification ........................................................... 52 
8.3 
Data Management and Coding...................................................................................... 53 
9 
STATISTICAL METHODS ............................................................................................... 55 
9.1 
Statistical and Analytical Plans ..................................................................................... 55 
9.2 
Populations to be Analyzed .......................................................................................... 55 
9.3 
Study Endpoints ............................................................................................................ 55 
9.3.1 
Primary Endpoint .................................................................................................... 55 
9.3.2 
Secondary Endpoints .............................................................................................. 55 
9.3.3 
Exploratory Endpoints ............................................................................................ 56 
9.4 
Statistical Methods ........................................................................................................ 56 
9.4.1 
Patient Disposition .................................................................................................. 56 
9.4.2 
Protocol Deviations ................................................................................................. 56 
9.4.3 
Demographics and Other Baseline Characteristics ................................................. 56 
9.4.4 
Extent of Exposure and Treatment Compliance ..................................................... 57 
9.4.5 
Efficacy/Pharmacodynamics................................................................................... 57 
9.4.6 
Pharmacokinetics .................................................................................................... 57 
9.4.7 
Safety ...................................................................................................................... 58 
9.4.8 
Handling of Withdrawals or Missing Data ............................................................. 58 
9.4.9 
Interim Analyses ..................................................................................................... 58 
9.5 
Determination of Sample Size ...................................................................................... 58 
10 
ETHICAL CONSIDERATIONS ........................................................................................ 59 
10.1 
Guidelines ..................................................................................................................... 59 
10.2 
Institutional Review Board and Regulatory Approval.................................................. 59 
10.3 
Informed Consent Process ............................................................................................ 59 
10.4 
Patient Confidentiality .................................................................................................. 59 
10.5 
Record Maintenance/Retention ..................................................................................... 60 


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11 
FINANCE AND INSURANCE .......................................................................................... 61 
12 
PUBLICATION POLICY ................................................................................................... 62 
13 
REFERENCES .................................................................................................................... 63 
14 
APPENDICES ..................................................................................................................... 66 
14.1 
Birth Control Methods For Women of Childbearing Potential Which May Be 
Considered As Highly Effective ............................................................................................... 66 
14.2 
12-lead ECC Requirement for Inclusion....................................................................... 67 
14.3 
Interpreting Adverse Event Causality ........................................................................... 68 
14.4 
Tiotropium Prescribing Highlights and Instructions for Use ........................................ 69 
 
List of Tables and Figures 
Table 1 Dose Levels and Concentrations of Study Medication ................................................. 29 
Table 2 Composition of Study Medication ................................................................................ 29 
Table 3 Restrictions for COPD Medications Prior to Screening ............................................... 33 
Table 4 Schedule of Assessments .............................................................................................. 36 
 
Figure 1 
Study Flow Chart ........................................................................................................ 20 
 
 
 
 
 


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LIST OF ABBREVIATIONS  
ANCOVA 
Analysis of covariance 
Anti-HBc 
Hepatitis B core antibody 
Anti-HBs 
Hepatitis B surface antibody 
ATS 
American Thoracic Society  
AUC 
Area under the curve 
BDI 
Baseline Dyspnea Index 
BMI 
Body mass index 
CAT 
COPD Assessment Test 
COPD 
Chronic obstructive pulmonary disease 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
E-RS™:COPD 
Evaluating Respiratory Symptoms for COPD 
EDTA 
Ethylenediaminetetraacetic acid 
ERS 
European Respiratory Society 
FAS 
Full analysis set 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
HBsAg 
Hepatitis B surface antigen 
HIV 
Human immunodeficiency virus 
HRT 
Hormone replacement therapy 
IC 
Inspiratory capacity 
ICH 
International Council on Harmonization 
ICS 
Inhaled corticosteroid 
INN 
International Nonproprietary Name 
IRT 
Interactive Response Technology (system) 
IUPAC 
International Union of Pure and Applied Chemistry 
LABA 
Long acting β2-agonists 
LAMA 
Long acting muscarinic antagonists 
mMRC 
Modified Medical Research Council (dyspnea scale) 
MMRM 
Mixed model for repeated measures 
NHANES 
National Health and Nutrition Examination Survey 
NYHA 
New York Heart Association 
PDE 
Phosphodiesterase 


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PGAC 
Patient global assessment of change 
PK 
Pharmacokinetics 
PPS 
Per protocol set 
pMDI 
Pressurized metered dose inhaler 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
Serious adverse event 
SAS 
Statistical analysis software 
SGRQ-C 
St. George’s Respiratory Questionnaire for COPD Patients 
SOC 
System organ class 
SOP 
Standard operating procedure 
SUSAR 
Suspected, unexpected serious adverse reaction 
TDI 
Transition Dyspnea Index 
TSH 
Thyroid stimulating hormone 


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1 
INTRODUCTION 
1.1 
Disease and Study Medication Review 
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow 
obstruction that is not fully reversible. Chronic inflammation of the respiratory tract, acute 
exacerbations primarily caused by viral and/or bacterial infections, airway remodeling, and 
excessive mucus production are believed to contribute to the airflow obstruction and lung 
parenchymal destruction. COPD is predicted to be the third leading cause of death and fourth most 
common cause of disability worldwide by 2030 and chronic tobacco smoke exposure is believed 
to be a key etiological factor (Stuckler, 2008).  
Current standard of care treatments include inhaled short- and long-acting bronchodilators, inhaled 
corticosteroids (ICS) and, more recently, the phosphodiesterase (PDE) 4 inhibitor roflumilast. 
These therapies have little or no effect on disease progression or mortality, although there is 
evidence to suggest that they can reduce exacerbation rates and improve quality of life 
(Rabe et al, 2005; Calverley et al, 2007; Rennard et al, 2011, Singh et al, 2015). Approximately 
30% to 40% of moderate to severe COPD patients on triple inhaled therapy (ICS/long-acting 
muscarinic antagonists [LAMA]/long-acting β2 agonists [LABA]) remain uncontrolled and 
continue to experience airway obstruction, COPD symptoms and exacerbations (Vestbo et al, 
2017). Thus, there is an urgent unmet medical need for drugs with novel mechanisms of action 
that can be used by these patients in addition to current therapies.  
RPL554, a small molecule isoquinolone derivative, is a dual inhibitor of two isoforms (type 3 and 
4) of the PDE family of enzymes. PDE3 and PDE4 are known to have a role in modulating the 
inflammatory airway response in respiratory diseases, including COPD, allergic asthma and 
allergic rhinitis. In general, PDE3 inhibitors act as bronchodilators (through interaction with 
smooth muscle cells), while PDE4 inhibitors have anti-inflammatory properties. There is also 
evidence to suggest that combined inhibition of PDE3 and PDE4 can have additive or synergistic 
anti-inflammatory and bronchodilator effects (reviewed by Abbott-Banner & Page, 2014). 
Pharmacological evidence from pre-clinical experiments with dual PDE3/4 inhibitors suggests that 
RPL554 may have potential therapeutic activity in COPD, cystic fibrosis and possibly asthma.  
PDE4 inhibitors (administered orally) have exhibited anti-inflammatory actions; however, they 
have been associated with unfavorable gastrointestinal side effects such as nausea, emesis, 
diarrhea, abdominal pain, loss of appetite, and weight loss (Harbinson 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 β2-agonists (Calzetta et 
al, 2013; Calzetta et al, 2015). RPL554, therefore, has the potential to benefit patients not 
satisfactorily treated with existing medicines. 
The safety, bronchodilator, bronchoprotective and anti-inflammatory activities of RPL554 have 
been evaluated in 13 completed clinical studies involving over 800 subjects. Initially, five studies 


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were conducted in healthy subjects, patients with mild-moderate persistent asthma and those with 
allergic rhinitis and COPD, using a nebulized solution 
 
(Franciosi et al, 2013; summarized in the Investigator’s Brochure).  
RPL554 was subsequently re-formulated
 
 
This formulation has been tested in eight completed clinical studies: 
1. 
Study RPL554-007-2014 was a Phase I study in which single and multiple ascending doses 
up to 24 mg were administered to healthy subjects and COPD patients (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 (PK) 
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 albuterol (2.5 mg and 7.5 mg) and placebo. RPL554 
produced a dose-dependent bronchodilation with a magnitude that was comparable to a 
maximal dose of albuterol, but with fewer of the well described albuterol side effects 
(e.g., hypokalemia, tachycardia, tremor and palpitations) (Bjermer et al, 2016).  
3. 
Study RPL554-009-2015 was a Phase II crossover study in moderate to severe COPD 
patients who received albuterol (200 µg), ipratropium (40 µg) or placebo using a pressurized 
metered dose inhaler (pMDI) followed immediately by nebulized RPL554 (6 mg) or 
placebo. RPL554 alone was as effective as standard of care bronchodilators, and importantly 
produced significant additive bronchodilation. Indeed, there was an approximately 60% 
additional increase in peak forced expiratory volume in 1 second (FEV1) in COPD patients 
administered RPPL554 in addition to either albuterol or ipratropium (RPL554-009-2015 
Clinical Study Report, 2017). 
4. 
Study RPL554-PK-101 was a Phase I study of the oral bioavailability of RPL554 in healthy 
subjects. Subjects were randomized to RPL554 6 mg given with, or without, a charcoal 
block. The study demonstrated a low oral bioavailability of 10.6% and a terminal half-life 
of 11.9 hours (RPL554-PK-101 Clinical Study Report, 2017). 
5. 
Study RPL554-CO-202 was a Phase II crossover study in patients with moderate to severe 
COPD who received tiotropium 18 µg once daily, plus RPL554 1.5 mg, RPL554 6 mg or 
placebo twice daily for 3 days. This study demonstrated a significant increase in peak FEV1 
(103 mL and 127 mL for RPL554 1.5 mg and 6 mg, respectively) as compared to tiotropium 
+ placebo. There was also significant improvement in both trough FEV1 and lung volumes, 
including residual volume and functional residual capacity. The time of onset of RPL554 + 
tiotropium was significantly faster than with tiotropium alone (4.2 versus 37 minutes) 
(Clinical Study Report pending). 
6. 
Study RPL554-CO-203 was a Phase II parallel group study in 403 patients with COPD who 
were administered either placebo or RPL554 at doses ranging from 0.75 mg to 6 mg over 
4 weeks. Clinically and statistically significant improvements in peak FEV1 compared to 
placebo were observed in all active dose groups at all time points. Secondary endpoints of 
average FEV1, COPD symptoms and quality of life were also met (Clinical Study Report 
pending). 


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7. 
Study RPL554-010-2015 was a Phase II crossover study in adult patients with cystic fibrosis. 
Patients received a single dose of RPL554, 1.5 mg, 6 mg, or placebo. This study 
demonstrated a significant increase (6.6%) in peak FEV1, as well as demonstrating PK levels 
that were similar to that seen in patients with COPD (Clinical Study Report pending). 
8. 
Study RPL554-CO-204 was a Phase II crossover study in patients with moderate to severe 
COPD who received tiotropium/olodaterol (Stiolto®) once daily, plus RPL554 1.5 mg, 
RPL554 6 mg or placebo twice daily for 3 days. This study demonstrated a non-significant 
but consistent increase in peak and average area under the curve (AUC)0-4h FEV1 
(approximately 34 mL to 62 mL for RPL554 1.5 mg and approximately -11 mL to 47 mL 
for RPL554 6 mg) as compared to tiotropium + placebo. There was a significant 
improvement in evening peak FEV1 and residual volume following the evening dose of 
RPL554 (Clinical Study Report pending). 
In general, RPL554 was considered safe and well tolerated in all studies, with adverse event rates 
that were similar to the subjects treated with placebo. All clinical studies are described in the 
Investigator’s Brochure.  
The purpose of this study is to investigate the dose response of RPL554 in patients with moderate 
to severe COPD that are still symptomatic despite treatment with a stable background of tiotropium 
over 4 weeks of treatment. This study is intended to support optimal dose selection for a Phase III 
program evaluating RPL554 as an add-on treatment to standard of care therapy.  
1.2 
Summary of Risks and Benefits 
Data from non-clinical studies had suggested a potential for hypotension and tachycardia. 
However, in the clinical studies to date, overall, RPL554 has been well tolerated in healthy subjects 
as well as patients with moderate to severe COPD, asthma and allergic rhinitis. The most common 
adverse events that were reported at least twice in subjects who received single or multiple doses 
of RPL554 were considered generally mild. In descending order of frequency, they included 
headache, cough, dizziness, and palpitations. Adverse events for single and multiple dose studies 
are summarized in the Investigator’s Brochure.  
There has been no evidence of clinically significant adverse events related to the cardiovascular or 
gastrointestinal systems. A small and transient increase in heart rate at 6 mg and 12 mg doses were 
reported; however, they were not considered clinically significant. Holter findings in completed 
studies did not show any arrhythmogenic potential.  
In single dose studies, there was an increase in the rate of headache that was most pronounced at 
doses over 6 mg. Results from multiple dose data in patients with COPD suggested a transient 
increase in dizziness, the majority of which occurred during spirometry or dosing; otherwise, the 
rate of adverse events was comparable for RPL554 and placebo treated patients. There was an 
increase in mild adverse events reported for healthy subjects treated with higher doses of RPL554 
(up to 24 mg) that were considered related to the higher serum levels of RPL554 achieved in 
healthy subjects than in those with COPD. 
 


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2 
OBJECTIVES 
2.1 
Primary Objective 
To investigate the bronchodilator effect of different doses of RPL554 administered by nebulizer 
on change from baseline in peak FEV1 (maximum over 3 hours following dosing) at the final study 
visit (i.e., Visit 6, after 4 weeks of treatment) when administered twice daily to patients with 
moderate to severe COPD on a background of once-daily tiotropium.  
2.2 
Secondary Objectives 
• 
To investigate the bronchodilator effect of RPL554 administered by nebulizer on average 
AUC0-3h FEV1 at Visit 6  
• 
To investigate the bronchodilator effect of RPL554 administered by nebulizer on average 
AUC0-12h FEV1 at Visit 6  
• 
To investigate the effect of RPL554 administered by nebulizer on change from baseline in 
morning trough FEV1 at Visit 6  
• 
To investigate the effects of RPL554 on COPD symptoms, as measured by daily diary 
(Evaluating Respiratory Symptoms for COPD [E-RS™:COPD], St. George’s Respiratory 
Questionnaire for COPD patients (SGRQ-C), Baseline Dyspnea Index (BDI)/Transition 
Dyspnea Index (TDI) and patient global assessment of change (PGAC) 
• 
To investigate the bronchodilator effect of RPL554 administered by nebulizer on peak 
FEV1, trough FEV1 and average AUC0-3h FEV1 at Visits 3, 4 and 5 (i.e., after 1, 2 and 3 
weeks of treatment) 
• 
To investigate the bronchodilator effect of RPL554 administered by nebulizer on peak 
FEV1, average AUC0-3h FEV1 and average AUC0-12h FEV1 at Visit 2 
• 
To investigate the safety of RPL554 when administered for 4 weeks in patients with COPD, 
as measured by adverse events, laboratory tests, 12-lead electrocardiograms (ECGs) and 
vital signs 
• 
To investigate the effect of RPL554 on rescue albuterol use  
• 
To investigate the bronchodilator effect of RPL554 administered by nebulizer on peak and 
average AUC0-3h forced vital capacity (FVC) at Visits 2 to 6, in average AUC0-12h FVC at 
Visits 2 and 6 and in morning trough FVC at Visits 3 to 6. 
• 
To evaluate the steady state exposure of RPL554  
• 
To evaluate the effect of RPL554 on tiotropium steady state exposure 
2.3 
Exploratory Objectives 
• 
To assess peak and average AUC0-12h FEV1 at Visit 6 compared to Visit 2  
• 
To investigate the effect of RPL554 on inspiratory capacity (IC) at Visits 2 and 6 
• 
To investigate the effects of RPL554 on COPD symptoms, as measured by the COPD 
Assessment Test (CAT) 
• 
To assess the effect of RPL554 on morning symptoms and activity limitation 
 


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3
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan Description 
This is a Phase IIb, randomized, double-blind, placebo-controlled, multiple dose, parallel group 
study. A flow chart illustrating the key components of the study is provided in Figure 1.  
Figure 1 
Study Flow Chart 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT PERIOD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0.375 mg RPL554 N=80 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0.75 mg RPL554 N=80 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication 
Washout 
Tiotropium  
Run-in Period 
 
 
1.5 mg RPL554 N=80 
 
 
Telephone 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 mg RPL554 N=80 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo N=80 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit  0                              1 
   2 
 
 3 
 
 4 
 
5 
 
 6 
 
 
Pre-Screen    
Screen 
 
 
Randomization      Í  Interim Treatment  Î   End of Study 
 
 
Follow-up 
  Day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Í2-28 daysÎ 
Í14 daysÎ 
 
 
 
 
 
 
 
 
 
 
 
 
Í1 week±2days daysÎ 
 
 
 
 
 
 
 
1 
 
7 
 
14 
 
21 
 
28 
 
 
 
 
 
The study comprises seven visits: Pre-screening (Visit 0), Screening (Visit 1) and then a Treatment 
Period consisting of Randomization (Visit 2), and weekly visits for 4 weeks (Visit 3 to Visit 6): 
The Pre-screening visit (Visit 0) will be conducted for the patient to sign the informed consent, 
receive a patient identification number and commence washout of prohibited medications. Patients 


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will be dispensed rescue medication to be used as needed for increased pulmonary symptoms 
during the Screening, Run-in and Treatment Period.  
At Visit 1, screening procedures will be performed following at least a 48-hour washout of all 
long-acting bronchodilators, and patients will be assessed for reversibility to albuterol.  
Eligible patients will then enter a 14-day Run-in, taking open-label tiotropium as Spiriva® 
Respimat® once daily in the morning starting the day after Visit 1, and dispensed an electronic 
diary (e-diary) for recording daily symptoms and activity, rescue medication use and confirming 
administration of tiotropium during run-in.  
Patients will then enter the Treatment Period lasting 4 weeks. At Visit 2, patients will be 
re-assessed for eligibility according to the randomization criteria. Eligible patients will be stratified 
based on reversibility to albuterol as determined at Screening (“reversible” defined as ≥12% and 
≥200 mL increase in FEV1, and “non-reversible” defined as ≤12% or <200 mL). Each reversibility 
stratum will be capped at 50%. Patients will then be randomized equally across the five possible 
treatment arms (four doses of RPL554 and placebo) within each reversibility stratum. Following 
randomization, patients will do the following: 
1) 
Be dispensed twice daily nebulized study medication    
2) 
Take their tiotropium dose followed within 2 minutes by double-blind study medication (see 
Section 5.3) 
3) 
Undergo serial spirometry and other assessments over 12 hours 
4) 
Be instructed by unblinded study staff in the use of the nebulizer, and demonstrate their 
ability when taking their second dose  
5) 
Take the second (evening) dose of study treatment prior to clinic discharge 
Between clinic visits, patients will self-administer both tiotropium and study medication every 
morning at home in the same order as described above, while only study medication treatment will 
be taken in the evening.  
Patients will be instructed to withhold study treatments (including tiotropium) and rescue albuterol 
prior to all study visits, and to bring their e-diary, open-label tiotropium and nebulized study 
medication to all study visits. Patients will be instructed to withhold albuterol for at least 6 hours 
prior to all visits. 
Patients will return for three interim, weekly visits (Visits 3, 4 and 5), where they will return used 
and unused double-blind study medication and receive new study medication from the unblinded 
study staff. The first dose of the newly dispensed study medication will be administered in the 
clinic with spirometry performed for 3 hours after dosing. Questionnaires, safety assessments, 
study treatment compliance (including tiotropium) and e-diary review will be conducted at Visits 2 
through 5. Blood samples for PK analysis will be collected pre-dose at Visits 2 and 4. 
At the End of Study visit (Visit 6) (after 4 weeks of treatment, or early termination), patients will 
take their last dose of tiotropium and study medication, and will be resident at the study center 
from the morning until at least 12 hours after dosing to allow for monitoring of lung function and 
study closeout procedures. A phone call will occur approximately 1 week after the final visit as a 
safety follow-up. 


