Conditions: COPD
Keywords: COPD, bronchodilation, FEV1
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 405
Healthy volunteers: no

Brief summary:
The study investigates the effect of 4 weeks of twice daily treatment of four different doses of RPL554 (a phosphodiesterase \[PDE\]3/4 inhibitor) or placebo in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Patients will be equally allocated to one of the five treatment options.

Detailed description:
RPL554 is a dual inhibitor of PDE3 and PDE4 which are known to have a role in modulating the inflammatory airway response in respiratory diseases, including COPD. PDE3 inhibitors act as bronchodilators whilst PDE4 inhibitors have anti-inflammatory properties and there is also evidence to suggest that combined inhibition of PDE3 and PDE4 can have additive or synergistic anti-inflammatory and bronchodilator effects. PDE4 inhibitors (administered orally) have, however been associated with unfavorable gastrointestinal side effects such as nausea, emesis, diarrhea, abdominal pain, loss of appetite and weight loss. Dual PDE3/PDE4 inhibitors (administered by inhalation) have exhibited both bronchodilator and anti-inflammatory actions, with a more favorable side effect profile. 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.

The purpose of this study is to investigate the dose response of RPL554 in patients with COPD over 4 weeks. This length of time should allow for study of the bronchodilator response, measured predominantly by the peak forced expiratory volume in one second (FEV1), and the anti-inflammatory response, as measured predominantly by trough FEV1.

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None

Interventions: intervention 1: RPL554 suspension intervention 2: Placebo
Intervention descriptions: intervention 1: A dual PDE3/PDE 4 inhibitor intervention 2: Placebo solution

Protocol document:
Prot_001.pdf: 





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SAP_000.pdf: 
Statistical Analysis Plan
Verona Pharma
RPL554-CO-203
Document:U:\My documents\ad hoc\Mark\Final SAP\Verona RPL554-CO-203 SAP v1.0.docx
Author: Eleonora Chiossi
Version: 1.0
Page 1 of 37
Version Date: 6 March 2018
STATISTICAL ANALYSIS PLAN
A Phase IIb, Randomized, 
Double Blind, Placebo Controlled Dose Ranging Study to 
Assess the Effect of RPL554 in Patients with Moderate to 
Severe COPD
Study No. RPL554-CO-203
Version 1.0 – 6 March 2018




 
 
Statistical Analysis Plan 
 
Verona Pharma 
RPL554-CO-203 
 
Document:U:\My documents\ad hoc\Mark\Final SAP\Verona RPL554-CO-203 SAP v1.0.docx 
Author: Eleonora Chiossi 
 
 
 
 
          
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Version Date: 6 March 2018 
Modification History 
 
Unique 
Identifier 
for this 
Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
1.0 
6 March 2018 
Eleonora Chiossi 
Final 
Version 
for 
implementation after DB lock 
 


 
 
Statistical Analysis Plan 
 
Verona Pharma 
RPL554-CO-203 
 
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Author: Eleonora Chiossi 
 
 
 
 
          
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Version Date: 6 March 2018 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation or 
special term 
Explanation/Definition 
AEs 
Adverse Events 
ANCOVA 
Analysis of Covariance 
ATS 
American Thoracic Society 
AUC 
Area under the curve 
BDI 
Baseline Dyspnea Index 
BID 
Twice a day 
BMI 
Body Mass Index 
Bpm 
Beats per Minute 
CIs 
Confidence Intervals 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
E-RS 
Evaluating – Respiratory Symptoms 
ERS 
European Respiratory Society 
EXACT-PRO 
Exacerbations of Chronic Pulmonary Disease Tool Patient-Reported Outcome 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced Vital Capacity 
ICS 
Inhaled corticosteroids 
Kg 
Kilograms 
LABA 
Long Acting Beta2 Agonist 
LAMA 
Long Acting Muscarinic Antagonist 
LDL 
Low-density Lipoprotein 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
m 
Meters 
mL 
Milliliters 
MMRM 
Mixed Model for Repeated Measures  
MRC 
Medical Research Council 
msec 
Milliseconds 
N 
Number of patients 
PGAC 
Patient Global Assessment of Change 
PT 
Preferred Term 
QTcF 
QT interval corrected for heart rate using Friderica’s formula 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis Software 
SD 
Standard Deviation 
SOC 
System Organ Class 
SGRQ-C 
St George’s Respiratory Questionnaire – COPD specific 
TDI 
Transition Dyspnea Index 
 
 


 
 
Statistical Analysis Plan 
 
Verona Pharma 
RPL554-CO-203 
 
Document:U:\My documents\ad hoc\Mark\Final SAP\Verona RPL554-CO-203 SAP v1.0.docx 
Author: Eleonora Chiossi 
 