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3.2 
Discussion of Study Design, including the Choice of Control Groups 
This study aims to determine the effect of RPL554 on the lung function, symptom improvement 
and safety measures on symptomatic patients with COPD on a stable background of tiotropium.  
Twice daily nebulized doses of RPL554 or placebo will be administered for 4 weeks on top of 
open-label tiotropium. Prior studies have demonstrated that twice daily dosing is appropriate given 
sustained bronchodilation observed over 12 hours. The treatment duration should allow for 
evaluation of RPL554 as a maintenance bronchodilator, including peak FEV1, and the 
anti-inflammatory response associated with the PDE3/4 dual mechanism of action, as measured 
by trough FEV1 and improvement in symptoms. An equal number of reversible and non-reversible 
patients is planned in order to enrich the population with patients expected to be more responsive 
to bronchodilator treatment to support optimal dose selection.  
A parallel group placebo-controlled design is used to allow for an examination of any dose 
dependent effects on efficacy and safety compared to placebo. This design makes it possible to 
obtain unbiased inferences about differences between treatments. Treatments will be administered 
double-blind with the Investigator and patient unaware of the treatment identity to further 
minimize any potential bias in the overall assessment of treatment effect and safety.  
An eight-fold dose range has been selected in order to show a separation between efficacious and 
sub-optimal doses. 
3.3 
Planned Duration of the Study 
The approximate planned duration for each patient (including the screening, run-in and treatment 
periods as well as the follow-up phone contact) will be between 44 and 83 days, as determined by 
adding the minimum and maximum time windows shown in Table 4. The total study duration, 
from screening of the first enrolled patient to completion of the last one, is expected to be 
approximately 6 months. 
3.4 
Definition of the End of the Study 
The end of the study is defined as the date of the follow-up phone call, 1 week (±2 days) after the 
End of Study visit of the last patient to complete the study. Consequently, any patient who for 
whatever reason does not have a follow-up phone call will be recorded as having early terminated 
in the electronic case report form (eCRF). 
4 
SELECTION OF STUDY POPULATION 
The population to be recruited into this study is stable patients with moderate to severe COPD, 
who continue to have symptoms and impaired lung function after 2-weeks of tiotropium 
maintenance therapy and without significant heart disease.  
Specific criteria are as follows: 
4.1 
Inclusion Criteria at Screening 
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. 


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3. 
Must agree to meet the following from the first dose up to 1 month after the last dose of 
study medication: 
 
If male: 
• 
Not donate sperm 
• 
Either: be sexually abstinent in accordance with a patient’s usual and preferred 
lifestyle (but agree to abide by the contraception requirements below should their 
circumstances change) 
 
Or: use a condom with all sexual partners. If the partner is of childbearing potential 
the condom must be used with spermicide and a second reliable form of contraception 
must also be used (e.g., diaphragm/cap with spermicide, established hormonal 
contraception, intra-uterine device) 
 
If female: be of non-childbearing potential or use a highly effective form of contraception as 
defined in Section 14.1.  
4. 
Have a 12-lead ECG recording at Screening showing none of the abnormalities listed in 
Section 14.2. 
5. 
Capable of complying with study restrictions and procedures, including ability to use the 
nebulizer correctly.   
6. 
Body mass index (BMI) between 18 and 35 kg/m2 (inclusive) with a minimum weight of 
45 kg. 
7. 
COPD diagnosis: Patients with a diagnosis of COPD as defined by the American Thoracic 
Society (ATS)/European Respiratory Society (ERS) guidelines (Celli and MacNee, 2004) 
with symptoms compatible with COPD for at least 1 year prior to Screening. 
8. 
Ability to perform acceptable and reproducible spirometry. 
9. 
Post-bronchodilator (four puffs of albuterol) spirometry at Screening demonstrating the 
following: 
• 
FEV1/ FVC ratio of ≤0.70 
• 
FEV1 ≥30% and ≤70% of predicted normal* 
*National Health and Nutrition Examination Survey (NHANES) III (Hankinson et al, 1999) will be used as the 
reference for normal predicted values. 
10. 
Clinically stable COPD in the 4 weeks prior to Screening (Visit 1) and during the period 
between Visits 1 and 2.  
11. 
A score of ≥2 on the modified Medical Research Council (mMRC) dyspnea scale at 
Screening. 
12. 
A chest X-ray (posterior-anterior) at Screening, or in the 12 months prior to Screening 
showing no clinically significant abnormalities unrelated to COPD. 
13. 
Meet the concomitant medication restrictions (within the time intervals defined in 
Section 5.9.1) and be expected to do so for the rest of the study.  
14. 
Current and former smokers with smoking history of ≥10 pack years.  
15. 
Capable of withdrawing from long acting bronchodilators (other than tiotropium) for the 
duration of the study, and short acting bronchodilators for 6 hours prior to dosing. 


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4.2 
Exclusion Criteria  
1. 
A history of life-threatening COPD including Intensive Care Unit admission and/or requiring 
intubation. 
2. 
COPD exacerbation requiring oral or parenteral steroids, or lower respiratory tract infection 
requiring antibiotics, within 3 months of Screening or prior to the first treatment. 
3. 
A history of one or more hospitalizations for COPD or pneumonia within 6 months of 
Screening or prior to the first treatment. 
4. 
Intolerance or hypersensitivity to albuterol, tiotropium or other muscarinic receptor 
antagonists. 
5. 
Other respiratory disorders: Patients with a current diagnosis of asthma, active tuberculosis, 
lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, interstitial lung diseases, uncontrolled 
or unstable sleep apnea, known alpha-1 antitrypsin deficiency, core pulmonale, clinically 
significant pulmonary hypertension or other active pulmonary diseases. 
6. 
Previous lung resection or lung reduction surgery. 
7. 
Pulmonary rehabilitation, unless such treatment has been stable from 4 weeks prior to 
Screening and remains stable during the study. 
8. 
Oral therapies for COPD (e.g. oral steroids, theophylline, and roflumilast) or antibiotics 
within 3 months prior to Screening, or ICS therapy within 4 weeks prior to Screening 
(additional prohibited medications, with shorter washout periods than those above, are 
shown in Table 3.) 
9. 
Prior exposure to RPL554. 
10. 
History of, or reason to believe a patient has, drug or alcohol abuse within the past 5 years. 
11. 
Received an experimental drug within 30 days or five half-lives, whichever is longer.  
12. 
Women who are pregnant or breast-feeding. 
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 moderate to severe renal 
impairment. 
14. 
Patients with historical or current evidence of clinically significant cardiovascular 
disease. Significant is defined as any disease that in the opinion of the investigator would 
put the safety of the subject at risk through participation or which could affect the efficacy 
or safety analysis if the disease/condition were to exacerbate during the study.  In particular, 
the following are excluded: 
• 
Myocardial infarction or unstable angina within 6 months prior to Screening 
• 
Unstable or life threatening cardiac arrythmia requiring intervention within 3 months 
prior to Screening 
• 
Diagnosis of NYHA class III and IV heart disease 
15. 
Use of non-selective oral β-blockers. 
16. 
Major surgery (requiring general anesthesia) within 6 weeks prior to Screening, lack of full 
recovery from surgery at Screening, or planned surgery through the end of the study. 
17. 
Required use of oxygen therapy, even on an occasional basis. 


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18. 
History of malignancy of any organ system within 5 years, with the exception of localized 
skin cancers (basal or squamous cell). 
19. 
Clinically significant abnormal values for laboratory safety tests (hematology, blood 
chemistry, viral serology or urinalysis) at Screening, as determined by the Investigator (see 
Section 7.1.5). Please note the following:  
• 
Alanine aminotransferase or aspartate aminotransferase cannot be more than twice the 
upper limit of normal.  
• 
A positive test at Screening for HIV, and/or active hepatitis C infection (anti-HCV 
reactive), are also exclusionary. 
• 
The following apply to hepatitis B findings: 
- 
Patients who are positive for both HBsAg and anti-HBc are excluded, as this 
indicates acute or chronic infection. 
- 
Patients who are negative for HBsAg and anti-HBs but positive for anti-HBc are 
excluded, as this may indicate current or resolving infection 
- 
Patients who are positive for anti-HBc and anti-HBs but negative to HBsAg are 
not excluded, as this indicates immunity due to natural infection. 
- 
Patients who are positive for anti-HBs but negative for HBsAg and anti-HBc are 
not excluded, as this indicates immunity due to hepatitis B vaccination 
20. 
Patients receiving immunotherapy (e.g., azathioprine, cyclophosphamide) whose effects 
could impact the PDE4 inhibition of RPL554. 
21. 
Patients with conditions which are sensitive to antimuscarinic effects such as narrow angle 
glaucoma, urinary retention, prostatic hypertrophy, or bladder neck obstruction. 
22. 
Current marijuana use (all forms). 
23. 
A disclosed history or one known to the Investigator, of significant non-compliance in 
previous investigational studies or with prescribed medications. 
24. 
Any other reason that the Investigator considers makes the patient unsuitable to participate.  
4.3 
Randomization Criteria (i.e. Additional Inclusion Criteria at Randomization) 
1. 
Subjects must score ≥2 on the modified mMRC dyspnea scale at Visit 2. 
2. 
Pre-dose FEV1 ≥30 % and ≤70% of predicted normal at Visit 2. 
3. 
E-diary compliance: Completion of the e-diary at least 5 of the last 7 days of the Run-in 
period. 
4. 
Patient must be at least 75% compliant with once-daily open-label tiotropium (according to 
e-diary) during the Run-in period. 
5. 
Patient must not have experienced a COPD exacerbation or lower respiratory tract infection 
between Visit 1 and Visit 2 (defined as use of any additional treatment other than current 
treatment and rescue medication and/or emergency department or hospital visit). 


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4.4 
Removal of Patients from the Study 
4.4.1 
Screen Failures 
All patients who provide informed consent but for whatever reason are not randomized will be 
considered a screen failure, and recorded as such in the Interactive Response Technology system 
(IRT).   
The following information will be recorded in the IRT for screen failures: 
• 
Date of Visit 0 
• 
Date of Visit 1 and/or Visit 2 (depending on when the patient screen fails) 
• 
Patient identification number 
• 
Reason for screen failure 
For all screen failures who experience an adverse event, and for those who perform at least one 
screening assessment at Visit 1, eCRFs will also be completed (the IRT system will provide a 
prompt for this purpose). The information to be recorded is as follows: 
• 
Same information as entered into IRT (per above) 
• 
Adverse events (if any) 
• 
Demographic information including race, age and gender* 
• 
COPD medications taken within 3 months prior to Visit 1*  
*These items will only be collected for screen failures for whom at least one screening assessment 
is performed at Visit 1. 
Patients will be stratified based on reversibility at Screening. Each stratum will be capped at 50% 
of total patients; therefore, when one of the reversibility strata is capped, additional patients 
meeting the criteria for that stratum will become ineligible for the study and will be considered 
screen failures. 
Patients who screen fail may be considered for re-Screening upon consultation with the Medical 
Monitor. Re-Screening in the event of failure to meet lung function criteria will generally not be 
allowed unless extenuating circumstances exist. Repeat, rescheduled, and unscheduled visits and 
procedures are permitted at the discretion of the Investigator (rescheduled visits are subject to the 
±1 day window mentioned above). 
4.4.2 
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 


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4.4.3 
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 tests 
will be recorded in the 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 End of Study visit 
may be performed.  
If a patient had signed a consent form but withdrew from the study without receiving any study 
medication, no further follow-up is necessary. 
4.4.4 
Study Discontinuation 
Conditions that may warrant termination of the study include, but are not limited to: 
• 
The discovery of an unexpected, serious, or unacceptable risk to patients enrolled in the 
study 
• 
The decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of RPL554 
• 
Serious failure of the Investigator to comply with the International Council on 
Harmonization ICH) Guidelines on Good Clinical Practice (GCP) or local regulations 
• 
Submission of knowingly false information from the research facility to the Sponsor, the 
institutional review board 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 institutional review board 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 institutional review board are notified. 


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4.4.5 
Replacement Policy 
It is planned to randomize approximately 400 patients; assuming a 10% early withdrawal rate, it 
is expected that approximately 360 patients will complete the study. Withdrawn patients may need 
to be replaced, depending on the actual discontinuation rate. 


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5 
STUDY TREATMENTS 
5.1 
Study Treatments Administered 
Patients will receive one of five possible different treatments as shown in Table 1, as determined 
by random assignment.  
Table 1 
Dose Levels and Concentrations of Study Medication 
Substance 
Dose Level (mg) 
 
RPL554 
0.375 
 
RPL554 
0.75  
 
RPL554 
1.5  
 
RPL554 
3.0  
 
Placebo 
N/A 
 
Abbreviations: N/A=not applicable 
5.2 
Identity of Study Treatments 
Note: For the purposes of this protocol, the term “study medication” refers to the nebulized, 
double-blind preparation of RPL554 or placebo, while “study treatment” refers collectively to both 
study medication and open label tiotropium. 
5.2.1 
Study Medication 
The recommended International Non-proprietary Name (INN) for RPL554 is ensifentrine. The 
International Union of Pure and Applied Chemistry (IUPAC) name for RPL554 drug substance is 
N-[2-{(2E)-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]-6,7-dihydro-2H-
pyrimido[6,1-a]isoquinolin-3(4H)-yl]ethyl]urea. The composition of the RPL554 and placebo 
formulations is shown in Table 2. 
Table 2 
Composition of Study Medication 
The RPL554 suspension formulations and 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 actives are sterile, micronized suspensions with surfactants to aid suspension. The 


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placebo is the same as the active formulation, except that the active ingredient is omitted. The 
RPL554 
active 
and 
placebo 
formulations 
are 
manufactured 
using 
aseptic manufacturing techniques in accordance with Good Manufacturing Practice (GMP) 
guidelines and will be provided to the sites as patient kits.  
5.2.2 
Tiotropium 
Tiotropium is a commercially available LAMA that will be supplied by study centers in open label 
fashion. Each supply will provide 30 days of dosing; therefore, two will be required for the duration 
of the study and will be dispensed at Visits 1 and 2. Instructions for use are provided in 
Appendix 14.4. 
5.3 
Study Medication Preparation and Labelling 
The vials and kits/cartons containing RPL554 and placebo will be labelled in compliance with 
GMP, released by a qualified person, where appropriate, and then shipped to the study center. 
 
 
At Visits 2 to 5, patients will be dispensed 18 vials of study medication for twice daily dosing over 
7 days (four vials provided as extras). For all visits, the first dose will be used for the in-clinic 
nebulization; for Visit 2 only the second dose will also be given in-clinic. The final dose 
administered in the morning at Visit 6 (final study visit) will be individually packaged. As such, 
the study medication administered in the clinic will always be stored only at the study center. 
 
 
 
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 should be dosed in a well-ventilated environment, and away from 
other patients (i.e., in a separate location of the clinic). 
For the in-clinic nebulizations, the following must be recorded in the eCRF: 
• 
Start and end times of nebulization (times will be rounded down to the nearest minute) 
• 
An estimation of the volume of residual product (in mL) at the end of nebulization 
5.4 
Selection of Doses and Dosing Schedule  
5.4.1 
Selection of Doses in the Study 
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 up to 4 weeks of dosing in COPD patients. These twice 
daily doses were shown to be effective as a bronchodilator over a 12-hour dosing interval, and to 
provide improvement in COPD symptoms and, in general, considered safe and well tolerated. 


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5.4.2 
Timing of Dose for Each Patient 
Double-blind study medication is to be administered twice daily, first in the morning between 7 
and 10 am, and then in the evening approximately 12 hours later. All doses for a given patient will 
be taken at approximately the same time each day (±1 hour). At each visit, study medication will 
be administered at the study center by unblinded personnel, and the precise time of administrations 
shall be documented in the eCRF.  
Tiotropium will be administered once-daily in the morning at approximately the same time each 
day, just prior to dosing with study medication. 
Patients will document whether each daily dose of all study treatments was taken in the e-diary. 
5.5 
Storage 
Study medication (RPL554 and placebo) should be stored below 77°F (25°C) and should not be 
frozen. 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 medication will be stored under the control of the Investigator or designee in a secure facility 
appropriate for the advised storage conditions. Study treatments that are to be returned by the 
Investigator/staff or have expired must be stored separately from the unused study treatments. 
Tiotropium is to be stored at room temperature 68°F to 77°F (20°C to 25°C).   
5.6 
Accountability 
The Investigator will be responsible for the dispensing, inventory and accountability of all study 
treatments (i.e., double-blind study medication and open label tiotropium), exercising accepted 
medical and pharmaceutical practices and ensuring that an accurate, timely record of the 
disposition is maintained. The study treatment supplies and inventory must be available for 
inspection by the designated representatives of the Sponsor upon request. 
Upon receipt of the study medication, the Investigator or designee will inspect the contents and 
return the completed acknowledgement of receipt. Copies of all study medication inventory 
records must be retained for accountability of study products and supplies. Accountability must be 
documented from the time of initial receipt at the study center to their final removal from the 
center.  
Written records must also be maintained to confirm the purpose and reason for any study 
medication disposal, e.g., the amount contaminated, broken, or lost, and the name/signature of the 
personnel responsible for reporting the event. Typically, study medication (including used vials) 
should be returned once final study medication accountability has been performed. If storage 
constraints require an earlier return of supplies, the study monitor should be contacted to make 
appropriate arrangements. 
At the end of the study, the unused double-blind study medication vials will be returned to the 
Sponsor after accountability has been verified.  


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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 be stratified at randomization according to reversibility testing at Screening, such that 
all treatment groups will have approximately equal numbers of patients who are reversible to 
albuterol (≥12% and ≥200 mL increase in FEV1) and those who are not. Each stratum will be 
capped at 50%. Within each stratum, patients will be equally randomized to one of the four doses 
or placebo before the first study medication administration at Visit 2. Medication identification 
numbers will be provided on the study medication kit.  
5.8 
Blinding 
With the exception of specified unblinded site personnel (per next paragraph), the active 
formulations of RPL554 and placebo will be double-blind. The placebo is the same as the RPL554 
active formulation, except that the active RPL554 ingredient is omitted
 
 
 
 
 
 These unblinded 
individuals will 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 (except for designated individuals responsible for pharmacovigilance 
and clinical supplies), Investigator (defined as Principal Investigator and all study physicians), all 
patients and all other research personnel (except bioanalytical personnel performing the PK assays 
and the unblinded study center personnel) will, therefore, be blinded to the treatment allocation.  
Note: Patients will also be aware of the appearance when pouring study medication into the 
nebulizer. Therefore, they should be instructed not to inform site personnel of the appearance of 
their study medication. Similarly, study personnel are not to discuss the appearance with patients. 
Patients will be instructed to seal the kit before returning it to the site at their next visit. 
The blind will be broken only if specific emergency treatment would require knowing the 
treatment status of the patient. If the blind needs to be broken, the Investigator will contact the 
Sponsor as soon as feasible. The Investigator may unblind the study medication immediately if 
he/she feels it is necessary prior to contacting the Sponsor. However, the Investigator should 
promptly document and explain to the Sponsor any premature unblinding. Otherwise, all blinding 
will be maintained until all queries are resolved and the database is locked.  
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 Visit 1 and all concomitant COPD 
therapies will be recorded in the eCRF, with the medication, dose, route and start and stop date(s) 


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and time(s) clearly recorded to document all required washout periods and compliance with the 
Inclusion and Exclusion Criteria. 
Tiotropium use at a stable dose once daily will be administered during the Run-in and Treatment 
Periods, starting on the morning after Visit 1.  
Upon providing informed consent, patients will discontinue COPD medications for the time 
periods described in Table 3 prior to the Screening visit and will remain off these medications for 
the duration of the study.  
Table 3 
Restrictions for COPD Medications Prior to Screening 
Medication 
Time Interval Prior to Screening Visit 
Oral COPD therapies – e.g. oral steroids, theophylline, 
roflumilast (Oral mucolytics allowed) 
3 months  
Antibiotics 
3 months 
Terbutaline 
1 day 
Short-acting antimuscarinics (e.g., ipratropium) 
1 day 
Once or twice daily bronchodilators (LAMA, LABA or 
LAMA/LABA) 
48 hours 
Inhaled corticosteroids  
4 weeks 
Nebulized therapies (other than study medication) 
1 week if a bronchodilator 
4 weeks if an ICS 
Abbreviations: COPD=chronic obstructive pulmonary disease; ICS=inhaed corticosteroids; LABA: long acting 
β2 agonist; LAMA=long acting muscarinic antagonist 
The following therapies are subject to restriction as indicated: 
• 
Patients must continue to take their background tiotropium medication at the same dose and 
regimen throughout the Run-in and Treatment Periods. Starting or stopping tiotropium or 
changes in dosing is not allowed.  
• 
Albuterol may be used as a rescue medication (see Section 5.10), but must be withheld for 
at least 6 hours prior to spirometry (per below), and this is to be confirmed in the spirometry 
system. 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: 
- 
6 hours prior to pre-reversibility spirometry at Visit 1 for Screening 
- 
6 hours prior to pre-dose spirometry for all subsequent visits 
- 
Until the completion of all spirometry assessments for all visits 
If following the above requirements provide inadequate symptom control, patients should contact 
the Investigator.  
• 
Pulmonary rehabilitation programs should not be started or completed during participation 
in the study, although an ongoing maintenance program is acceptable in accordance with 
Exclusion Criterion #7 
• 
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 


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5.9.2 
Other (non-COPD) Prior and Concomitant Medications  
All concomitant medications must be documented on the eCRF, as well as any prior medications 
taken within 3 months of the Screening visit (Visit 1).  
Patients may continue other prescribed non-respiratory therapies during the study that the 
Investigator considers to neither compromise patient safety nor affect study data. Such other prior 
prescription or non-prescription medications (medication, dose, route, treatment duration and 
indication) taken 3 months before Visit 1 must be recorded in order to confirm compliance with 
the Inclusion and Exclusion Criteria.  
5.10 
Rescue Medication 
Albuterol is to be used for rescue use. Rescue medication will be sourced by the study center and 
dispensed at Visit 0. See Section 5.9.1 for withholding requirements prior to spirometry and 
rescheduled visit allowances.  
Rescue albuterol use during each study visit, if required by the patient, must be separately 
documented by site staff on the eCRF (dose, route, and date and time of each administration). 
Rescue use between study visits will be documented by the patient daily in the e-diary (number of 
puffs).  
5.11 
Treatment after the End of Study 
There are no plans to provide study medication for compassionate use following study completion. 
At the end of the treatment period (Visit 6 or early termination), patients may resume conventional 
COPD therapy as prescribed by the investigator or other physician. 
Medications initiated after Visit 6 should not be entered into the eCRF except for those given for 
a serious adverse event (SAE).  
 