 
 
 
          
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Version Date: 6 March 2018 
 
Table of Content 
 
1. 
Introduction ......................................................................................................................... 7 
2. 
Study objectives ................................................................................................................... 7 
2.1. 
Primary objective ........................................................................................................ 7 
2.2. 
Secondary objectives .................................................................................................. 7 
2.3. 
Exploratory Objectives ............................................................................................... 7 
3. 
Study design ......................................................................................................................... 8 
3.1. 
General Description .................................................................................................... 8 
3.2. 
Treatments .................................................................................................................. 8 
3.2.1. Treatments Administered ............................................................................... 8 
3.2.2. Method of Assigning Patients to Treatment Groups...................................... 9 
3.2.3. Blinding ......................................................................................................... 9 
3.3. 
Determination of Sample Size .................................................................................... 9 
3.4. 
Changes in the Conduct of the Study or Planned Analyses ........................................ 9 
3.5. 
Analysis Sets ............................................................................................................... 9 
3.6. 
Major Protocol Deviations ........................................................................................ 10 
3.7. 
General Methodology ............................................................................................... 10 
3.7.1. Baseline ....................................................................................................... 10 
3.7.2. End of Study ................................................................................................ 11 
3.7.3. Visit Windows ............................................................................................. 11 
3.7.4. Duration ....................................................................................................... 11 
3.7.5. Treatment period .......................................................................................... 11 
3.8. 
Handling of Dropouts or Missing Data ..................................................................... 11 
3.8.1. Missing data in efficacy analysis ................................................................. 11 
3.8.2. Missing data in safety analysis .................................................................... 11 
3.8.3. Partial Date Imputation ................................................................................ 11 
3.8.4. Partial Dates for AEs ................................................................................... 12 
3.8.5. Partial Dates for Concomitant Medications ................................................. 12 
3.9. 
Interim Analyses and Data Monitoring .................................................................... 12 
3.10. 
Pooled country/region ............................................................................................... 12 
4. 
Patient disposition, demographic and baseline characteristics, medical history, 
prior and concomitant medications, treatment compliance and exposure .................. 12 
4.1. 
Patient disposition ..................................................................................................... 12 
4.2. 
Demographic and Other Baseline Characteristics .................................................... 12 
4.3. 
Medical History ........................................................................................................ 13 
4.4. 
Prior COPD, Prior and Concomitant Medications .................................................... 13 
4.4.1. Special grouping of medications.................................................................. 13 
4.5. 
Exposure and compliance ......................................................................................... 15 
4.5.1. Treatment Compliance ................................................................................. 15 
4.5.2. Extent of Exposure ...................................................................................... 15 
5. 
Efficacy Endpoints ............................................................................................................ 15 


 
 
Statistical Analysis Plan 
 
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RPL554-CO-203 
 
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5.1. 
Primary Efficacy Endpoint ....................................................................................... 15 
5.2. 
Secondary Efficacy Endpoints .................................................................................. 16 
5.3. 
Exploratory Efficacy Endpoints ................................................................................ 16 
5.4. 
Selected secondary endpoints ................................................................................... 17 
5.5. 
Efficacy Endpoints details ........................................................................................ 17 
5.5.1. Pulmonary Function Tests ........................................................................... 17 
5.5.2. Symptom Diary [EXACT-PRO] .................................................................. 17 
5.5.3. St. George’s Respiratory Questionnaire – COPD specific (SGRQ-C) ........ 18 
5.5.4. Medical Research Council (MRC) Breathlessness Scale ............................ 19 
5.5.5. Patient Global Assessment of Change (PGAC) ........................................... 19 
5.5.6. Baseline and Transition Dyspnea Indices (BDI and TDI) ........................... 19 
5.6. 
Efficacy Endpoint Analysis ...................................................................................... 20 
5.6.1. General consideration on the analysis of efficacy ....................................... 20 
5.6.2. Analysis of Primary Endpoint ..................................................................... 20 
5.6.3. Analyses of Secondary and exploratory Endpoints ..................................... 21 
5.6.4. Multiple Comparison Adjustment for the Primary Efficacy Endpoint ........ 21 
5.6.5. Multiple Comparison Adjustment for the Secondary Efficacy Endpoints .. 21 
5.6.6. Examination of Subgroups .......................................................................... 22 
6. 
Safety Endpoints ............................................................................................................... 22 
6.1. 
Adverse Events ......................................................................................................... 22 
6.1.1. Analysis of Adverse Events ......................................................................... 22 
6.2. 
Clinical Laboratory Evaluations ............................................................................... 23 
6.2.1. Analysis of Clinical Laboratory Evaluation ................................................ 23 
6.3. 
Electrocardiograms ................................................................................................... 24 
6.3.1. Analysis of ECG Evaluations ...................................................................... 24 
6.3.2. Holter Monitors ........................................................................................... 24 
6.4. 
Vital Signs ................................................................................................................ 24 
6.4.1. Analysis of Vital Signs ................................................................................ 25 
6.5. 
Physical Findings ...................................................................................................... 25 
6.6. 
Drug induced bronchospasm .................................................................................... 25 
6.6.1. Analysis of drug induced bronchospasm ..................................................... 25 
7. 
Pharmacokinetic ............................................................................................................... 25 
7.1. 
Analysis of pharmacokinetic .................................................................................... 25 
8. 
REFERENCES .................................................................................................................. 27 
9. 
Appendices ......................................................................................................................... 28 
9.1. 
Appendix 1: Schedule of Events ............................................................................... 28 
9.2. 
Appendix 2: EXACT-PRO Scoring Instructions ...................................................... 31 
9.3. 
Appendix 3: SGRQ-C ............................................................................................... 36 
9.4. 
Appendix 4: SAS code for efficacy analysis ............................................................ 38 
 