 


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6 
STUDY PROCEDURES AT EACH VISIT 
The study will consist of seven visits: 
• 
Pre-Screening (Visit 0), occurring between 2 and 28 days before Visit 1 (sufficient to allow 
for washout of prohibited medications) 
• 
Screening (Visit 1), occurring 14 (±1) days prior to the first study treatment administration. 
Screening procedures ideally should occur over the course of a single day, but may be done 
over more than one day if necessary. All Screening procedures must be performed prior to 
initiation of the run-in (i.e., administration of open-label tiotropium) 
• 
Five treatment visits (Visit 2 to Visit 6) each separated by 7 (±1) days  
The schedule of assessments at each visit is shown in Table 4 and listed in Section 6.1 to 
Section 6.6. The study assessments are described in Section 7. 
Post-dose assessments generally should be performed in the following order (as applicable): 
1) 12-lead ECG, 2) vital signs, 3) PK blood sample, 4) spirometry.  
 
 


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Table 4 
Schedule of Assessments 
Visit 
 
Visit 0 
Pre-Screen  
Visit 1 
Screening 
(Week -2 ±1 d) 
Visit 2 
Randomiza-
tion 
Visit 3 
(Week 1 ±1 d) 
Visit 4 
(Week 2 ±1 d) 
Visit 5 
(Week 3 ±1 d) 
Visit 6 
End of Study 
(Week 4 ±1 d 
or ET) 
Telephone 
Follow-up 
(1 week after 
Visit 6 ±2 d) 
Informed consent  
X 
 
 
 
 
 
 
 
Assign patient number 
X 
 
 
 
 
 
 
 
Dispense albuterol(a) 
X 
 
 
 
 
 
 
 
Prohibited medication washout 
X 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
Medicallsurgical & disease history 
 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
X 
X 
 
 
 
 
 
Randomization criteria 
 
 
X 
 
 
 
 
 
Prior/concomitant medications/therapies 
 
X 
X 
X 
X 
X 
X 
 
Physical examination 
 
X 
 
 
 
 
X 
 
Height and body weight 
 
X 
 
 
 
 
X(b) 
 
mMRC questionnaire 
 
X 
X 
 
 
 
 
 
12-lead ECG (QTcF and heart rate) 
 
X 
X(c) 
X(c) 
 
 
X(c) 
 
Vital signs (blood pressure, pulse) 
 
X 
X(d) 
X(e) 
X(e) 
X(e) 
X(d) 
 
Laboratory safety tests  
 
X 
 
 
 
 
X 
 
Urinalysis 
 
X 
 
 
 
 
X 
 
Viral serology 
 
X 
 
 
 
 
 
 
Pregnancy test(f) 
 
X 
X 
 
 
 
X 
 
Reversibility test 
 
X 
 
 
 
 
 
 
Chest X-ray (if needed) 
 
X 
 
 
 
 
 
 
Adverse event questioning 
 
X 
X 
X 
X 
X 
X 
X 
Slow spirometry (inspiratory capacity) -
30 min & +2 hours(g) 
 
 
X 
 
 
 
X 
 
Forced spirometry -30 min to +12 hours(h) 
 
 
X 
 
 
 
X 
 
Forced spirometry -30 min to +3 hours(i) 
 
 
 
X 
X 
X 
 
 


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Visit 
 
Visit 0 
Pre-Screen  
Visit 1 
Screening 
(Week -2 ±1 d) 
Visit 2 
Randomiza-
tion 
Visit 3 
(Week 1 ±1 d) 
Visit 4 
(Week 2 ±1 d) 
Visit 5 
(Week 3 ±1 d) 
Visit 6 
End of Study 
(Week 4 ±1 d 
or ET) 
Telephone 
Follow-up 
(1 week after 
Visit 6 ±2 d) 
Dispense tiotropium 
 
X 
X 
 
 
 
 
 
Dispense symptom e-diary 
 
X 
 
 
 
 
 
 
Review symptom e-diary 
 
 
X 
X 
X 
X 
X 
 
SGRQ-C, BDI/TDI & CAT 
questionnaires 
 
 
X 
 
X 
 
X 
 
Pre-dose PK blood sample(j) 
 
 
X 
 
X 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
Administer study treatments (tiotropium 
& double-blind study medication)(k) 
 
 
X(0 
X 
X 
X 
X 
 
Nebulization inhalation training 
 
 
X 
 
 
 
 
 
Dispense study medication & nebulizer 
 
 
X 
X 
X 
X 
 
 
Dispense compressor 
 
 
X 
 
 
 
 
 
Collect study medication & nebulizer 
 
 
 
X 
X 
X 
X 
 
Study treatment compliance (including 
tiotropium) 
 
 
X 
X 
X 
X 
X 
 
Administer PGAC questionnaire 
 
 
 
 
X 
 
X 
 
Collect compressor 
 
 
 
 
 
 
X 
 
Collect symptom e-diary 
 
 
 
 
 
 
X 
 
Abbreviations: BDI/TDI=Baseline Dyspnea Index/Transition Dyspnea Index; CAT=COPD assessment test; d=days; ECG=electrocardiogram; ET=early termination; 
mins=minutes; mMRC=modified Medical Research Council; QTcF=QT interval corrected using Fridericia’s formula; PGAC=Patient Global Assessment of Change; 
PK=pharmacokinetics; SGRQ-C=St George’s Respiratory Questionnaire-COPD specific  
(a) 
A second canister of albuterol may be dispensed during the study if necessary 
(b) 
Body weight only at Visit 6 
(c) 
ECG at Visits 2, 3 and 6 is performed pre-dose and 2 hours post-dose 
(d) 
Vital signs at Visits 2 and 6 are measured pre-dose and 30 minutes, 1, 2, 4, 6, 8 and 12 hours post-dose 
(e) 
Vital signs at Visits 3, 4 and 5 are measured pre-dose and 30 minutes, 1, 2 and 3 hours post-dose 
(f) 
Serum pregnancy test at Visit 1; urine pregnancy test at Visits 1, 2 and 6 
(g) 
Inspiratory capacity is performed via slow maneuver prior to forced efforts at Visits 2 and 6, 30 minutes pre-dose and 2 hours post-dose.  
(h) 
Forced efforts at Visits 2 and 6 are performed 30 minutes pre-dose (after inspiratory capacity), followed by 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose 
(i) 
Spirometry at Visits 3, 4 and 5 is performed 30 minutes pre-dose, followed by 30 minutes and 1, 2 and 3 hours post-dose 


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Visit 
 
Visit 0 
Pre-Screen  
Visit 1 
Screening 
(Week -2 ±1 d) 
Visit 2 
Randomiza-
tion 
Visit 3 
(Week 1 ±1 d) 
Visit 4 
(Week 2 ±1 d) 
Visit 5 
(Week 3 ±1 d) 
Visit 6 
End of Study 
(Week 4 ±1 d 
or ET) 
Telephone 
Follow-up 
(1 week after 
Visit 6 ±2 d) 
(j) 
Pre-dose samples are for assay of tiotropium steady state exposure prior to and following 14 days of treatment with RPL554. PK samples from Visit 4 will also be used for 
assay pf RPL554 concentrations 
(k) 
Study medication is to be dosed following administration of tiotropium  
(l) 
At Visit 2, study medication is to be administered twice; first, just after randomization and again 12 hours later once all assessments are complete 
 
 


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6.1 
Pre-visit Restrictions 
The following restrictions should be adhered to (for all study visits except where noted): 
• 
Patients should refrain, where possible, from xanthine (chocolate, caffeine containing drinks 
and food), for at least 24 hours before and during visits. Decaffeinated beverages are 
permitted 
• 
Patients should refrain from alcohol for 24 hours before and during visits (including visits 
for laboratory safety tests) and until all procedures for that study visit are completed 
• 
Patients must fast (water permitted) from 2 hours pre-dose until 1 hour post-dose (does not 
apply to Visits 0 or 1) 
• 
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 visits and should 
undertake no unaccustomed strenuous exercise between visits 
6.2 
Visit 0 (Pre-screening) 
The following will be performed at the Pre-screening visit: 
• 
Obtain written informed consent (see Section 10.3) 
• 
Assign patient identification number (see Section 5.7) 
• 
Dispense rescue albuterol and instruct patient to wash out of prohibited medications  
• 
Instruct patient to return 2 to 28 days later (as required for medication washout) for Visit 1 
6.3 
Visit 1 (Screening) 
Patients will be screened to determine eligibility against the Inclusion and Exclusion Criteria 
14 days before the first dose of study treatment. Patients must observe the medication restrictions 
described in Section 5.9.1, and other restrictions described in Section 6.1. To account for diurnal 
variability in pulmonary function, the Screening visit is to take place in the morning. 
The following assessments will be performed, generally in the order indicated (to the extent 
feasible):  
• 
Demographic information, height and body weight 
• 
Medical/surgical and disease history, including assessment of chronic bronchitis (see 
Section 7.1.2) 
• 
Prior medications and therapies 
• 
mMRC questionnaire 
• 
12-lead ECG 
• 
Vital signs 
• 
Physical examination 
• 
Pre-albuterol spirometry 
• 
Reversibility test (four puffs of albuterol) 
• 
Post-albuterol spirometry (20 to 30 minutes after administration) 
• 
Urinalysis 


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• 
Blood samples for laboratory safety tests (hematology and blood chemistry), viral serology 
and serum pregnancy (the latter for women of childbearing potential) 
• 
Urine pregnancy test (for women of childbearing potential). The result should be obtained 
prior to chest X-ray for females of childbearing potential 
• 
Chest X-ray (unless historical X-ray performed in last 12 months is available) 
• 
Questioning for adverse events 
If the patient meets all of the Inclusion and none of the Exclusion Criteria: 
• 
Dispensing of tiotropium and instructions on its use 
• 
Dispensing of e-diary and instructions on its use. The patient will log into the electronic 
device and answer all of the questions to ensure comprehension (see Section 7.2.2) 
The patient will be instructed on the following: 
• 
Instruct patient to return in 14 days for Visit 2 
• 
Observe the medication restrictions described in Section 5.9.1, and other restrictions 
described in Section 6.1 
• 
Contact the site for any significant increase in COPD symptoms 
6.4 
Treatment Period: Visit 2 (Randomization) 
Patients must withhold all medications described in Section 5.9 prior to treatment in accordance 
with the washout times provided. If not, the visit must be rescheduled so as to occur within the 
permitted windows. All restrictions defined in Section 6.1 should also be adhered to.  
6.4.1 
Pre-dose Assessments 
• 
The following assessments will be performed prior to dosing: Inclusion/Exclusion Criteria, 
including randomization criteria (see Section 4.1 to Section 4.3)  
• 
Concomitant medications; confirm that medications were withheld as required 
• 
Review of e-diary to confirm compliance with the device 
• 
Assessment of tiotropium compliance 
• 
mMRC questionnaire 
• 
Questioning for adverse events 
• 
Urine pregnancy test (females of childbearing potential only) 
• 
12-lead ECG 
• 
Vital signs 
• 
SGRQ-C, BDI and CAT questionnaires 
• 
Blood sample for tiotropium PK measurement 
• 
Slow spirometry (to obtain inspiratory capacity), performed 30 (±10) minutes pre-dose 
• 
Forced spirometry, performed following completion of slow maneuver  
• 
Inhalation training 
• 
Administration of tiotropium 


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6.4.2 
Study Medication Administration 
Patients will be administered either RPL554 or placebo by the unblinded study staff member 
according to the randomization scheme, and again approximately 12 hours later upon completion 
of the assessments listed below. 
Note: If possible, the unblinded study staff member should administer both doses at Visit 2, but if 
this cannot be arranged for the evening dose it may be done by a blinded staff member provided 
that he/she does not directly observe the patient pouring the suspension into the nebulizer. 
6.4.3 
Post-dose Assessments  
The following assessments will be performed, at the times indicated relative to the end of dosing: 
• 
12-lead ECG at 2 hours (±10 minutes) 
• 
Vital signs at 30 minutes and 1, 2, 4, 6, 8 and 12 hours (±10 minutes)  
• 
Spirometry: Forced efforts at 30 (±10) minutes and 1, 2, 3, 4, 6, 8 and 12 hours (the latter 
assessments all ±15 minutes). At 2 hours post-dose, a slow IC maneuver will precede the 
forced efforts 
• 
Questioning for adverse events 
Patients completing the visit will be dispensed a compressor, nebulizer, open label tiotropium and 
a box of double-blind study medication. They will demonstrate their ability to use the study 
medication and nebulizer by administering the evening dose while in the clinic that day. They will 
be instructed/reminded of the following: 
• 
Take tiotropium followed by study medication each morning (other than the morning of the 
next visit), and study medication each evening 
• 
Use of the e-diary 
• 
Return in 7 days (± 1 day) for Visit 3 
• 
Observe the medication restrictions described in Section 5.9.1, and other restrictions 
described in Section 6.1 
• 
Contact the site for any significant increase in COPD symptoms 
6.5 
Treatment Period: Visits 3 through 5 (Interim Treatment Visits) 
Patients will return for study visits at 1, 2 and 3 weeks post-randomization. The visits shall be 
scheduled to begin in the morning, such that dosing occurs within 1 hour of the time of 
administration at Visit 2. 
Patients must withhold all medications described in Section 5.9 prior to treatment in accordance 
with the washout times provided. If not, the visit must be rescheduled so as to occur within the 
permitted windows. All restrictions defined in Section 6.1 should also be adhered to.  
6.5.1 
Pre-dose Assessments 
The following assessments will be performed prior to dosing: 
• 
Concomitant medications; confirm that medications were withheld as required 
• 
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• 
Review compliance with study treatments (study medication and tiotropium), and nebulizer 
technique and maintenance 
• 
Review of e-diary to confirm compliance with the device 
• 
Assessment of tiotropium and study medication compliance 
• 
Questioning for adverse events  
• 
Visit 3 only: 12-lead ECG 
• 
Vital signs  
• 
Visit 4 only: PK measurement (tiotropium and RPL554) 
• 
Visit 4 only: SGRQ-C, TDI, CAT and PGAC questionnaires 
• 
Spirometry at 30 (± 10) minutes pre-dose (forced efforts only) 
• 
Administration of tiotropium 
6.5.2 
Study Medication Administration 
Patients will be administered either RPL554 or placebo by the unblinded study staff member 
according to the randomization scheme. 
6.5.3 
Post-dose Assessments  
The following assessments will be performed, at the times indicated relative to the end of dosing: 
• 
Visit 3 only: 12-lead ECGs at 2 hours (±10 minutes) 
• 
Vital signs at 30 minutes and 1, 2 and 3 hours (±10 minutes) 
• 
Spirometry at 30 (±10) minutes and 1, 2 and 3 hours (the latter assessments all ±15 minutes). 
• 
Questioning for adverse events 
Patients completing the visit will be dispensed a new nebulizer and box of study medication, and 
will be instructed/reminded of the following: 
• 
Use of the e-diary  
• 
Withhold use of all long acting (once or twice daily) bronchodilators (except for tiotropium) 
• 
Return in 7 days (± 1 day) for the next visit 
• 
Observe the medication restrictions described in Section 5.9.1, and other restrictions 
described in Section 6.1 
• 
Contact the site for any significant increase in COPD symptoms 
6.6 
Treatment Period: Visit 6 (End of Study [or Early Termination]) 
Patients will return for the final visit 4 weeks post-randomization. The visit shall be scheduled to 
begin in the morning, such that dosing occurs within 1 hour of the time of administration at Visit 2. 
Patients must withhold all medications described in Section 5.9 prior to treatment in accordance 
with the washout times provided. If not, the visit must be rescheduled so as to occur within the 
permitted windows. All restrictions defined in Section 6.1 should also be adhered to. 
6.6.1 
Pre-dose Assessments 
The following assessments will be performed prior to dosing: 
• 
Concomitant medications; confirm that medications were withheld as required 


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• 
Unblinded study staff will collect nebulizer, compressor and any used/unused study 
medication 
• 
Collect e-diary and review for compliance with the device  
• 
Assessment of tiotropium and study medication compliance 
• 
Questioning for adverse events 
• 
Physical examination and body weight 
• 
Blood samples for laboratory safety tests 
• 
Urinalysis 
• 
Urine pregnancy test (females of childbearing potential only) 
• 
12-lead ECG 
• 
Vital signs 
• 
SGRQ-C, TDI, CAT and PGAC questionnaires 
• 
Slow spirometry (to obtain inspiratory capacity), performed 30 (± 10) minutes pre-dose 
• 
Forced spirometry, performed following completion of slow maneuver 
• 
Administration of tiotropium 
6.6.2 
Study Medication Administration 
Patients (other than for whom this is an Early Termination visit) will be administered either 
RPL554 or placebo by the unblinded study staff member according to the randomization scheme. 
Study medication for Visit 6 is packaged separately, and is maintained on site throughout the 
patient’s participation in the study. 
6.6.3 
Post-dose Assessments 
The following assessments will be performed, at the times indicated relative to the end of dosing: 
• 
12-lead ECG at 2 hours (±10 minutes) 
• 
Vital signs at 30 minutes and 1, 2, 4, 6, 8 and 12 hours (±10 minutes) 
• 
Spirometry: Forced efforts at 30 (±10) minutes and 1, 2, 3, 4, 6, 8 and 12 hours (the latter 
assessments all ±15 minutes). At 2 hours post-dose, a slow IC maneuver will precede the 
forced efforts 
• 
Questioning for adverse events 
• 
Scheduling of telephone follow-up, 1 week (±2 days) after Visit 6 to review adverse events 


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7 
STUDY METHODOLOGY 
7.1 
Demographics, Baseline Characteristics and Eligibility Assessments  
Safety assessments (pregnancy testing, laboratory safety assessments [hematology, blood 
chemistry and urinalysis], vital signs, 12-lead ECG and physical examination) will be performed 
at Screening as part of the eligibility assessment as described in Section 7.4. 
7.1.1 
Demographic Variables 
Demographic variables, including date of birth, sex, height, 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. COPD disease 
history, including date of diagnosis will also be recorded.  In addition, the patient will be assessed 
for the presence of chronic bronchitis, which is defined as follows: productive cough and sputum 
production on most days for three months in each of two consecutive years (Pauwels et al, 2001). 
7.1.3 
Reversibility Test 
Reversibility in response to albuterol will be assessed at Screening as an eligibility measure. 
Spirometry (FEV1 and FVC) assessment before and after four puffs (400 µg) of albuterol, 
administered using a pMDI, will be performed. Pre- and post-reversibility spirometry will be 
performed in accordance with the information in Section 7.2.1. 
7.1.4 
Modified Medical Research Council (mMRC) Questionnaire  
The mMRC will be completed by patients at Visit 1, in accordance with Inclusion Criterion 11 in 
Section 4.1. It uses a simple grading system to assess a patient's level of breathlessness. It relates 
well to other health status measures and predicts future mortality risk (Pocket Guide to COPD 
Diagnosis, Management and Prevention, 2018).  
7.1.5 
Screening Laboratory Assessments and Chest X-ray  
Blood samples will be taken and analyzed for viral serology (human immunodeficiency virus, 
hepatitis B and hepatitis C serology) as well as thyroid stimulating hormone (TSH), 
triiodothyronine and thyroxine at Screening only.  
All female patients of childbearing potential will have a serum pregnancy test at Screening. 
Follicle-stimulating hormone (FSH) will be measured at Screening, where appropriate, to confirm 
post-menopausal status.  
Samples will be taken and handled according to the manual provided by the central laboratory. 
Safety laboratory assessments at Screening will be performed in accordance with the information 
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A chest X-ray (post-anterior) must be performed at Screening or in the 12 months prior to 
Screening. 
7.1.6 
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. 
7.2 
Efficacy/Pharmacodynamic Assessments  
7.2.1 
Pulmonary Function Tests 
Forced spirometry maneuvers (FEV1 and FVC) will be performed at all study visits, and slow IC 
maneuvers will be performed at Visits 2 and 6, in accordance with the information in Section 6. 
These should be conducted as separate maneuvers and should not be linked (i.e. slow maneuver 
leading directly into a fast effort).  
Post-dose measurements will be taken in relation to the morning dose of RPL554 or placebo. As 
noted in Section 5.3, all post-dose measurements will be relative to the end time of nebulization 
(sputtering).  
Spirometry assessments will be made in accordance with ATS/ERS guidelines (Miller et al, 2005). 
At all time points, 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. 
Inspiratory capacity (IC) is an indirect assessment of resting lung hyperinflation. IC maneuvers 
will be conducted according to ATS/ERS guidelines (Miller et al, 2005). At all time points where 
IC is collected, it will be performed prior to the forced maneuvers.  Three technically acceptable 
measurements should be made and recorded. The average of at least three acceptable maneuvers 
will be reported. Patients should be asked to breathe regularly for several breaths (typically at least 
three tidal maneuvers) until end expiratory lung volume is stable, then urged to take a deep breath 
to total lung capacity with no hesitation.  
Spirometry will be performed using equipment provided by the Sponsor and reviewed centrally, 
and sites will be instructed in proper use of the equipment prior to study initiation. 
7.2.2 
Electronic Diary 
At Visit 1 an e-diary will be dispensed to the patients continuing in the study, who will use it twice 
daily in the morning and at bedtime. In addition to  assessing use of tiotriopium, study medication 
and rescue use, the e-diary will collect symptom and activity information.  
In the morning, patients will be prompted to answer the following questions: 
• 
Please rate your overall COPD symptom severity in the early morning before your first 
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wheezing, shortness of breath, tightness in chest, chest congestion, difficulty bringing up 
phlegm. 
- 
Rate your symptoms on a scale of 0 to 4: 0= no symptoms and 4= very severe 
symptoms 
• 
Please rate your early morning activity limitation due to COPD symptoms before your 
first dose of any COPD medication. 
- 
Rate your ability to perform your daily activities in the morning upon awakening such 
as showering, making breakfast, dressing, etc.)  on a scale of 0 to 4: 0= I do not have 
any difficulty in performing) to 4= I have great difficulty in performing. 
In the evening, symptoms will be assessed using the E-RS™:COPD scale (EXACT-PRO® Initiative 
website, 2018). E-RS™:COPD uses the 11 respiratory symptom questions in the EXACT-PRO® 
instrument. Three subscales are used to assess breathlessness, cough/sputum and chest symptoms. 
The E-RS™:COPD has a scoring range of 0 to 40. 
At Screening (Visit 1), study staff will train the patients on use of the e-diary as follows: 
• 
Have patients log into the device using a password and read and answer all of the 
14 questions to ensure comprehension 
• 
Instruct patients to reflect on their day and answer the questions based on how they felt 
over the day 
• 
Remind patients there are no right or wrong answers 
• 
Remind patients that all 14 items are to be answered daily 
7.2.3 
St. George’s Respiratory Questionnaire – COPD specific (SGRQ-C) 
Patients will be asked to complete the SGRQ-C while they are at the study site at Visits 2, 4 and 
6. The SRGQ-C is designed to measure impact on overall health, daily life, and perceived 
well-being in patients with COPD (Meguro et al, 2007). It is a revised version of the original 
SGRQ (Jones et al, 1991) in that it is intended only for COPD patients, is shorter in length and 
does not specify a recall period.  
The study staff should explain to patients why they are completing it and ask them to complete it 
as honestly as possible, stressing that there are no right or wrong answers. It is important that the 
questionnaire is completed in a quiet area by patients on their own, and that a member of the study 
staff is available to give advice if required. It is appropriate to clarify a question, but not to provide 
an answer on behalf of the patient. It is designed to elicit the opinion of the patient, not someone 
else’s; consequently, any family members or friends present should not influence the responses. 
Once the patient has completed the SRGQ-C it is important that a member of the study team check 
that a response has been given for every question and if this is not the case, that it is returned to 
the patient for completion. 
7.2.4 
Baseline and Transition Dyspnea Indexes (BDI and TDI) 
The BDI will be performed at Visit 2 and the TDI at Visits 4 and 6. These questionnaires are 
interviewer administered ratings of dyspnea severity. It is based on three components that evoke 
dyspnea in activities of daily living. The BDI is scored from 0 to 12 and is only assessed at baseline. 
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severity from the baseline as measured by the BDI. It is rated by seven grades ranging from -
3 (major deterioration) to +3 (major improvement) (Mahler et al, 1984).  
7.2.5 
COPD Assessment Test (CAT) 
Patients will complete the CAT at the same visits as the SGRQ. Given that the impact of COPD 
on patients goes beyond dyspnea, the CAT was developed as a more comprehensive assessment 
of symptoms (Pocket Guide to COPD Diagnosis, Management and Prevention, 2018).  
Similar guidelines as indicated in Section 7.2.3 above apply to the CAT as well. 
7.2.6 
Patient Global Assessment of Change (PGAC) 
At Visits 4 and 6, patients will be asked to respond to a PGAC question asking, “Compared with 
prior to the study start, how do you feel your breathing is?” on a scale of ‘1=much worse’ to 
‘5=much better’, with ‘3=no change’. 
7.2.7 
Diary Compliance 
Site staff will review compliance with e-diary entries at study visits. Patients who not at least 75% 
compliant should be re-educated on the importance of completing their e-diary twice daily; such 
non-compliance will be recorded as a deviation.  
7.2.8 
Tiotropium and Study Medication Compliance 
Patients will return their tiotropium and study medication at each treatment visit. Patients who are 
not at least 75% compliant with study treatment administration should be re-educated on the 
importance of taking these study treatments as specified in the protocol; such non-compliance will 
be recorded as a protocol deviation. 
7.3 
Pharmacokinetic Assessments 
Determination of plasma concentrations of tiotropium will be performed on blood samples taken 
pre-dose at Visit 2, and concentrations of tiotropium and RPL554 will be performed at Visit 4. 
Blood samples of 4 mL will be collected by venipuncture in the forearm vein using a Vacuette® 
Blood Collection System into a lithium heparin tube and then into a K2 ethylenediaminetetraacetic 
acid (EDTA) tube. Once mixed by inversion, the samples will be promptly chilled in an 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 appropriately 
labelled screw capped polypropylene tubes. After each blood collection, the plasma will be 
dispensed into two aliquots for each analyte. 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. Additional handling and shipment instructions 
will be provided in the laboratory manual. 


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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. 
Since (per Section 3.4) the follow-up phone call is defined as the End of Study, all adverse events 
occurring from the time of informed consent until the follow-up phone call are to be reported in 
the eCRF. 
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 
• 
Is a congenital anomaly/birth defect 
• 
Other important 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 
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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 telephone follow-up. 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) 
• 
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) 


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• 
Seriousness (yes or no) 
7.4.1.3 
Reporting Procedure for SAEs 
The Investigator must report all SAEs to the Sponsor as soon as practical, but in call cases within 
24 hours of awareness. Any fatal SAEs notified in the 28-day period after the last dose of study 
medication must also be reported. 
SUSARs will be determined by the Sponsor’s Medical Monitor. 
SAEs will be reported to the 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 
Urine pregnancy tests will also be performed by the study center at Screening (confirmed to be 
negative prior to the chest X-ray) and pre-dose at Visits 2 and 6. 
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 safety tests detailed below, unscheduled and/or repeat testing may be 
performed at the discretion of the Investigator. Any additional laboratory results will also be 
merged into the final database. Laboratory results will be provided to the Investigator for each 
patient and each visit. The Investigator should assign whether each abnormal result is not clinically 
significant or a clinically significant by manually annotating a print out of the results.  
Samples will be taken and handled according to the manual provided by the central laboratory. 
7.4.3.1 
Hematology  
The following will be measured: hemoglobin, hematocrit, total white cell count, leukocyte 
differential count and platelet count.  
At each time point, a sample of venous blood will be collected in a collection tube containing 
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7.4.3.2 
Blood Chemistry 
The following will be measured: creatinine, total bilirubin, alkaline phosphatase, aspartate 
aminotransferase, alanine transaminase, gamma-glutamyl transferase, lactate dehydrogenase, 
creatine kinase, TSH, triiodothyronine, thyroxine, glucose, potassium, sodium and calcium. These 
assessments will be performed at the same times as for hematology. Note: TSH, triiodothyronine 
and thyroxine will be analyzed for samples obtained at Visit 1 only, to assess for hyperthyroidism, 
in accordance with Exclusion Criterion 10 and Section 7.1.5. 
At each time point, 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 the same time points as 
hematology and blood chemistry. The following will be tested: leukocytes, blood, ketones, 
bilirubin, urobilinogen, protein and glucose. If urinalysis on Dipstick is positive for leukocytes 
and/or blood/hemoglobin, a microscopic examination including erythrocytes, leukocytes, bacteria, 
casts, epithelial cells and crystals will be performed. 
7.4.4 
Vital Signs 
Blood pressure and pulse rate will be measured at each study visit in accordance with the 
information provided in Section 6. Post-dose measurements will be taken in relation to the morning 
dose of RPL554 or placebo.  
At each time point, supine vital signs will be assessed while the patient has been at rest for at least 
5 minutes. 
7.4.5 
Physical Examination 
A full physical examination, covering major body systems (assessments of the nose, throat, skin, 
thyroid gland, neurological system, respiratory system, cardiovascular system, abdomen [liver and 
spleen], lymph nodes and extremities) will be performed at Screening (Visit 1) and End of Study 
(Visit 6). Results will be recorded in the eCRF as normal, abnormal not clinically significant or 
abnormal clinically significant and abnormal results described.. 
7.4.6 
12-Lead ECG 
12-lead ECGs will be performed at Visits 1, 2, 3 and 6 in accordance with the information provided 
in Section 6. 
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. The ECGs will be centrally collected and analyzed. 
 
 
 
 


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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 institutional review board, 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 


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


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


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9 
STATISTICAL METHODS 
9.1 
Statistical and Analytical Plans 
This section presents a summary of the planned statistical analyses. A detailed plan describing the 
analyses to be conducted will be defined prior to database lock 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 (FAS) will consist of all randomized patients with sufficient data collected 
after intake of study treatment to compute the pharmacodynamic parameters based on FEV1 on at 
least one occasion.  
The per-protocol set (PPS) will consist of all patients in FAS without any major protocol deviations 
considered to influence the treatment effect of RPL554. 
The safety set will consist of all randomized patients who took at least one dose of study 
medication.  
The PK data set will consist of all randomized patients with blood sampling performed and a 
quantitative value of tiotropium and/or RPL554 concentration determined. 
9.3 
Study Endpoints  
9.3.1 
Primary Endpoint 
The primary endpoint is the change from baseline in peak FEV1 (maximum value during 3 hours 
following dose) at Visit 6 (after 4 weeks of treatment). 
9.3.2 
Secondary Endpoints 
• 
Change from baseline in average AUC0-3h FEV1 at Visits 2 to 6 
• 
Change from baseline in average AUC0-12h FEV1 at Visits 2 and 6 
• 
Change from baseline in peak FEV1 at Visits 2 to 5 
• 
Change from baseline in morning trough FEV1 at Visits 3 to 6 
• 
Change from baseline (i.e., mean over the last 7 days of Run-in) to the mean weekly values 
over weeks 1 to 4 in COPD symptoms, as measured by daily e-diary (E-RS™:COPD) 
• 
Change from baseline in the SGRQ-C questionnaire at Visits 4 and 6 
• 
TDI questionnaire at Visits 4 and 6 
• 
PGAC questionnaire at Visits 4 and 6 
• 
Change from baseline (i.e., mean over the last 7 days of Run-in) to the mean weekly values 
over weeks 1 to 4 in rescue medication use 
• 
Change from baseline in peak and average AUC0-3h FVC at Visits 2 to 6, in average AUC0-12h 
FVC at Visits 2 and 6 and in morning trough FVC at Visits 3 to 6. 


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• 
Trough plasma concentration of tiotropium at Visits 2 and 4, and trough plasma 
concentration of RPL554 at Visit 4 
• 
Safety and tolerability: 
− 
Continuous monitoring of adverse events 
− 
Laboratory safety tests (hematology, blood chemistry and urinalysis) 
− 
12-lead ECG (including QTcF and heart rate), supine vital signs (blood pressure and 
pulse rate) 
9.3.3 
Exploratory Endpoints 
• 
Change in peak and average AUC0-12h FEV1 between Visits 2 and 6 
• 
Change from baseline in IC after 4 weeks of treatment 
• 
Change from baseline in the CAT questionnaire at Visits 4 and 6 
• 
Change from baseline (i.e., mean over the last 7 days of Run-in) to the mean weekly values 
over weeks 1 to 4 in morning symptoms 
• 
Change from baseline (i.e., mean over the last 7 days of Run-in) to the mean weekly values 
over weeks 1 to 4 in morning activity limitation 
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 prior COPD medications by therapeutic class including ICS, LABA, LAMA or 
combinations thereof) will be listed and summarized appropriately.  
Medical history, prior and concomitant medications, viral serology results, mMRC score, 
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9.4.4 
Extent of Exposure and Treatment Compliance 
Compliance will be calculated based on two parameters – the number of used and unused vials 
returned and the dosing recorded in the e-diary. Total exposure will be based on the compliance 
with dose and the dose group the subject was randomized into. For in-clinic dosing, the RPL554 
exposure will be calculated based on the nominal dose. 
 
9.4.5 
Efficacy/Pharmacodynamics  
The FAS will be the primary efficacy population; outcomes based on the PPS will be considered 
as a sensitivity analysis.  
FEV1 and FVC will be summarized as actual value and change from baseline using descriptive 
statistics over time for all treatments and both study parts. 
The peak effect on FEV1 will be computed as the maximum value in the 3 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 included as the change from the pre-dose 
Day 1 baseline value.  
Computed pharmacodynamic parameters based on FEV1 will be compared between the treatments 
using a mixed model for repeated measures (MMRM) with fixed effects for treatment, visit and 
treatment by visit interaction, baseline as covariate, patient as random and covariance structure by 
visit.  
RPL554 treatments will be compared to placebo using a closed testing procedure. The highest dose 
(3 mg) will first be compared to placebo, and if found statistically significant then the next dose 
(1.5 mg) will be compared to placebo, and so on. Secondarily, doses will be compared pairwise. 
Results of the comparisons will be expressed as the mean effect difference with 95% confidence 
intervals and associated, 2-sided, p-value.  
Pharmacodynamic parameters based on FVC, average daily use of rescue medication, average 
weekly E-RS™:COPD means, SGRQ-C, TDI, CAT and PGAC scores will be compared between 
the treatments using similar MMRM models as for the primary variable. Subdomain scores of the 
E-RS™:COPD, SGRQ-C and weekly morning symptoms and activity limitation will be 
summarized and subjected to exploratory analyses. 
The number of COPD exacerbations will be summarized by treatment group. 
As a sensitivity analysis the primary endpoint (peak FEV1 at Visit 6), the average AUC0-12h FEV1 
at Visit 6 and the total E-RS™:COPD score at week 4 will also be compared using analysis of 
covariance (ANCOVA) models with fixed factors for treatment, reversibility strata and the 
pre-dose baseline value as a covariate. 
9.4.6 
Pharmacokinetics 
Plasma concentrations of tiotropium and RPL554 will be summarized by dose level using 
descriptive statistics (n, geometric mean, coefficient of variation, arithmetic mean, standard 
deviation, minimum, maximum and median). 


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9.4.7 
Safety  
Safety data including laboratory safety tests, 12-lead ECG, vital signs and physical examinations, 
will be summarized by treatment group and time point of collection, when appropriate, for each of 
the two parts separately. For continuous variables, the change from baseline (pre-dose at Visit 2) 
to each post-dose time point will also be calculated and summarized. Data will further be illustrated 
by shift tables (showing changes from low/normal/high) and shift plots for selected time points. 
Separate listings will be generated of abnormal values occurring after the first dose of study 
treatment. 
Coded adverse event terms will be presented by system organ class (SOC) and preferred term and 
summarized by treatment group for each part. Summary tables by treatment group with total 
number and number of patients with adverse events, SAEs, adverse events leading to 
discontinuation of study treatment, causally related adverse events and severe adverse events will 
be produced. Further SAEs, causally related adverse events and adverse events of each intensity 
will be summarized by SOC and preferred term.   
9.4.8 
Handling of Withdrawals or Missing Data 
Imputation of data for calculation of average (AUC) effects for FEV1 and FVC will be described 
in the statistical analysis plan. No other imputation of missing data will be performed for the 
parameter computations. For the sensitivity ANCOVA analyses, missing data will be imputed 
using the last observation carried forward method prior to analysis. 
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.  
9.4.9 
Interim Analyses 
No formal, unblinded interim analysis is planned for the study. To assess the plausibility of the 
assumptions in the sample size calculation, an estimate of the standard deviation of peak and 
AUC0-3h FEV1 will be made based on blinded data after completion of 125 patients. If the estimated 
standard deviations are markedly higher than the 200 mL assumed (>20%), a revised sample size 
estimation using the new standard and the previously used detectable difference (89) will be made. 
If the outcome is an increase of the sample size, an amendment will be submitted for approval.  
9.5 
Determination of Sample Size 
The standard deviation for peak FEV1 is estimated to be 200 mL. With a 2-sided test at a 5% 
significance level and 73 evaluable patients per group, there will be 80% power to detect a true 
difference of 93 mL between any two treatments. This detectable limit has been considered 
sufficient to identify an effective dose of RPL554. Assuming a 10% early withdrawal rate, 
80 patients per group will be randomized. 
 


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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 
Institutional Review Board and Regulatory Approval 
The Sponsor will supply all background data necessary to enable submission to the appropriate 
institutional review boards and regulatory authorities. The study will not commence before formal 
ethical and regulatory approvals have been granted. 
All changes or revisions of this protocol will be documented. The reason for the amendment will 
be stated. The Sponsor will ensure ethical and regulatory approval is obtained for all substantial 
amendments to the original approved documents. 
10.3 
Informed Consent Process 
It is the responsibility of the Investigator to obtain written informed consent from patients. All 
consent documentation must be in accordance with applicable regulations and ICH GCP. Each 
patient is requested to sign and date the informed consent form after (s)he has received and read 
the patient information sheet and received an explanation of what the study involves, including but 
not limited to: the objectives, potential benefits and risk, inconveniences and the patient’s rights 
and responsibilities. Patients will be given adequate time to evaluate the information given to them 
before signing the informed consent form. 
One original of the signed informed consent form must remain on file and must be available for 
verification by the study monitor at any time. A second original of the informed consent form plus 
the patient information sheet must be given to the patient or the patient’s legally authorized 
representative. 
10.4 
Patient Confidentiality 
Data collected during this study may be used to support the development, registration or marketing 
of the study medication. The Sponsor will control all data collected during the study and will abide 
by the European Union Directive on Data Privacy concerning the processing and use of patient’s 
personal data. For the purpose of data privacy legislation, the Sponsor will be the data controller. 
After patients have consented to take part in the study, their medical records and the data collected 
during the study will be reviewed by the Sponsor and/or its representatives. These records and data 
may, in addition, be reviewed by the following: independent auditors who validate the data on 
behalf of the Sponsor; regulatory authorities and the institutional review board 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 


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level of protection that applies within the European Union. The purpose of any such transfer would 
be to support regulatory submissions made by the Sponsor in such countries. 
10.5 
Record Maintenance/Retention 
The Investigator will retain the originals of all source documents generated at the location where 
the study is being conducted, either: 1) until after regulatory agency approval is obtained for the 
study medication in the country/countries in which the results of this study comprise the 
submission dossier, or 2) for a period of 2 years after the report of the study has been finalized, in 
the absence of a regulatory approval. After that time, all study-related documents will be archived 
according to ICH GCP regulations. 
 
 


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


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


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13 
REFERENCES 
Abbott-Banner KH, Page CP. Dual PDE3/4 and PDE4 inhibitors: novel treatments for COPD and 
other inflammatory airway diseases. Basic Clin Pharmacol Toxicol. 2014 May;114(5):365-376. 
Doi: 10.1111/bcpt.12209. Epub 2014 Mar 6. 
Bjermer L, Stewart J, Abbott-Banner KH et al. RPL554, a first-in-class dual PDE3/4 inhibitor is 
equi-effective as a bronchodilator to maximal doses of salbutamol in asthmatics but with fewer 
adverse events. Am J Resp Crit Care Med 2016;193:A7770. 
Calverley PM, Sanchez-Toril F, McIvor A et al. Effect of 1-year treatment with roflumilast in 
severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 176(2):154-161. 
Calzetta L, Page CP, Spina D, et al. The effect of the mixed phosphodiesterase 3/4 inhibitor 
RPL554 on human isolated bronchial smooth muscle tone. J Pharmacol Exp Ther 2013; 346: 414–
423. 
Calzetta L, Cazzola M, Page CP, et al. Pharmacological characterization of the interaction between 
the dual phosphodiesterase (PDE) 3/4 inhibitor RPL554 and glycopyrronium on human isolated 
bronchi and small airways. Pulm Pharmacol Ther 2015 Apr 18. pii: S1094-5539(15)00042-5.  
Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of patients 
with COPD: a summary of the ATS/ERS position paper. Eur Respir J, 2004; 2:932-946. 
Compton CH, Gubb J, Nieman R et al. Cilomilast, a selective phosphodiesterase-4 inhibitor for 
treatment of patients with chronic obstructive pulmonary disease: a randomized, dose-ranging 
study. Lancet 2001; 358(9278):265-270. 
EU Directive 95/46/EC: The Data Protection Directive. 
EXACT-PRO® Initiative website, 2018. Accessed from the following URL in November 2018: 
http://www.exactproinitiative.com. 
Franciosi LG, Diamant Z, Banner KH, et al. Efficacy and safety of RPL554, a dual PDE3 and 
PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary 
disease: findings from four clinical trials. Lancet Respiratory Medicine 2013; 1(9):714-727. 
Gamble E, Grootendorst DC, Brightling CE et al. Anti-inflammatory effects of the 
phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am J 
Respir Crit Care Med 2003; 168(8):976-982. 
Grootendorst D, Gauw SA, Verhoosel RM, et al. Reduction in sputum neutrophil and eosinophil 
numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007; 62(12); 1081-
1087. 
Hankinson JL, Odencrantz JR, Fedan KB. Spirometry reference values from a sample of the 
general U.S. Population. Am J Respir Crit Care 1999;159:179-187. 
Harbinson PL, MacLeod D, Hawksworth R et al. The effect of a novel orally active selective PDE4 
isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects. Eur Respir J 
1997;10(5):1008-1014. 
International Conference on Harmonisation Topic E6(R2). ICH Harmonised Tripartite Guideline. 
Good Clinical Practice. 


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Jones PW, Quirk FH, Baveystock CM. The St. George's Respiratory Questionnaire. Resp Med 
1991; 85 (suppl B): 2531. 
Mahler DA, Weinberg DH, Wells CK, et al. The measurement of dyspnea. Contents, interobserver 
agreement and physiologic correlates of two new clinical indexes. Chest 1984;85: 751-758. 
Meguro M, Barley EA, Spencer S, Jones PW. Development and validation of an improved, COPD-
specific version of the St. George Respiratory Questionnaire. Chest 2007; 132: 456-463. 
Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 
2005;26(2):319-338. 
Pauwels RA, Buist AS, Calverley PM, et al. Global strategy for the diagnosis, management, and 
prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic 
Obstructive Lung Disease (GOLD) workshop summary. Am J Respir Crit Care Med 2001; 
163:1256-1276. 
Pocket Guide to COPD Diagnosis, Management and Prevention, 2018 Edition.  Global Initiative 
for Chronic Obstructive Lung Disease (GOLD). 
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. Accessed from the following URL in 
November 2018:  
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/ 
2014_09_HMA_CTFG_Contraception.pdf. 
Rennard SI, Schachter N, Strek M, et al. Cilomilast for COPD: results of a 6-month placebo 
controlled study of a potent, selective inhibitor of phosphodiesterase 4. Chest 2006;129(1):56-66. 
Rennard SI, Calverley PM, Goehring UM, et al. Reduction of exacerbations by the PDE4 inhibitor 
roflumilast – the importance of defining different subsets of patients with COPD. Respir Res 2011; 
27:12-18.  
Singh D. New combination bronchodilators for chronic obstructive pulmonary disease: current 
evidence and future perspectives. Br J Clin Pharmacol 2015;79(5):695-708. 
Stuckler D. Population causes and consequences of leading chronic diseases: a comparative 
analysis of prevailing explanations. Milbank Q 2008; 86(2): 273-326. 
Ukena D, Rentz K, Reiber C, et al. Effects of the mixed phosphodiesterase III/IV inhibitor, 
zardaverine, on airway function in patients with chronic airflow obstruction. Respir Med 1995;89 
(6):441-444. 
van Schalkwyk E, Strydom K, Williams Z et al. Roflumilast, an oral, once-daily phosphodiesterase 
4 inhibitor, attenuates allergen-induced asthmatic reactions. J Allergy Clin Immunol 2005;116 
(2):292-298.  
Verona Pharma plc RPL554 Investigator Brochure, Version 18.0, February 2019.  
Verona Pharma plc RPL554 Investigational Medicinal Product Dossier current version. 
Verona Pharma plc.  RPL554-007-2014 Clinical Study Report, August 2016. 


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Verona Pharma plc.  RPL554-009-2015 Clinical Study Report (February 2017). 
Verona Pharma plc.  RPL554-010-2015 Clinical Study Report (in preparation). 
Verona Pharma plc.  RPL554-PK-101 Clinical Study Report (December 2017). 
Verona Pharma plc.  RPL554-CO-202 Clinical Study Report (in preparation). 
Verona Pharma plc.  RPL554-CO-203 Clinical Study Report (in preparation). 
Vestbo J et al.  Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist 
therapy for chronic obstructive pulmonary disease (TRINITY); a double-blind, parallel-group, 
randomised controlled trial.  Lancet 2017;389:1919-29. 
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 (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
- 
Oral 
- 
Intravaginal 
- 
Transdermal 


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● 
Progestogen-only hormonal contraception associated with inhibition of ovulation1: 
- 
Oral 
- 
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 Vasectomized 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 
14.2 
12-lead ECG Requirement for Inclusion 
The ECG obtained at Screening must be free from any of the following abnormalities: 
• 
Sinus tachycardia ≥110bpm (Sinus tachycardia ≥110bpm should be confirmed by 2 
additional readings at least 5 minutes apart.) 
• 
Sinus bradycardia < 45bpm (Sinus bradycardia < 45bpm should be confirmed by 2 
additional readings at least 5 minutes apart) 
• 
Multifocal atrial tachycardia 
• 
Junctional (heart rate > 100bpm) 
• 
Junctional escape complexes 
• 
Supraventricular tachycardia (> 100bpm) 
• 
Ventricular tachycardia  
• 
Atrial fibrillation with rapid ventricular response (rate > 100bpm) 
• 
Atrial flutter 
• 
Bigeminy, trigeminy or multifocal premature ventricular complexes 
• 
Ventricular flutter 
• 
Ventricular fibrillation 
• 
Torsades de Pointes 
• 
R on T phenomenon 
• 
Wide QRS tachycardia (diagnosis unknown) 
• 
Electrical alternans 
• 
Pacemaker 
• 
Idioventricular rhythm – heart rate < 100bpm 
• 
Mobitz type II second degree or third degree atrioventricular (AV) block 
• 
AV dissociation  
• 
Bifascicular Block  


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• 
Trifascicular Block  
• 
Left bundle branch block 
• 
Subjects without complete right bundle branch block:  QTc(F) ≥ 450msec or an ECG that 
is unsuitable for QT measurements (e.g. poorly defined termination of the T wave) 
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. 
 
 


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14.4 
Tiotropium Prescribing Highlights and Instructions for Use  
Note: The information below is excerpted from the US package insert for tiotropium. Full 
prescribing information in the US is available at:   
https://docs.boehringer-
ingelheim.com/Prescribing%20Information/PIs/Spiriva%20Respimat/spirivarespimat.pdf#page=
15 
Instructions for Use 
SPIRIVA® RESPIMAT® (speh REE 
vah - RES peh mat) (tiotropium 
bromide) 
inhalation spray, for oral inhalation 
 
For oral inhalation only 
Do not spray SPIRIVA RESPIMAT into your eyes. 


RPL554-CO-205 
 
Version 5.0 
 
 
22 July 2019 
 
CONFIDENTIAL 
Page 70 of 75 
 
 
Read this Instructions for Use before you start using SPIRIVA 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 1 time each day, at the same time each day. Each time you use it take 2 puffs. 
 
Use SPIRIVA RESPIMAT exactly as prescribed by your doctor. Do not change your dose or how often 
you use SPIRIVA RESPIMAT without talking with your doctor. Children should use SPIRIVA RESPIMAT 
with the help of an adult, as instructed by their doctor. 
 
Tell your doctor about all of the medicines you take, including prescription and over-the-counter 
medicines, vitamins, and herbal supplements. SPIRIVA RESPIMAT may affect the way some medicines 
work and some other medicines may affect the way SPIRIVA RESPIMAT works. Do not use other inhaled 
medicines with SPIRIVA RESPIMAT without talking to your doctor. 
 
The SPIRIVA RESPIMAT inhaler has a slow moving mist that helps you inhale the medicine. 
 
Do not turn the clear base before inserting the cartridge. 
 
Your SPIRIVA RESPIMAT may have either an aqua or a blue cap, depending on the strength prescribed by 
your doctor. The steps shown below should be followed. 
 
 
How to store your SPIRIVA RESPIMAT inhaler 
● 
Store SPIRIVA RESPIMAT at room temperature between 68°F to 77°F (20°C to 25°C). 
● 
Do not freeze your SPIRIVA RESPIMAT cartridge and inhaler. 
● 
If SPIRIVA RESPIMAT has not been used for more than 3 days, release 1 puff towards the ground. 
● 
If SPIRIVA 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 SPIRIVA RESPIMAT cartridge, inhaler, and all medicines out of the reach of children. 
How to care for your SPIRIVA RESPIMAT inhaler 


RPL554-CO-205 
 
Version 5.0 
 
 
22 July 2019 
 
CONFIDENTIAL 
Page 71 of 75 
 
Clean the mouthpiece, including the metal part inside the mouthpiece, with a damp cloth or tissue only, at 
least 1 time each week. Any minor discoloration in the mouthpiece does not affect your SPIRIVA 
RESPIMAT inhaler. 
When to get a new SPIRIVA RESPIMAT inhaler 
● 
The scale on your inhaler shows the number of puffs in the inhaler. You should use 2 puffs 1 time each day. 
● 
The dose indicator shows approximately how many puffs are left in the inhaler. 
● 
When the dose indicator enters the red area of the scale you need to refill your prescription as soon as possible. 
● 
When the dose indicator reaches the end of the red scale, your SPIRIVA 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 SPIRIVA RESPIMAT even if it has not been used, or 
when the inhaler is locked, or when it expires, whichever comes first. 
 
 


RPL554-CO-205 
 
Version 5.0 
 
 
22 July 2019 
 
CONFIDENTIAL 
Page 72 of 75 
 
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. 
 
6. Press 
• 
Point the inhaler toward the ground. 
• 
Press the dose-release button. 
• 
Close the cap. 
• 
If you do not see a mist, repeat steps 4 to 6 until a mist is seen. 
• 
After a mist is seen, repeat steps 4 to 6 three more times. 
• 
After complete preparation of your inhaler, it will be ready to 
deliver the number of puffs on the label. 
 
 
 
 


RPL554-CO-205 
 
Version 5.0 
 
 
22 July 2019 
 
CONFIDENTIAL 
Page 73 of 75 
 
Daily use (T O P) 
Turn 
• 
Keep the cap closed. 
• 
Turn the clear base in the direction of the arrows 
on the label until it clicks (half a turn). 
 
Open 
• 
Open the cap until it snaps fully open. 
 
 
 
 
 
Press 
●
Breathe out slowly and fully. 
●
Close your lips around the mouthpiece without 
covering the air vents. 
●
Point the inhaler to the back of your throat. 
●
While taking a slow, deep breath through your 
mouth, Press the dose-release button and continue to 
breathe in. 
●
Hold your breath for 10 seconds or for as long as 
comfortable. 
●
Repeat Turn, Open, Press (TOP) for a total of 2 
puffs. 
●
Close the cap until you use your inhaler again. 


RPL554-CO-205 
 
Version 5.0 
 
 
22 July 2019 
 
CONFIDENTIAL 
Page 74 of 75 
 
Answers to Common Questions 
 
IT IS DIFFICULT TO INSERT THE CARTRIDGE DEEP ENOUGH: 
Did you accidentally turn the clear base before inserting the cartridge? Open the cap, press the dose-release 
button, then insert the cartridge. 
 
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 SPIRIVA RESPIMAT pointing to 0 (zero)? The SPIRIVA RESPIMAT inhaler 
is locked after the labeled number of puffs have been used. Prepare and use your new SPIRIVA 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 SPIRIVA RESPIMAT pointing to 0 (zero)? The SPIRIVA RESPIMAT inhaler 
is locked after the labeled number of puffs have been used. Prepare and use your new SPIRIVA RESPIMAT 
inhaler. 
 
THE DOSE INDICATOR ON THE SPIRIVA RESPIMAT REACHES 0 (ZERO) TOO SOON:  
DID YOU USE SPIRIVA RESPIMAT AS INDICATED (2 PUFFS 1 TIME EACH DAY)? 
 
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 SPIRIVA RESPIMAT is working? After you 
have prepared SPIRIVA RESPIMAT, no test-spraying is required if used daily. 
 
Did you insert the cartridge into a used SPIRIVA RESPIMAT? Always insert a new cartridge into a 
new SPIRIVA RESPIMAT. 
 
MY SPIRIVA 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. 


RPL554-CO-205 
 
Version 5.0 
 
 
22 July 2019 
 
CONFIDENTIAL 
Page 75 of 75 
 
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 SPIRIVA RESPIMAT DOES NOT SPRAY:U  
Did you insert a cartridge? If not, insert a cartridge. 
 
Did you repeat Turn, Open, Press (TOP) less than 3 times after inserting the cartridge? Repeat Turn, 
Open, Press (TOP) 3 times after inserting the cartridge as shown in steps 4 to 6 under “Prepare for first use”. 
 
Is the dose indicator on the SPIRIVA RESPIMAT pointing to 0 (zero)? You have used up all your 
medicine and the inhaler is locked. 
 
For more information about SPIRIVA RESPIMAT, including current prescribing information, or a video 
demonstration on how to use SPIRIVA RESPIMAT, go to www.spiriva.com, or scan the code below. You 
may also call 1-800-542-6257 or (TTY) 1-800-459-9906 for further information about SPIRIVA RESPIMAT. 
 
This 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® and RESPIMAT® are registered trademarks and are used under license from Boehringer 
Ingelheim International GmbH 
 
Copyright © 2019 Boehringer Ingelheim 
International 
GmbH 
ALL 
RIGHTS 
RESERVED 
Revised: February 2019 
IT5904IB252019 
 

SAP_000.pdf: 


PROTOCOL No. RPL554-CO-205 
Statistical Analysis Plan 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V1.0 (Dated 05DEC2019) for Protocol No. RPL554-CO-205. 
 
Name 
Signature
Date 
Author: 
 
 
 
 
 
 
 
 
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: 
 
 
 
 
 
 
 
Approved By: 
 
 
 
 
 
 
 
Approved By: 
 
 
Position: 
Company: 




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Abbreviations 
 
ACS 
Abnormal Clinically Significant 
ALT 
Alanine Amino Transferase 
ANCS 
Abnormal Not Clinically Significant 
AEs 
Adverse Events 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Amino Transferase 
ATC
Anatomical Therapeutic Chemical Classification System
AUC0-t 
Area under the curve over t hours 
BDI 
Baseline Dyspnea Index 
BMI 
Body Mass Index 
CAT 
COPD Assessment Test 
CIs
Confidence Intervals
COPD 
Chronic Obstructive Pulmonary Disease 
CV 
Coefficient of Variation 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ENR 
All Patients Enrolled Set
E-RSTM: COPD 
Evaluating Respiratory Symptoms for COPD 
FAS 
Full Analysis Set 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GGT 
Gamma Glutamyl Transferase 
IC 
Inspiratory capacity 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
Non-TEAE 
Non-treatment emergent adverse event 
PD 
Pharmacodynamic 
PGAC 
Patient Global Assessment of Change 
PK 
Pharmacokinetic 
PPS 
Per-Protocol Set 
PT 
Preferred Term 
QTcF 
QT interval corrected for heart rate using Friderica’s formula 
RND 
All Patients Randomized Set 
SAE 
Serious Adverse Event
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 


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SAS 
Statistical Analysis Software 
SGRQ-C 
St. George’s Respiratory Questionnaire 
SI 
Standard International 
SOC 
System Organ Class 
TDI 
Transition Dyspnea Index 
TEAE
Treatment-emergent Adverse Event 
WHO 
World Health Organization 


PROTOCOL No. RPL554-CO-205 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................................................................................ 9 
2. 
STUDY OBJECTIVES ....................................................................................................................................... 9 
2.1.
PRIMARY OBJECTIVE ......................................................................................................................................................................... 9 
2.2.
SECONDARY OBJECTIVE .................................................................................................................................................................... 9 
2.3.
EXPLORATORY OBJECTIVE ............................................................................................................................................................. 10 
3. 
STUDY DESIGN ............................................................................................................................................ 10 
3.1.
GENERAL DESCRIPTION ................................................................................................................................................................. 10
3.2.
SCHEDULE OF EVENTS .................................................................................................................................................................... 11 
3.3.
CHANGES TO ANALYSIS FROM PROTOCOL .................................................................................................................................... 11 
4. 
PLANNED ANALYSES ................................................................................................................................... 12 
4.1.
DATA MONITORING COMMITTEE (DMC) ........................................................................................................... 12 
4.2.
INTERIM ANALYSIS ......................................................................................................................................................................... 12 
4.3.
FINAL ANALYSIS ............................................................................................................................................................................. 12 
5. 
ANALYSIS SETS ............................................................................................................................................ 13 
5.1.
ALL PATIENTS ENROLLED SET [ENR] ................................................................................................................. 13 
5.2.
ALL PATIENTS RANDOMIZED SET [RND] ............................................................................................................ 14 
5.3.
FULL ANALYSIS SET [FAS] ............................................................................................................................... 14 
5.4.
PER-PROTOCOL SET [PPS] .............................................................................................................................. 14 
5.5.
SAFETY ANALYSIS SET [SAF] ............................................................................................................................ 14 
5.6.
PK DATA SET [PKS] ....................................................................................................................................... 14 
6.
GENERAL CONSIDERATIONS ....................................................................................................................... 14
6.1.
REFERENCE START DATE AND PERIOD DAY .................................................................................................................................. 14 
6.2.
BASELINE ........................................................................................................................................................................................ 15 
6.3.
RETESTS AND UNSCHEDULED VISITS ............................................................................................................................................. 15 
6.4.
WINDOWING CONVENTIONS ........................................................................................................................................................ 15 
6.5.
STATISTICAL TESTS AND SUMMARIES............................................................................................................................................ 16 
6.6.
COMMON CALCULATIONS ............................................................................................................................................................. 16 
6.7.
ACTUAL TREATMENT ..................................................................................................................................................................... 17 
6.8.
SOFTWARE VERSION ...................................................................................................................................................................... 17 
7. 
STATISTICAL CONSIDERATIONS ................................................................................................................... 17 
7.1.
ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN ANALYSES ......................................................................... 17 
7.2.
MISSING DATA ............................................................................................................................................................................... 17 
7.3.
MULTIPLE COMPARISONS/ MULTIPLICITY .................................................................................................................................... 18 
7.4.
EXAMINATION OF SUBGROUPS ..................................................................................................................................................... 18 
8. 
OUTPUT PRESENTATIONS ........................................................................................................................... 18 
9. 
DISPOSITION AND WITHDRAWALS ............................................................................................................. 18 


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10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .......................................................................... 18 
10.1. 
DERIVATIONS ................................................................................................................................................................................. 19 
10.2. 
MMRC........................................................................................................................................................ 19 
11. 
SURGICAL AND MEDICAL HISTORY.............................................................................................................. 20 
12. 
PRIOR AND CONCOMITANT THERAPIES AND MEDICATIONS ...................................................................... 20 
12.1. 
DERIVATIONS ................................................................................................................................................................................. 21 
13. 
STUDY TREATMENT EXPOSURE ................................................................................................................... 21 
13.1. 
DERIVATIONS ................................................................................................................................................................................. 21 
14. 
STUDY TREATMENT COMPLIANCE .............................................................................................................. 22 
14.1. 
DERIVATIONS ................................................................................................................................................................................. 22 
15. 
E-DIARY COMPLIANCE ................................................................................................................................ 22 
15.1. 
DERIVATIONS ................................................................................................................................................................................. 22 
16. 
EFFICACY OUTCOMES ................................................................................................................................. 23 
16.1. 
PRIMARY EFFICACY ........................................................................................................................................................................ 23 
16.1.1. 
Primary Efficacy Variables & Derivations ........................................................................................ 23 
16.1.2. 
Primary Analysis of Primary Efficacy Variables ............................................................................... 23 
16.2. 
SECONDARY EFFICACY ................................................................................................................................................................... 24 
16.2.1. 
Secondary Efficacy Variables & Derivations .................................................................................... 25 
16.2.2. 
Analysis of Secondary Efficacy Variables ......................................................................................... 29 
16.3. 
EXPLORATORY EFFICACY ................................................................................................................................................................ 29 
16.3.1. 
Exploratory Efficacy Variables & Derivations .................................................................................. 30 
16.3.2. 
Analysis of Exploratory Efficacy Variables ....................................................................................... 30 
16.4. 
MISSING DATA METHODS FOR EFFICACY VARIABLES .................................................................................................................. 31 
16.5. 
SENSITIVITY ANALYSIS FOR EFFICACY VARIABLES .......................................................................................................................... 32 
16.6. 
INTERIM ANALYSIS ......................................................................................................................................................................... 33 
16.6.1. 
Blinded ANCOVA analysis ................................................................................................................ 33 
16.6.2. 
Blinded MMRM analysis ................................................................................................................. 34 
17. 
SAFETY OUTCOMES .................................................................................................................................... 34 
17.1. 
ADVERSE EVENTS ........................................................................................................................................................................... 34 
17.1.1. 
Severity ............................................................................................................................................ 35 
17.2. 
LABORATORY EVALUATIONS .......................................................................................................................................................... 35 
17.2.1. 
Laboratory Markedly Abnormal Criteria ......................................................................................... 36 
17.3. 
ECG EVALUATIONS ........................................................................................................................................................................ 37 
17.3.1. 
ECG Specific Derivations .................................................................................................................. 37 
17.4. 
VITAL SIGNS ................................................................................................................................................................................... 38 
17.4.1. 
Vital Signs Markedly Abnormal Criteria .......................................................................................... 38 
17.5.
PHYSICAL EXAMINATION ...............................................................................................................................................................39
17.6. 
PHARMACOKINETICS ...................................................................................................................................................................... 39 


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18. 
REFERENCES ................................................................................................................................................. 40 
APPENDIX 1. 
PROGRAMMING CONVENTIONS FOR OUTPUTS ....................................................................... 41 
APPENDIX 2. 
PARTIAL DATE CONVENTIONS .................................................................................................. 43 
APPENDIX 3. 
REVERSIBILITY ROUNDING CRITERIA ........................................................................................ 47 
APPENDIX 4. 
ANNOTATED EXACT FOR RAW SCORE ASSIGNEMENT ............................................................... 48 
APPENDIX 5. 
RAW SUMMED SCORE TO SCALE CONVERSION TABLE FOR EXACT TOTAL SCORE ..................... 50 
APPENDIX 6. 
SGRQ-C ITEM WEIGHTS ............................................................................................................ 51 


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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 as described in Section 9 of the study protocol. It describes the data to be 
summarized and analyzed, including specifics of the statistical analyses to be performed. 
This statistical analysis plan (SAP) is based on protocol version 5.0, dated 22nd July 2019. 
 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
To investigate the bronchodilator effect of different doses of RPL554 administered by nebulizer 
on change from baseline in peak forced expiratory volume in 1 second (FEV1) (maximum over 3 
hours following dosing) at the final study visit (i.e., Week 4) when administered twice daily to 
patients with moderate to severe chronic obstructive pulmonary disease (COPD) on a 
background of once-daily tiotropium. 
2.2. 
Secondary Objective 
x To investigate the bronchodilator effect of RPL554 administered by nebulizer on average 
area under the curve AUC0-3h FEV1 at Week 4 
x To investigate the bronchodilator effect of RPL554 administered by nebulizer on average 
AUC0-12h FEV1 at Week 4 
x To investigate the effect of RPL554 administered by nebulizer on change from baseline in 
morning trough FEV1 at Week 4 
x To investigate the effects of RPL554 on COPD symptoms, as measured by daily diary 
(Evaluating Respiratory Symptoms for COPD [E-RS™:COPD], St. George’s Respiratory 
Questionnaire [SGRQ-C], Baseline Dyspnea Index [BDI]/Transition Dyspnea Index [TDI] 
and patient global assessment of change [PGAC]) 
x To investigate the bronchodilator effect of RPL554 administered by nebulizer on peak 
FEV1, trough FEV1 and average AUC0-3h FEV1 at Weeks 1, 2 and 3 
x To investigate the bronchodilator effect of RPL554 administered by nebulizer on peak 
FEV1, average AUC0-3h FEV1 and average AUC0-12h FEV1 at Day 1 
x To investigate the safety of RPL554 when administered for 4 weeks in patients with 
COPD, as measured by adverse events (AEs), laboratory tests, 12-lead electrocardiograms 
(ECGs) and vital signs 
x To investigate the effect of RPL554 on rescue albuterol use 
x To investigate the bronchodilator effect of RPL554 administered by nebulizer on peak and 
average AUC0-3h forced vital capacity (FVC) on Day 1 and at Weeks 1 to 4, in average 
AUC0-12 FVC on Day 1 and at Week 4 and in morning trough FVC at Weeks 1 to 4. 


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x To evaluate the steady state exposure of RPL554 
x To evaluate the effect of RPL554 on tiotropium steady state exposure 
2.3. 
Exploratory Objective 
x To assess the change from baseline FEV1 to peak and average AUC0-12h FEV1 at Week 4 
compared to Day 1 
x To investigate the effect of RPL554 on inspiratory capacity (IC) on Day 1 and at Week 4 
x To investigate the effects of RPL554 on COPD symptoms, as measured by the COPD 
Assessment Test (CAT) 
x To assess the effect of RPL554 on morning symptoms and activity limitation 
 
3. 
STUDY DESIGN 
3.1. 
General Description 
This is a Phase IIb, randomized, double-blind, placebo-controlled dose ranging, parallel group 
study. A flow chart illustrating the key components of the study is provided in Figure 1. 
 
Figure 1: 
Study Flow Chart 
 
 


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At the pre-screen visit patient will be asked to sign the informed consent, will receive their 
patient identification number and commence washout of prohibited medications. Patients will be 
dispensed rescue medication to be used as needed for increased pulmonary symptoms during the 
screening run-in and treatment periods. 
 
After patients provide informed consent and following at least a 48-hour washout of all long- 
acting bronchodilators, they will be screened for eligibility including a reversibility test 
(spirometry both pre- and post-four puffs of albuterol). Eligible patients will enter a 14-day run- 
in and be dispensed open-label tiotropium (Spiriva® Respimat) and an electronic diary (e-diary) 
for recording symptoms, assessing rescue usage and confirming twice daily dosing with study 
treatment. Starting the day after Screening (Visit 1) patients will start taking open-label 
tiotropium (Spiriva® Respimat®) once daily in the morning. 
 
At Day 1 patients will be re-assessed for eligibility according to the Randomization Criteria, 
which can be found in Section 4.3 of the study protocol. Eligible patients will be stratified based 
on the reversibility to albuterol, as determined at Screening (“reversible”, “non-reversible”), then 
randomized to one of the five treatment groups within each reversibility stratum. After 
randomization, patients will take their tiotropium dose 2 minutes prior to their first dose of 
double-blind study treatment (RPL554 or placebo). Patients will remain in the clinic for 12 hours 
to undergo serial spirometry and other assessments. They will then take their second dose of 
study treatment in the evening prior to clinic discharge. Patients will return to the clinic for 3 
weekly visits. In between visits, patients will take the study treatment twice a day (morning and 
evening) and tiotropium once a day in the morning, in the same order as described above. 
 
Patients will be instructed to withhold study treatment, tiotropium and rescue medication prior to 
study visits. Rescue medication will need to be withhold prior to the visit for at least 6 hours. 
 
Approximately 400 patients with COPD aged 40 to 80 years (inclusive) will be randomized 
equally to receive RPL554 (four possible doses) or placebo (Figure 1). Study treatment will be 
administered double-blind to minimize any potential bias in the overall assessment of treatment 
effect and safety. 
3.2. 
Schedule of Events 
Schedule of events can be found in Section 6.0 of the study protocol. 
3.3. 
Changes to Analysis from Protocol 
No changes to the analysis outlines in the protocol are planned. 


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4. 
PLANNED ANALYSES 
A final analysis after database lock is planned for this study. 
4.1. 
Data Monitoring Committee (DMC) 
There will be no data monitoring committee (DMC) for this study. 
4.2. 
Interim Analysis 
There will be no formal, unblinded interim analysis for this study. To assess the plausibility of 
the assumptions in the sample size calculation, peak FEV1, trough FEV1, AUC0-3 FEV1 and 
AUC0-12h FEV1 will be calculated on blinded data after completion of 125 patients. If the 
estimated standard deviation has an increase of 12% or less, then there will be no revised sample 
size made. However, if the estimated standard deviation has an increase of 20% or more, a 
revised sample size estimation using the new standard deviation and the previously assumed 
difference of 93 mL will be performed. If the increase in estimated standard deviation will be 
between 12% and 20% then a decision to review the sample size will be taken based on further 
examination of the data. 
4.3. 
Final Analysis 
All final, planned analyses identified in this SAP will be performed by IQVIA Biostatistics 
following sponsor authorization of this SAP (and associated output shells), database lock, 
analysis sets and unblinding of treatment. 


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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. 
Analyses will be performed for the population sets described in Table 1. 
 
Table 1: 
Use of the analysis set 
 
 
All 
Patients 
Enrolled 
Set 
All Patients 
Randomized 
Set 
Full 
Analysi
s Set 
Per- 
Protocol 
Analysis 
Set 
Safety 
Analysis 
Set 
PK 
data 
Set 
Disposition of patients 
X 
 
 
 
 
Protocol deviations 
X 
 
 
 
 
Demographic and other 
baseline characteristics 
 
X 
 
 
 
Medical history 
 
X 
 
 
 
Prior and concomitant 
medication 
 
X 
 
X 
 
Treatment compliance and 
extent of exposure 
 
 
 
X 
 
Efficacy: Primary endpoint  
 
X 
X 
 
 
Efficacy: Secondary 
endpoints 
 
 
X 
X 
 
 
Efficacy: Exploratory 
endpoints 
 
 
X 
 
 
Sensitivity Analyses (incl. 
primary and selected 
secondary endpoints) * 
 
 
X 
 
 
Safety 
 
 
 
X 
 
Pharmacokinetic 
 
 
 
 
X 
* ANCOVA analyses of the primary endpoint (change from baseline FEV1 to peak FEV1 at 
Week 4), and key secondary endpoints (change from baseline FEV1 to average AUC0-12h FEV1 at 
Week 4 and change from baseline in total E-RSTM:COPD score at Week 4). 
5.1. 
All Patients Enrolled Set [ENR] 
The all patients enrolled (ENR) set will contain all patients who provide informed consent for 
this study. Depending on the data that is being analysed, patients will either be classified 
according to randomized treatment or actual treatment received, specified in the relevant section. 


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5.2. 
All Patients Randomized Set [RND] 
The all patients randomized (RND) set will contain all patients in the ENR set who are 
randomized to study treatment. For analyses and displays based on the RND set, patients will be 
classified according to randomized treatment. 
5.3. 
Full Analysis Set [FAS] 
The full analysis set (FAS) will contain all patients in the RND set who have collected sufficient 
data after intake of study treatment to compute any of the FEV1 parameters (including peak 
FEV1, trough FEV1, AUC0-12h FEV1 and AUC0-3h FEV1) on at least one occasion. Patients will be 
classified according to randomized treatment. 
5.4. 
Per-Protocol Set [PPS] 
The per-protocol set (PPS) will contain all patients in the FAS set who had no major protocol 
deviations considered to influence the treatment effect of RPL554. Protocol deviations will be 
agreed and documented prior to database lock and unblinding. Patients will be classified 
according to randomized treatment. 
5.5. 
Safety Analysis Set [SAF] 
The safety analysis set (SAF) will contain all patients in the RND set who received at least one 
dose of study treatment. Patients will be classified according to actual treatment received. 
5.6. 
PK data Set [PKS] 
The pharmacokinetic (PK) data set (PKS) will contain all patients in the RND set who have 
blood sampling performed and a quantitative value of tiotropium and/ or RPL554 concentration 
determined. Patients will be classified according to actual treatment. 
 
6. 
GENERAL CONSIDERATIONS 
6.1. 
Reference Start Date and Period Day 
The reference start date is defined as the day of the first dose of study treatment (RPL554 or 
placebo) 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 start date, then: 
Study Day = (date of event – reference start date) + 1. 
If the date of the event is prior to the reference start date, then: 
Study Day = (date of event – reference start date).
In the situation where the event date is partial or missing, Study Day and any corresponding 
durations will appear partial or missing in the listings, unless otherwise stated. 


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6.2. 
Baseline 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior 
to study treatment start date (including unscheduled assessments). In the case where the last 
non-missing measurement and the study treatment start date coincide, the measurement will be 
considered pre-baseline, unless time is present. If time of the assessment is on or after the study 
treatment start date, then the assessment is not considered baseline. AEs and medications 
commencing on the reference start date will be considered post-baseline. 
6.3. 
Retests and Unscheduled Visits 
Retests, reschedules and unscheduled visits are permitted at the discretion of the Investigator. 
 
All the data available, including unscheduled or unplanned readings will be presented within the 
patient listings, however only scheduled readings will be used in the summaries. 
6.4. 
Windowing Conventions 
Each visit will have ±1 day window. No visit windowing will be applied during the analysis for 
patients that have completed the study, and therefore the data will be presented as per the visit 
reported in the database. 
For the discontinued patients End of Study (EOS) visit will be windowed to the corresponding 
visit, based on the study day, for questionnaire, spirometry and rescue medication data. The rules 
for the windowing are as follows: 
- 
For questionnaires that only happen at certain visits, windowing will only be done for 
those corresponding visits. 
o For SGRQ-C and CAT: 
 Day 1 = Day 1 
 Week 2 = after day 1 and up to and including day 16 
 Week 4 = after day 16 and up to and including day 30 
o For TDI and PGAC: 
 Week 2 = after day 1 and up to and including day 16 
 Week 4 = after day 16 and up to and including day 30 
o For rest of the questionnaires requiring windowing: 
 Day 1 = Day 1 
 Week 1 = after day 1 and up to and including day 9 
 Week 2 = after day 9 and up to and including day 16 
 Week 3 = after day 16 and up to and including day 23 
 Week 4 = after day 23 and up to and including day 30 
- 
For spirometry raw data and derived data that happens at every visit, windowing will be 
done as per the corresponding visits. 
o Day 1 = Day 1 


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o Week 1 = after day 1 and up to and including day 9 
o Week 2 = after day 9 and up to and including day 16 
o Week 3 = after day 16 and up to and including day 23 
o Week 4 = after day 23 and up to and including day 30 
- 
For spirometry derived data that only happen at certain visits, windowing will be done for 
the corresponding visits. 
o For morning trough: 
 Week 1 = after day 1 and up to and including day 9 
 Week 2 = after day 9 and up to and including day 16 
 Week 3 = after day 16 and up to and including day 23 
 Week 4 = after day 23 and up to and including day 30 
o For AUC0-12h: 
 Day 1 = Day 1 
 Week 4 = after day 1 and up to and including day 30 
- 
For rescue medication data, windowing will be done as per the corresponding visits. 
o Day 1 = Day 1 
o Week 1 = after day 1 and up to and including day 9 
o Week 2 = after day 9 and up to and including day 16 
o Week 3 = after day 16 and up to and including day 23 
o Week 4 = after day 23 and up to and including day 30 
6.5. 
Statistical Tests and Summaries 
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. 
 
The default significance level will be 5%; confidence intervals (CIs) will be 95% and all 
hypothesis testing will be done using two-sided alternative hypotheses, unless otherwise 
specified. 
6.6. 
Common Calculations 
x Change from baseline: Test Value at Visit X – Baseline Value 
x Percentage change from baseline: 
Test Value at Visit X – Baseline Value
Baseline Value 
כ 100% 


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6.7. 
Actual Treatment 
Once the study unblinds, the patient’s actual treatment will be assigned based on the most 
frequent dose they have received throughout the study. The external vendor, Cenduit, will 
provide the Material List document after confirmation of a Database Lock. This document will 
contain the kit numbers, which will be merged with the site data to the dosage that was dispensed 
at each visit. 
 
If a patient takes more than one dose and the ratio of patient taking them is the same, then 
assigning actual treatment will follow the two rules: 
- 
RPL554 overrides Placebo 
- 
Higher dose overrides lower dose, i.e. if a patient takes for 50% of the time 1.5 mg dose 
and for another 50% of the time 0.75 mg dose, then the patient would be assigned 1.5 mg 
as their actual treatment. 
6.8. 
Software Version 
All analyses will be conducted using SAS 9.4. 
 
7. 
STATISTICAL CONSIDERATIONS 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses 
The following covariates and factors will be used in the analyses. For details of their inclusion in 
the models, see the specific analysis section. 
x Fixed effects: treatment (RPL554 0.375 mg, RPL554 0.75 mg, RPL554 1.5 mg, RPL554 3 
mg, Placebo), visit (Day 1, Weeks 1, 2, 3 and 4), visit*treatment, actual reversibility strata 
(reversible, non-reversible) 
x Random effect – patient 
x Covariate – baseline 
7.2. 
Missing data 
Missing data will only be imputed for the calculation of average (AUC) effects for FEV1 and 
FVC, which is described in Section 16.4. 
 
For the sensitivity analysis using analysis of covariance (ANCOVA), missing data will be 
imputed using the last observation carried forward (LOCF) method prior to analysis described in 
Section 16.4. 


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7.3. 
Multiple Comparisons/ Multiplicity 
To address multiplicity in the analysis of the endpoints, statistical testing of the PD parameters 
and questionnaire scores will be done in a hierarchical order. Firstly, the 3 mg dose will be 
compared to placebo. If significant then the 1.5 mg dose will be compared to placebo. If found 
significant, the next lower dose will be compared to placebo. This process will continue until 
either all doses are compared to placebo, or if one of the comparisons is found to not be 
significant. There will also be a pairwise comparison between all RPL554 doses, where all doses 
are compared with each other, as shown in Table 2 in Section 16.1.2. 
7.4. 
Examination of Subgroups 
The subgroup analysis will be performed for smoking status, chronic bronchitis and actual 
reversibility.
The subgroups will be analysed using an MMRM approach, as described in Section 16.1.2 for 
the primary endpoint, with separate models for the different strata. Reversible patients are those 
who are reversible to albuterol (12% and 200 mL increase in FEV1), as defined in Section 5.7 
of the study protocol and Section 10 of this Statistical Analysis Plan. 
 
8. 
OUTPUT PRESENTATIONS 
Appendix 1 shows conventions for presentation of data in outputs. 
The shells document provided with this SAP describes the presentations for this study and 
therefore the format and content of the summary tables, figures, and listings to be provided by 
IQVIA Biostatistics. 
 
9. 
DISPOSITION AND WITHDRAWALS 
All patients who provide informed consent will be accounted for in this study. Patient disposition 
and withdrawals, and protocol deviations, including inclusion and exclusion criteria will be 
presented for RND set. Reasons for exclusion from each analysis set will be presented for the 
ENR set with patients classified according to randomized treatment.
 
Protocol deviations will be defined in a separate document. The list will be finalized before 
database lock. 
 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be listed for the ENR set, with patients 
classified according to randomized treatment, and summarized for the RND set. 
  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: 
x Age (years) - calculated relative to date of consent 
x Age category (<65 years and 65 years) 
x Gender 
x Ethnicity 
x Race 
x Height (cm) 
x Weight (kg) 
x Body mass index (BMI) (kg/m2) 
x Reversibility status (reversible or non-reversible) – ,planned and actual 
x Modified Medical Research Council (mMRC) questionnaire scores 
x Pre- and post-bronchodilator FEV1 (both in litres and in percentage of predicted normal) 
x Post-bronchodilator FEV1/FVC
x FEV1 actual reversibility (in mL and as a percentage)
x Time since initial diagnosis of COPD (years) 
x Chronic Bronchitis (yes/no) 
x Smoking status (current smoker (yes/no), number of packs per day, number of years 
smoking, and smoking exposure in pack-years) 
10.1. Derivations 
x BMI (kg/ m2) = weight (kg)/ height (m)2 
x Time since initial diagnosis of COPD = (date of consent - date first diagnosed)/ 365.25 
x Smoking exposure (pack-years) = number of packs per day * number of years smoking 
 
Reversibility status is calculated based on pre-dose and post-dose FEV1 values taken at 
Screening. If patient has increase of 12% and 200mL then patient is reversible, else patient is 
non-reversible. 
Actual reversibility strata will be decided on the value calculated pre-rounding, however rounded 
reversibility values will be presented in the outputs. See Appendix 3 for the rounding rules that 
are used by the Vendor. 
10.2. mMRC 
Modified Medical Research Council (mMRC) questionnaire is used to assess a patient’s level of 
breathlessness and the score will be listed. The scores range from 0 to 4, with the following 
definitions: 
0 = “I only get breathless with strenuous exercise”, 
1 = “I get short of breath when hurrying on the level or walking up a slight hill”, 


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2 = “I walk slower than people of the same age on the level because of breathlessness, or I have 
to stop for breath when walking on my own pace on the level”, 
3 = “I stop for breath after walking about 100 meters or after a few minutes on the level”, 
4 = “I am too breathless to leave the house, or I am breathless when dressing or undressing”. 
 
11. 
SURGICAL AND MEDICAL HISTORY 
Surgical and Medical History information will be listed and summarized for the ENR set. 
x Surgical History will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) central coding dictionary, Version 22.0. 
Data captured on the ‘Surgical Procedure History’ page of the electronic case report 
form (eCRF) will be presented by System Organ Class (SOC) and Preferred Term 
(PT). 
x Medical History will be coded using the MedDRA central coding dictionary, Version 22.0. 
Medical History conditions are defined as those conditions which stop prior to or at 
Screening. 
Concomitant illnesses are identified as “Ongoing” at Screening. 
Data captured on the ‘Medical History’ page of the eCRF will be presented by SOC 
and PT. 
x Patients with multiple events within a SOC/PT will only be counted once for that category. 
 
12.
PRIOR AND CONCOMITANT THERAPIES AND MEDICATIONS
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
drug code and summarized by therapeutic subgroup (Anatomical Therapeutic Chemical 
Classification System (ATC) level 2). Potential therapeutic subgroups include ICS, LABA, 
LAMA or combinations thereof, which are defined in a separate spreadsheet provided by the 
medic. 
Prior medications will be listed for ENR set with patients classified according to randomized 
treatment and summarized for the RND set . Concomitant medications will be listed for ENR set 
with patients classified according to actual treatment received and summarized for the SAF set. 
 
See Appendix 2 for handling of partial dates for medications. In the case where it is not possible 
to define a medication as prior, concomitant, or post treatment, the medication will be classified 
by the worst case; i.e. concomitant. 


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x ‘Prior’ medications are medications which started prior to the first dose of study treatment 
and stopped prior to or on the first dose of study treatment. 
x ‘Concomitant’ medications are defined as medications with onset dates on or after the first 
dose of study treatment and on or before last dose of study treatment, or medications with 
onset dates prior to first dose of study treatment without a stop date or with a stop date 
after first dose of study treatment. 
x ‘Post treatment’ medications are defined as medications with an onset date after the date of 
last dose of study treatment. 
 
Patients taking COPD medications prior to the study will be listed by therapeutic class for the 
ENR set, classified according to randomized treatment, and summarized by therapeutic class for 
the RND set. 
Patient with multiple medications within an ATC level/therapeutic subgroup will only be 
counted once for that level. 
12.1. Derivations 
Time since first diagnosed with COPD = (Date of informed consent – Date of COPD first 
diagnosed + 1) / 365.25. 
 
13. 
STUDY TREATMENT EXPOSURE 
Exposure to study treatment will be presented for the SAF set. 
 
The date of first and last study treatment administration will be taken from the e-Diary entry. 
The number of vials dispensed and returned will be taken from “Drug Accountability” page in 
the eCRF. 
13.1. Derivations 
The RPL554 exposure will be calculated as: 
 
Duration of exposure (in days) to study treatment: 
(stop date – start date) +1 
 
Total exposure (in mg): 
(Number of vials dispensed - Number of vials returned) x Content of each vial in mg 
 
The mean duration of exposure in days and the mean exposure in mL will be summarized by 
treatment group. 


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14. 
STUDY TREATMENT COMPLIANCE 
Compliance to study treatment and tiotropium will be summarized and listed for the SAF. 
14.1. Derivations 
Treatment compliance will be summarized by treatment group in 2 ways: 
x 100*((total number of vials dispensed – total number of vials returned)/ (expected number 
of vials to be taken during the study)) 
x Drug intake as recorded in the e-diary: percent of ‘yes’ responses. The denominator is the 
number of records for which the patient provided an answer (Yes or No) to drug intake 
questions (morning and evening) in the e-diary. 
 
15. 
E-DIARY COMPLIANCE 
Compliance to e-diary will be summarized and listed for the SAF. 
15.1. Derivations 
E-diary compliance for study treatment will be summarized by treatment group, for the duration 
of the treatment, as per the following: 
100*((total number of e-diary entries for study treatment)/ (expected number of e-diary entries 
for study treatment during the study)) 
Each patient should have a morning and evening dose, which should be recorded in the e-diary, 
including the dosing at site visits, however only dosing not at the site visit will be included in the 
compliance calculation. At Week 4 visit there should only be morning dose recorded. 
 
Number of e-diary entries will be calculated as per the following: 
[(reference end date – reference start date) *2 – 1 evening dose] – expected number of CRF 
entries 
The 1 evening dose will be subtracted for the completed patients. 
Expected number of CRF entries for study treatment during the study will be 5 for all patients 
that have completed the study. In cases where patient discontinues early the following strategy 
explained below will be used. 
1. Count how many entries there are in the “Drug Exposure” CRF dataset. 
2. Select how many site visits patient should have based on the following window for each 
visit: 
a. Calculate reference end day = reference end date – reference start date +1 
b. 0 site visits if reference end day is missing 
c. 1 site visit if 1 <= reference end day <= 7 


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d. 2 site visits if 8 <= reference end day <= 14 
e. 3 site visits if 15 <= reference end day <= 21 
f. 4 site visits if 22 <= reference end day 
3. Choose the minimum number between points 1 and 2. 
 
16. 
EFFICACY OUTCOMES 
16.1. Primary Efficacy 
16.1.1. Primary Efficacy Variables & Derivations 
The primary endpoint is the change from baseline FEV1 to peak FEV1 (maximum value 
following dose during the first 3 hours) at Week 4 (after 4 weeks of treatment). 
16.1.2. Primary Analysis of Primary Efficacy Variables 
Peak FEV1 will be summarised as actual value at Week 4 and change from baseline FEV1 to 
peak FEV1 at Week 4 using descriptive statistics for all treatment groups.
 
Peak FEV1 will be computed as the maximum value in the 3 hours after dosing. Baseline FEV1 is 
the latest measurement taken before study drug on the day of first dosing, i.e. 30 minutes pre- 
dose at Day 1. 
The primary objective of this study is to test the hypothesis that there is a difference between 
different dose levels of study treatment (RPL554) in comparison with placebo, all administered 
by nebulizer and added on to tiotropium. The change from baseline FEV1 to peak FEV1 will be 
compared between the treatments using a mixed model for repeated measures (MMRM) with 
fixed effects for treatment, visit and treatment by visit interaction, patient as random effect and 
baseline as covariate. An unstructured covariance structure will be used to model the within- 
patient errors. If the model does not converge a compound symmetry covariance structure will be 
used. Kenward-Roger method will be used to estimate the model degrees of freedom. 
 
Treatment comparisons will be summarised using mean effect differences with 95% CI and 
associated 2-sided p-values. 
Firstly, RPL554 treatments will be compared to placebo using a closed testing procedure. The 
testing will begin with the highest dose (3 mg) compared to placebo. If found statistically 
significant then the lower dose (1.5 mg) will be compared to placebo. If found significant then 
the next lower dose will be compared to placebo until either all doses are compared to placebo, 
or a result is found to be non-significant and therefore the comparison ends. Secondly, the doses 
will be compared in a pairwise fashion as shown in Table 2, below. 


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Table 2: 
Pairwise comparison between the RPL554 treatment groups: 
 
RPL554 dose 
 
 
 
 
0.375 mg 
 
The primary efficacy analysis will be performed on the FAS set. The analysis will also be 
repeated for the subgroups specified in Section 7.4. 
 
A bar chart to present the least squares mean change from baseline FEV1 to peak FEV1 for Day 
1, Weeks 1 to 4 (based on the MMRM analysis) will be created. 
16.2. Secondary Efficacy 
The secondary efficacy endpoints include: 
x Change from baseline FEV1 to average AUC0-3h FEV1 on Day 1 and at Weeks 1 to 4 
x Change from baseline FEV1 to average AUC0-12h FEV1 on Day 1 and at Week 4 
x Change from baseline FEV1 to peak FEV1 on Day 1 and at Weeks 1 to 3 
x Change from baseline FEV1 to morning trough FEV1 at Weeks 1 to 4 
x Change from baseline (i.e., mean over the last 7 days of run-in) to the mean weekly values 
over Weeks 1 to 4 in COPD symptoms, as measured by daily diary (E-RSTM:COPD) 
x Change from baseline in the SGRQ-C questionnaire at Weeks 2 and 4 
x TDI questionnaire at Weeks 2 and 4 
x PGAC questionnaire at Weeks 2 and 4 
x Change from baseline (i.e., mean over the last 7 days of run-in) to the mean weekly values 
over Weeks 1 to 4 in the number of puffs of rescue medication 
x Change from baseline FVC to peak FVC on Day 1 and at Week 4 
x Change from baseline FVC to average AUC0-3h FVC on Day 1 and at Week 4 
x Change from baseline FVC to average AUC0-12h FVC on Day 1 and at Week 4 
x Change from baseline FVC to morning trough FVC at Weeks 1 to 4 
x Proportion of patients with an improvement from baseline in SGRQ-C total score of 4 or 
more 


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x Trough plasma concentration of tiotropium on Day 1 and at Week 2, and trough plasma 
concentration of RPL554 at Week 2 
x Safety and tolerability: 
o Continuous monitoring of AEs 
o Laboratory safety tests (hematology, blood chemistry and urinalysis) 
o 12-lead ECG (including the QT interval corrected for heart rate using Friderica’s 
formula (QTcF) and heart rate), supine vital signs (blood pressure and pulse rate) 
16.2.1. Secondary Efficacy Variables & Derivations 
16.2.1.1. PULMONARY FUNCTION TESTS 
16.2.1.1.1. 
SPIROMETRY 
Spirometry (FEV1 and FVC) will be performed at Screening and the following time points 
during each treatment:
x Day 1 and Week 4 (End of Study): 30 minutes pre-dose; 30 minutes and 1, 2, 4, 6, 8 and 
12 hours post-dose. 
x Week 1 – Week 3: 30 minutes pre-dose; 30 minutes and 1, 2 and 3 hours post-dose. 
 
At each time point, three acceptable measurements of FEV1 and FVC will be recorded and the 
highest reading from each time point will be used in all summaries and analyses. Each 
measurement will be graded based on the quality of the measurement. Grades “Acceptable” and 
“Borderline Acceptable” will be used in the analyses, as these will indicate usable 
measurements. Grade “Unacceptable” will not be used in the analysis, as the measurement will 
be identified as poor quality. 
 
Morning trough FEV1 is the last value collected prior to the morning dose. 
Peak, average and trough FEV1 and FVC will be summarized as actual value and change from 
baseline FEV1 and FVC (e.g. change from baseline FEV1 to peak/average/trough FEV1). 
16.2.1.1.2. 
AUC0-T 
The average effect will be calculated as the AUC divided by the length of the time interval of 
interest (for example, 12 hours for AUC0-12h or 3 hours for AUC0-3h). AUC will be calculated 
using the trapezoidal method, as follows: 
 
ܣܷܥ= 
1 σ݊െ1(ܶ
െ ܶ)(ܥ 
+ ܥ ) 
2 
݅=1 
݅+1 
݅ 
݅+1 
݅ 
 
Where Ti is the ith time value, Ci is the ith concentration value, n is the number of time values. 
The change from the baseline FEV1 to average FEV1 (AUC) will be summarised and analysed.


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If two last data points are missing the AUC is set to missing, that is for AUC0-12h we require at 
least up to 8 hours of assessments and for AUC0-3h we require at least up to 2 hours of 
assessments. If first measurement for the calculation of the AUC is missing, then the AUC will 
not be calculated. 
16.2.1.2. DIARY DATA 
16.2.1.2.1. 
E-RSTM: COPD 
Evaluating Respiratory Symptoms for COPD (E-RSTM: COPD) data will be collected within 
EXACT-PRO questionnaire (consisting of 14 questions), as shown in the Appendix 4. Please 
note that items 3, 8, 9, 10, 11 and 14 have separate scoring instructions, namely with the same 
raw score being assigned to several answer options. E-RSTM: COPD consists of 11 questions, 
with subdomains of: Breathlessness, Cough and Sputum, and Chest Symptoms. This data will be 
collected everyday throughout the duration of the study. 
Calculating the score 
E-RS subdomains: 
x Breathlessness – items 7, 8, 9, 10 and 11 (score range: 0-17) 
x Cough and Sputum – items 2, 3 and 4 (score range: 0-11) 
x Chest Symptoms – items 1, 5 and 6 (score range: 0-12) 
Total and subdomain scores are derived weekly as the mean over total number of days between 
previous visit (inclusive) and the following visit, using only days where data was recorded. For 
the last visit, when patient completes the study the derivation will use days between previous 
visit (inclusive) and the following/last visit (inclusive). Baseline is the mean over the 7 days prior 
to the first intake of study treatment, using only days where data was recorded. If less than 4 days 
of data are available for the week, the weekly mean is set to missing, e.g. if data is entered for 
less than 4 days between Visits 2 and 3 then no result will be presented for Week 1. Furthermore, 
all questions need to be answered to be evaluable for that day. 
If a patient discontinued then use treatment study end date, as the date of their last expected visit. 
 
The EXACT-PRO total score will be calculated by first summing all raw scores and then looking 
up the corresponding EXACT-PRO total score in the table described in the Appendix 5. 
 
E-RS subdomain score is calculated as the sum from the relevant questions. 
16.2.1.2.2. 
SGRQ-C 
St. George’s Respiratory Questionnaire – COPD specific (SGRQ-C) is a questionnaire consisting 
of 14 questions, split into two parts. Part 1 consists of the first 7 questions and is related to the 
Symptoms subdomain. The remaining 7 questions are in Part 2, which are related to the Activity 
and Impacts subdomains. Each possible answer to each question has a weight assigned described 
in the Appendix 6. 


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Calculating the score 
Subdomains: 
x Symptoms – items 1 to 7 
x Activity – items 9 and 12 
x Impacts – items 8, 10, 11, 13 and 14 
The score for each component is calculated separately by dividing the summed weights by the 
maximum possible weight for that component and expressing the result as a percentage. A 
positive component has a non-zero response. It is not possible to have missing items in the 
questionnaire, as the data is collected in the e-diary which doesn’t allow patients to skip between 
items. 
 
 
ܵܿ݋ݎ݁ = 100 כ ܵݑ݉ ݋݂ ݓ݄݁݅݃ݐݏ ݂ݎ݋݉ ݈݈ܽ ݌݋ݏ݅ݐ݅ݒ݁ ݅ݐ݁݉ݏ ݅݊ ݐ݄ܽݐ ܿ݋݉݌݋݊݁݊ݐ 
 
ܵݑ݉ ݋݂ ݉ܽݔ݅݉ݑ݉ ݓ݄݁݅݃ݐݏ ݂݋ݎ ݈݈ܽ݅ݐ݁݉ݏ ݅݊ ݐ݄ܽݐ ܿ݋݉݌݋݊݁݊ݐ 
 
The total score is calculated similarly 
 
 
ܵܿ݋ݎ݁= 100 כ ܵݑ݉݋݂ݓ݄݁݅݃ݐݏ݂ݎ݋݈݈݉ܽ݌݋ݏ݅ݐ݅ݒ݁݅ݐ݁݉ݏ݅݊ݐ݄ܽݐݍݑ݁ݏݐ݅݋݊݊ܽ݅ݎ݁
 
ܵݑ݉ ݋݂ ݉ܽݔ݅݉ݑ݉ ݓ݄݁݅݃ݐݏ ݂݋ݎ ݈݈ܽ ݅ݐ݁݉ݏ ݅݊ ݐ݄ܽݐ ݍݑ݁ݏݐ݅݋݊݊ܽ݅ݎ݁ 
 
The higher the score the more severe impact of COPD on patient’s life. 
16.2.1.2.3. 
BDI/TDI 
BDI and TDI are questionnaires that focus on three subdomains: Functional impairment, 
Magnitude of task and Magnitude of effort. BDI is collected at baseline (Day 1) and TDI is 
collected post-baseline (Weeks 2 and 4). 
 
Subdomain score is calculated as the sum from the related questions. 
Total score is calculated as the sum of the subdomain scores. 
 
If at least one of the scores is missing, then total score is set to missing. 
16.2.1.2.4. 
PGAC 
Patient Global Assessment of Change (PGAC) is a single question assessment to determine 
whether patients have noticed a change in their breathing since the start of the study. 
16.2.1.2.5. 
CAT 
CAT is designed to assess further the COPD symptoms. There are 8 subdomains, each having 
only one question and these include Cough, Mucus, Chest Tight, Breathless, Limited Activities, 
Confident, Sleep and Energy. Each question is scored 1-5. The higher the score the more severe 
impact of COPD on patient’s life. 


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16.2.1.3. COPD EXACERBATIONS 
Patients with at least one AE meeting both the following criteria will be included in the analysis 
of exacerbations: 
x MedDRA LLT = ”COPD exacerbation” 
x Use of a systemic steroid (ATC2=H02) at or after the AE date of onset and before the end 
date, lasting for at least 3 days 
16.2.1.4. RESCUE MEDICATIONS 
Rescue medication use will be presented for the FAS set. 
 
Baseline use of rescue medication is the mean over the last 7 days of run-in phase, using only 
days where data was recorded: 
 
ܵݑ݉ ݋݂݊ݑܾ݉݁ݎ ݋݂ ݌ݑ݂݂ݏ ݐܽ݇݁݊ 
݀ܽݕݏ ݎ݁ܿ݋ݎ݀݁݀ 
 
Use of medication per visit is calculated as the mean use daily over total number of days between 
previous visit (inclusive) and the following visit, e.g. Week 1 is defined as the period between 
Visit 2 and Visit 3, calculated only based on the days data was recorded/verified. For the last 
visit, when patient completes the study the derivation will use days between previous visit 
(inclusive) and the following/last visit (inclusive).
If less than 4 days of data are available for the week, the weekly mean is set to missing, e.g. if 
data is entered for less than 4 days between Visits 2 and 3 then no result will be presented for 
Week 1. 
If a patient discontinued then use treatment study end date, as the date of their last expected visit. 
This will be documented in the “Rescue Medication” page of the eCRF, as well as in the “Rescue 
Medication Use” diary entry. 
 
The rescue medication use will be confirmed in the diary using the following rules: 
1. If patient has put in rescue medication use then analyse as expected 
2. If patient has not put in rescue medication use, then to confirm that there was no diary 
compliance issue, or IT issue, question “No Rescue Medication Confirmation” will be 
checked to make sure it is filled in correctly. 
3.  If patient has not put in rescue medication use and question “No Rescue Medication 
Confirmation” was not filled in correctly then this will be treated as diary compliance or 
IT issue and therefore this day will not be used as the day recorded for the weekly means 
calculation. 


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16.2.2. Analysis of Secondary Efficacy Variables 
PD parameters (trough FEV1, peak FEV1, FEV1 AUC0-T, trough FVC, peak FVC and FVC 
AUC0-T), rescue medication, average weekly E-RSTM:COPD, SGRQ-C, TDI and PGAC scores 
will be analysed using an MMRM approach, as described in Section 16.1.2 for the primary 
endpoint. The change from baseline will be analysed for all endpoints except TDI and PGAC. 
The BDI will be used as baseline for TDI. The baseline term will not be included in the MMRM 
analysis of PGAC. 
For exploratory purposes, the subdomain scores of E-RSTM:COPD and SGRQ-C will also be 
summarised and analysed in the same way. 
A plot of the mean change from baseline FEV1 to each post-dose FEV1 result over time will be 
created by visit and treatment group. 
 
The number of patients experiencing at least one COPD exacerbation and the number of 
exacerbations will be summarized by treatment group. 
Individual questions for E-RS and SGRQ-C questionnaires will be listed. 
 
A plot of the least squares means change from baseline to total score E-RS over time will be 
presented (based on the MMRM analysis). 
 
Furthermore, an analysis of the proportion of responder patients, with an improvement from 
baseline in SGRQ-C total score of 4 or more, will be summarised by visit and treatment group 
and analysed using logistic regression. The model for each visit will include randomised 
treatment groups and actual reversibility strata as factors. Patients with a missing response, either 
due to withdrawal or that the SGRQ-C questionnaire was not filled in properly, will be assumed 
to be a non- responder. 
A bar chart of the percentage of responders at each visit will also be presented by treatment 
group. 
 
Total score will be used for the TDI analysis; BDI and TDI total and subdomain scores will be 
listed. 
 
The secondary efficacy analyses (excluding the PK summaries) will be performed on the FAS 
set. The PK results will be summarised for the PKS set. 
The analyses of the secondary safety endpoints are described in Section 17. 
16.3. Exploratory Efficacy 
The exploratory endpoints include: 
x Change in peak FEV1 from Day 1 to Week 4 
  
x   Change in average AUC0-12h FEV1  from Day 1 to Week 4 
 


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x Change from baseline in IC on Day 1 and at Week 4 
x Change from baseline in the CAT questionnaire at Weeks 2 and 4 
x Change from baseline (i.e. mean over the last 7 days of run-in) to the mean weekly values 
over Weeks 1 to 4 in morning symptoms 
x Change from baseline (i.e. mean over the last 7 days of run-in) to the mean weekly values 
over Weeks 1 to 4 in morning activity limitations 
x Proportion of patients with an improvement from baseline in CAT total score of 4 or more 
16.3.1. Exploratory Efficacy Variables & Derivations 
Peak FEV1 is defined in Section 16.2.1.1.1. AUC0-T will be derived as detailed in Section 
16.2.1.1.2. 
16.3.1.1. DIARY DATA 
16.3.1.1.1. 
MORNING SYMPTOMS 
Morning symptoms are scored based on the overall COPD symptom severity in the early 
morning before the first dose of COPD treatment. COPD symptoms include: cough, wheezing, 
shortness of breath, tightness in chest, chest congestion, difficulty bringing up phlegm. Patients 
will be asked to rate their symptoms between 0 to 4, 0= ”no symptoms” and 4= ”severe 
symptoms”. 
 
Weekly means are calculated as per method detailed in section 16.2.1.2.1. 
16.3.1.1.2. 
MORNING ACTIVITY LIMITATIONS 
Morning activity limitations are scored based on the activity limitations in the early morning 
before the first dose of COPD treatment. Morning activities will include: showering, making 
breakfast, dressing, etc. Patients will be asked to rate their activity limitations between 0 to 4, 0 
=” I do not have any difficulty in performing” and 4 =”I have great difficulty in performing”. 
 
Weekly means are calculated as per method detailed in section 16.2.1.2.1. 
16.3.2. Analysis of Exploratory Efficacy Variables 
Peak FEV1, CAT scores, morning symptoms and morning activity limitations will be analysed 
using an MMRM approach, as described in Section 16.1.2. 
 
Due to AUC0-12h FEV1 only being derived for Day 1 and Week 4, an ANCOVA analysis of the 
change from baseline will be performed with fixed effects for treatment and actual reversibility 
strata, and baseline as a covariate. Each measurement will be graded based on the quality of the 
measurement. Grades “Acceptable” and “Borderline Acceptable” will be used in the analyses, as 


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these will indicate usable measurements. Grade “Unacceptable” will not be used in the analysis, 
as the measurement will be identified as poor quality. 
 
Total score data will be used for the CAT questionnaire analysis. 
An analysis of the proportion of patients with an improvement from baseline in CAT total score 
of 4 or more will be summarised by visit and treatment group and analysed using logistic 
regression. The model will include randomised treatment groups and actual reversibility strata as 
factors. Patients with a missing response will be assumed to be a non-responder. Also, total score 
and subdomain scores will be listed. A plot of the least square means change from baseline in 
total score over time will be presented (based on the MMRM analysis). 
 
Due to IC only being collected on Day 1 and at Week 4 for two timepoints 30 minutes pre-dose 
and 2 hours post-dose, an ANCOVA analysis of the change from baseline (Day 1, 30 minutes 
pre-dose) to remaining 3 timepoints will be performed with fixed effects for treatment and actual 
reversibility strata, and baseline as a covariate. Each measurement will be graded based on the 
quality of the measurement. Grades “Acceptable” and “Borderline Acceptable” will be used in 
the analyses, as these will indicate usable measurements. Grade “Unacceptable” will not be used 
in the analysis, as the measurement will be identified as poor quality. 
16.4. Missing Data Methods for Efficacy Variables 
Data for calculation of average (AUC) effects for FEV1 will be imputed if the pre-dose is not 
missing. This will be done using the following method: 
x ‘bounded’ missing data will use interpolation through the trapezoidal method described in 
section 16.2.1.1.2, 
x ‘unbounded’ missing data will not be imputed 
o 
If last measurement is missing, then the AUC will be calculated up to the point 
where data is not missing, however if two or more last measurements will be 
missing, then the AUC will be set to missing. 
o 
If first measurement is missing, the AUC will not be calculated and set to 
missing. 
For the analysis of responder on SGRQ-C and CAT missing responses will be treated as 
indicating non-responders in the analysis. 
All other missing data, including for when pre-dose is missing, will not be imputed. 
For the sensitivity and interim analysis missing data will be imputed using LOCF method. In 
cases where patient discontinues early and has spirometry data reported at the EOS visit, the 
following strategy explained below will be used. 
1. Check the visit day at which EOS visit was performed against the following window for


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each visit: 
a. Day 1 = Day 1 
b. Week 1 = after day 1 and up to and including day 9 
c. Week 2 = after day 9 and up to and including day 16 
d. Week 3 = after day 16 and up to and including day 23 
e. Week 4 = after day 23 and up to and including day 30 
2. Set the value for the corresponding visit, and any subsequent visits, to be the value from 
EOS. If the corresponding visit has a measurement already, then the next available visit 
must be used for EOS. 
3. If there are missing values before the EOS corresponding visit, we would impute using 
LOCF in the usual manner.
In the case where patient discontinues early and did not have spirometry data recorded at the 
EOS visit, or cases of missing data for patients who did not discontinue early, LOCF will be 
applied in the usual manner. 
16.5. Sensitivity analysis for Efficacy Variables 
Sensitivity analyses will be done for the primary endpoint (change from baseline FEV1 to peak 
FEV1 at Week 4) and for key secondary endpoints (change from baseline FEV1 to average 
AUC0-12h FEV1 at Week 4, and change from baseline in total E-RSTM:COPD score at Week 4). 
An ANCOVA approach will be used to compare treatment groups, with fixed factors for 
treatment and actual reversibility strata, and the baseline result as a covariate. RPL554 treatments 
will be compared to placebo and to each other, as described in Section 16.1.2. 
As a sensitivity analysis, the primary analysis (i.e. MMRM) of the efficacy endpoints described 
above will be repeated on the PPS set. 
 
Furthermore, an analysis of the proportion of patients with an improvement from baseline in 
SGRQ-C total score of 4 or more will be summarised by visit and treatment group and analysed 
using logistic regression. The model will include randomised treatment groups and actual 
reversibility strata as factors. Patients with a missing response will be handled according to last 
known responder status (LOCF). 
Any missing data post-baseline will be imputed using the LOCF method described in Section 
16.4. 
 
Sensitivity analysis, with respect to impact of rescue use during clinic visits, will only be 
performed if at least one patient is excluded from this analysis due to taking rescue medication 
within 6 hours of spirometry test. Patient can only be excluded from the analysis if enough of the 
spirometry tests are affected for the function tests not being able to be calculated, i.e. if first 


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FEV1 measurement is affected by the rescue medication then AUC cannot be calculated for that 
visit. 
This additional sensitivity analysis, taking into account rescue medication, will be performed for 
a secondary endpoint, change from baseline FEV1 to average AUC0-12h FEV1 at Week 4. 
16.6. Interim Analysis 
To check the assumptions in the sample size calculation, as detailed in Section 9.5 of the study 
protocol, a blinded sample size-re-estimation is planned after 125 patients who have been 
randomized, have collected sufficient data after intake of study treatment to compute any of the 
FEV1 parameters and either completed the study or had early termination. Analyses will be based 
on data that is as clean as possible at the time of the data cut-off. 
Two different models will be fitted to the data and both will estimate blinded standard deviation 
which will be compared to the standard deviation assumption of 200 mL included in the original 
sample size calculation. Using each of these blinded estimates of the standard deviation, the 
original sample size calculation, based on a two-sample t-test, will be repeated for each of the 
following scenarios. 
x Calculation 1 – unknown sample size (per treatment group), known detectable treatment 
difference (93 mL) and power (80%) 
x Calculation 2 – unknown power (%), known detectable treatment difference (93 mL) and 
sample size (73 per treatment group) 
x Calculation 3 – Unknown detectable treatment difference (mL), known power (80%) and 
sample size (73 per treatment group) 
The ANCOVA analysis will be performed on the following endpoints. The MMRM analysis will 
be performed for the first endpoint only: 
x Change from baseline FEV1 to peak FEV1 at Visit 6 
x Change from baseline FEV1 to average AUC0-3h FEV1 at Visit 6 
x Change from baseline FEV1 to average AUC0-12h FEV1 at Visit 6 
x Change from baseline FEV1 to morning trough FEV1 at Visit 6 
16.6.1. Blinded ANCOVA analysis 
To analyse the four endpoints above, an ANCOVA approach will be used with a fixed factor for 
reversibility strata, and the baseline result as a covariate. Any missing data at Visit 6/Week 4 will 
be imputed using the LOCF method described in Section 16.4. 
 
The ANCOVA model will use the square root of mean square error to estimate the blinded 
standard deviation. 


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16.6.2. Blinded MMRM analysis 
To analyse the change from baseline FEV1 to peak FEV1, an MMRM approach will be used with 
a fixed factor for visit, patient as a random effect, and the baseline result as a covariate. An 
unstructured covariance structure will be used to model the within-patient errors. If the model 
does not converge a compound symmetry covariance structure will be used. Kenward-Roger 
method will be used to estimate the model degrees of freedom. 
Sample size calculation is based on the number of patients with available data at Visit 6/week 4 
included in the analysis, therefore any assessment of sample size based on MMRM should also 
consider the drop-out rate observed in the study. 
 
The MMRM model will use the square root of variance representing Visit 6/Week 4 taken from 
variance-covariance matrix to estimate the blinded standard deviation. 
 
17. 
SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the SAF set, unless otherwise stated. 
 
There will be no statistical comparisons between the treatment groups for safety data, unless 
otherwise specified within the relevant section. 
17.1. Adverse Events 
AEs will be listed for ENR set, with patients classified according to actual treatment received, 
and summarized for SAF set. 
 
AEs will be coded using the MedDRA central coding dictionary, Version 22.0. 
 
Treatment emergent adverse events (TEAEs) are defined as all AEs which start after the first 
dose of study treatment or start prior to first dose of study treatment and worsen, based on the 
investigator’s assessment of severity, on or after first dose of study treatment. 
 
Non-treatment emergent adverse events (non-TEAEs) are defined as AEs that start prior to first 
dose of study treatment and end prior to first dose of study treatment, or do not worsen, based on 
the investigator’s assessment of severity, on or after first dose of study treatment. 
 
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. 
 
If any AE records contain only partial dates, these will be handled by imputation, as described in 
the Appendix 2. 


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An overall summary of the number of patients with at least one event in each of the categories 
listed below will be provided as specified in the templates. In addition, the number of patients 
with each of the following AE events will be presented by SOC and PT and summarized by 
treatment group: 
x TEAE 
x TEAEs leading to discontinuation of study treatment 
x TEAEs causally related to study treatment 
x TEAEs by maximum severity 
x Serious TEAEs 
x Serious TEAEs causally related to study treatment 
x Serious TEAEs by maximum severity 
x Serious TEAEs leading to discontinuation of study treatment 
x TEAEs with an outcome of death 
AEs will be identified by using the ‘Adverse Events’ page of the eCRF. Listings will include 
TEAEs and Non-TEAEs. 
17.1.1. Severity 
Severity is classed as mild/ moderate/ severe. TEAEs starting after the first dose of study 
treatment with a missing severity will be classified as severe. If 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. 
17.2. Laboratory Evaluations 
Results from the central laboratory will be included in the reporting of this study for 
Hematology, Blood Chemistry, Urinalysis and Viral Serology. Measurements and timepoints for 
each laboratory assessment can be found in Table 3. 
 
Presentations will use standard international (SI) Units. 
The handling of re-tests and unscheduled measurements is detailed in Section 6.3. 






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ܴܴ (msec) =  1000 כ 
60 
ܪܴ (ܾ݌݉) 
x Fridericia’s Correction (msec) 
ܳܶܿܨ (msec)  =  
ܳܶ (݉ݏ) 
3 
݉ݏ 
ξܴܴ1000 
17.4. Vital Signs 
The following Vital Signs measurements will be reported for this study: 
x Supine Systolic Blood Pressure (mmHg) 
x Supine Diastolic Blood Pressure (mmHg) 
x Supine Pulse Rate (bpm) 
x Body weight (kg) 
x BMI (kg/m2) 
 
Blood pressure and Pulse Rate are measured in a following way: 
x Screening 
x Day 1 and Week 4 (End of Study)– pre-dose and 30 minutes, 1, 2, 4, 6, 8 and 12 hours 
post-dose 
x Week 1 – Week 3 – pre-dose and 30 minutes, 1, 2 and 3 hours post-dose 
BMI is calculated at Screening and End of Study visit using height measured at Screening, and 
body weight measured at Screening and End of Study visit. 
The following summaries will be provided for Vital Signs data, summarised by treatment group: 
x Change from baseline table by post-dose time-point of collection for continuous variables 
x Shift tables representing changes from Normal/ Low/ High, defined in the Table 5. 
x Listings of patients meeting markedly abnormal criteria after the first dose 
 
A plot over time will be presented for all vital signs by treatment group and visit. 
17.4.1. Vital Signs Markedly Abnormal Criteria 
Markedly abnormal quantitative vital signs measurements will be identified in accordance with 
the predefined markedly abnormal criteria found in Table 5. 




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18. 
REFERENCES 
EMA. 
EXACT-PRO 
Initiative. 
October 
2014. 
<http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/04/WC500185444.pdf>. 
ICH. "E9 Statistical Principles for Clinical Trials." 1998. 
Jones, P W, F H Quirk and C M Baveystock. "The St George's Respiratory Questionnaire." Respiratory Medicine (1991): 
25-31. 
Jones, Professor Paul. "ST GEORGE’S RESPIRATORY QUESTIONNAIRE FOR COPD PATIENTS (SGRQ-C) MANUAL." April 
2012. <http://www.healthstatus.sgul.ac.uk/SGRQ_download/sgrq-c-manual-april-2012.pdf>. 
SAS Institute, Inc. SAS Procedures Guide, version 8. Cary, NC: SAS Institute, 1999. 
The European Agency for the Evaluation of Medicinal Products. "Points to consider on multiplicity issues in clinical 
trials." 2002. 


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APPENDIX 1. 
PROGRAMMING CONVENTIONS FOR OUTPUTS 
Dates & Times
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss. 
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, Listings and Figures 
RPL554 0.375 mg 
RPL554 0.375 mg 
RPL554 0.75 mg 
RPL554 0.75 mg 
RPL554 1.5 mg 
RPL554 1.5 mg 
RPL554 3 mg 
RPL554 3 mg 
Placebo 
Placebo 
Decimal Places 
The decimal places for this study will use the following rules, unless otherwise stated. 
Value = x dp 
Mean = x+1 dp 
Standard Deviation = x+2 dp 
Median = x+1 dp 
Q1/Q3 = x+1 dp 
Minimum/Maximum = x dp 
CI = x+1 dp 
 
For spirometry data we will present outputs with decimal places for value as follows: 
x Values in litres = 3dp 
x Values in millilitres = 0dp 
x Percentage values = 1dp 
 
P-values will be presented to 4dp. 


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Presentation of Visits 
For outputs, visits will be represented as follows and in that order, unless otherwise specified: 
 
Long Name (default) 
Short Name 
Pre-Screening 
Pre-Screening 
Screening 
Screening 
Baseline 
Baseline 
Day 1 
Day 1 
Week 1 
Week 1 
Week 2 
Week 2 
Week 3 
Week 3 
Week 4 
Week 4 
Follow-up 
FUP 
Listings 
All listings will be ordered by the following (unless otherwise indicated in the template): 
x Randomized treatment group (or treatment received if it’s a safety output) 
x Centre-patient ID, 
x Treatment day (where applicable), 
x Date and time (if applicable), 
x For listings where non-randomized patients are included, these will appear in a category 
after the randomized treatment groups labelled ‘Not Randomized’. 
Tables 
All tables presenting multiple events that map to a SOC and PT will be counted only once, per 
unique patient, for incidence counts. Events will be presented in descending frequency of SOC 
and PT (unless otherwise indicated in the template). 








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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


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APPENDIX 3. 
REVERSIBILITY ROUNDING CRITERIA 
 
 
 
 
 


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APPENDIX 4. 
ANNOTATED EXACT FOR RAW SCORE ASSIGNEMENT 
 
 
1. Did your chest feel congested today? 
0.Not at all 
1.Slightly 
2.Moderately 
3.Severely 
4.Extremely 
2. How often did you cough today? 
0.Not at all 
1.Rarely 
2.Occasionally 
3.Frequently 
4.Almost constantly 
3. How much mucus (phlegm) did you bring up when 
coughing today? 
0.None at all 
1.A little 
1.Some 
2.A great deal 
3.A very great deal 
4. How difficult was it to bring up mucus (phlegm) 
today? 
0.Not at all 
1.Slightly 
2.Moderately 
3.Quite a bit 
4.Extremely 
5. Did you have chest discomfort today? 
0.Not at all 
1.Slight 
2.Moderate 
3.Severe 
4.Extreme
6. Did your chest feel tight today? 
0.Not at all 
1.Slightly 
2.Moderately 
3.Severely 
4.Extremely 
7. Were you breathless today? 
0.Not at all 
1.Slightly 
2.Moderately 
3.Severely 
4.Extremely 


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8.Describe how breathless you were today 
0.Unaware of breathlessness 
1.Breathless during strenuous activity 
2.Breathless during light activity 
3.Breathless when washing or dressing 
3.Present when resting 
9. Were you short of breath today when performing 
your usual personal care activities like washing or 
dressing? 
0.Not at all 
1.Slightly 
2.Moderately 
3.Severely 
3.Extremely 
4.Too breathless to do these 
10. Were you short of breath today when performing 
your usual indoor activities like cleaning or household 
work? 
0.Not at all 
1.Slightly 
2.Moderately 
3.Severely 
3.Extremely 
3.Too breathless to do these 
11. Were you short of breath today when performing 
your usual activities outside the home such as yard 
work or errands? 
0.Not at all 
1.Slightly 
2.Moderately 
3.Severely 
3.Extremely 
3.Too breathless to do these 
12. Were you tired or weak today? 
0.Not at all 
1.Slightly 
2.Moderately 
3.Severely 
4.Extremely 
13. Last night, was your sleep disturbed? 
0.Not at all 
1.Slightly 
2.Moderately 
3.Severely 
4.Extremely 
14. How scared or worried were you about your lung 
problems today? 
0.Not at all 
1.Slightly 
2.Moderately 
3.Severely 
3.Extremely 


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APPENDIX 5. 
RAW SUMMED SCORE TO SCALE CONVERSION TABLE FOR 
EXACT TOTAL SCORE
 
Raw Summed 
Score 
EXACT Total 
Score 
Raw Summed 
Score 
EXACT Total 
Score 
0 
0 
26 
50
1 
8 
27 
51
2 
13 
28 
52
3
17
29
53
4 
20 
30 
54
5 
23 
31 
55
6 
25 
32 
57
7 
27 
33 
58
8 
28 
34 
59
9 
30 
35 
60
10 
31 
36 
61
11 
33 
37 
63
12 
34 
38 
64
13 
36 
39 
65
14 
37 
40 
67
15 
38 
41 
68
16 
39 
42 
70
17 
40 
43 
72
18 
41 
44 
73
19 
42 
45 
75
20 
43 
46 
77
21 
44 
47 
80
22 
46 
48 
83
23 
47 
49 
87
24 
48 
50 
92
25 
49 
51 
100


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APPENDIX 6. 
SGRQ-C ITEM WEIGHTS 
 
Question 
Answers 
Weight 
Part 1
Question 1: I cough
 
Most days 
80.6 
Several days 
46.3 
With chest infections
28.1
Not at all 
0.0 
Question 2: I bring up phlegm (sputum) 
 
Most days 
76.8 
Several days 
47.0 
With chest infections 
30.2 
Not at all 
0.0 
Question 3: I have shortness of breath 
Most days 
87.2 
Several days 
50.3 
Not at all 
0.0 
Question 4: I have attacks of wheezing 
 
Most days 
86.2 
Several days 
71.0 
A few days 
45.6 
With chest infections 
36.4 
Not at all 
0.0 
Question 5: How many attacks of chest 
trouble have you had 
 
3 or more 
80.1 
1 or 2 attacks 
52.3 
None 
0.0 
Question 6: How often do you have good 
days (with little chest trouble) 
 
None 
93.3 
A few 
76.6 
Most are good 
38.5 
Every day 
0.0 
Question 7: If you have a wheeze, is it 
worse in the morning? 
 
No 
0.0 
Yes 
62.0 
Part 2
 
 


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Question 8: How would you describe your 
chest condition? 
The most important problem I have 
82.9 
Causes me a few problems 
34.6 
Causes no problem 
0.0 
Question 9: Questions about what 
activities usually make you feel breathless
 
Getting washed or dressed 
82.8 
Walking around the home 
80.2 
Walking outside on the level 
81.4 
Walking up a flight of stairs 
76.1 
Walking up hills 
75.1 
Question 10: More questions about your 
cough and breathlessness 
 
My cough hurts 
81.1 
My cough makes me tired 
79.1 
I get breathless when I talk 
84.5 
I get breathless when I bend over
76.8 
My cough or breathing disturbs my 
sleep 
87.9 
I get exhausted easily 
84.0 
Question 11: Questions about other 
effects your chest trouble may have on 
you 
 
My cough or breathing is 
embarrassing in public 
74.1 
My chest trouble is a nuisance to my 
family, friends or neighbors 
79.1 
I get afraid or panic when I cannot get 
my breath 
87.7 
I feel that I am not in control of my 
chest problem 
90.1 
I have become frail or an invalid 
because of my chest 
89.9 
Exercise is not safe for me 
75.7 
Everything seems too much of an 
effort 
84.5 
Question 12: Questions about how 
activities may be affected by your 
breathing 
 
I take a long time to get washed or 
dressed 
74.2 
I cannot take a bath or shower, or I 
take a long time 
81.0 
I walk more slowly than other people, 
or I stop for rests 
71.7


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Jobs such as housework take a long 
time, or I have to stop for rests
70.6 
If I walk up one flight of stairs, I have 
to go slowly or stop 
71.6 
If I hurry or walk fast, I have to stop 
or slow down 
72.3 
My breathing makes it difficult to do 
things such as walk up hills, carry 
things up 
stairs, light gardening such as 
weeding, dance, play bowls or play 
golf 
74.5 
My breathing makes it difficult to do 
things such as carry heavy loads, dig 
the 
garden or shovel snow, jog or walk at 
5 miles per hour, play tennis or swim 
71.4
Question 13: We would like to know how 
your chest trouble actually affects your 
daily life 
 
I cannot play sports or games 
64.8 
I cannot go out for entertainment or 
recreation 
79.8 
I cannot go out of the house to do the
shopping 
81.0
I cannot do housework 
79.1 
I cannot move far from my bed or 
chair 
94.0 
Question 14: Tick the statement which 
you think best describes how your chest 
affects you 
 
It does not stop me doing anything I 
would like to do 
0.0 
It stops me doing one or two things I 
would like to do 
42.0 
It stops me doing most of the things I 
would like to do 
84.2 
It stops me doing everything I would 
like to do 
96.7