 


 
 
Statistical Analysis Plan 
 
Verona Pharma 
RPL554-CO-203 
 
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Author: Eleonora Chiossi 
 
 
 
 
          
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Version Date: 6 March 2018 
1. 
Introduction 
This document describes the rules and conventions to be used in the presentation and analysis of 
efficacy and safety data for protocol RPL554-CO-203. It describes, in detail, the data to be 
summarized and analyzed, including specifics of the statistical analyses to be performed. 
This statistical analysis plan is based on the final protocol version 2.0, dated 18th of April 2017. 
2. 
Study objectives 
The purpose of this study is to investigate the dose response of RPL554 in patients with Chronic 
Obstructive Pulmonary Disease (COPD) over 4 weeks. Clinical practice indicates that this 
length of time should allow for the study of the bronchodilator response (measured 
predominantly by peak FEV1) and the anti-inflammatory response (measured predominantly by 
trough FEV1). 
2.1. 
Primary objective 
The primary objective of this study is to investigate the placebo-corrected effect of RPL554 
administered by nebulizer on change from baseline in peak FEV1 (maximum over 3 hours 
following dosing) over 4 weeks when administered to patients with moderate to severe 
COPD.  
2.2. 
Secondary objectives 
The secondary objectives of this study are as follows: 
 
x 
To investigate the placebo-corrected effect of RPL554 administered by nebulizer on change 
from baseline in morning trough FEV1 over 4 weeks when administered to patients with 
moderate to severe COPD 
x 
To investigate the bronchodilator placebo-corrected effect of RPL554 administered by 
nebulizer on AUC0-12 hours FEV1 after 4 weeks of dosing  
x 
To investigate the single-dose bronchodilator placebo-corrected effect of RPL554 on peak 
and average FEV1 at Visit 2 (first dose) 
x 
To investigate the bronchodilator placebo-corrected effect of RPL554 on peak and average 
FEV1 over 3 hours at Visits 3 to- 6 (Weeks 1 to 4) 
x 
To investigate the placebo-corrected effects of RPL554 on COPD symptoms, as measured 
by daily diary (E-RS from the Exacerbations of Chronic Pulmonary Disease Tool Patient-
Reported Outcomes [EXACT-PRO+], Transition Dyspnea Index [TDI], St George’s 
Respiratory Questionnaire – COPD specific [SGRQ-C], Medical Research Council [MRC] 
scale, and patient global assessment of change (PGAC) 
x 
To investigate the safety of RPL554 when administered for 4 weeks in patients with COPD, 
as measured by adverse events, electrocardiograms (ECGs), Holter monitoring and vital 
signs 
x 
To compare the amount of rescue albuterol/salbutamol use required 
2.3. 
Exploratory Objectives 
Additional, exploratory objectives of this study are as follows: 
 
x 
To compare peak and AUC0-12 hour FEV1 at the final study visit (visit 6) to baseline (Day 1) 
x 
To correlate trough pharmacokinetics with pharmacodynamics effects 


 
 
Statistical Analysis Plan 
 
Verona Pharma 
RPL554-CO-203 
 
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Version Date: 6 March 2018 
3. 
Study design 
This is a phase IIb, randomized, double-blind, placebo-controlled, parallel group study designed 
to evaluate the efficacy and safety of nebulized RPL554 in patients with moderate to severe 
COPD over 4 weeks.  
3.1. 
General Description 
A total of approximately 400 patients between the ages of 40 and 75 years, inclusive, with a 
clinical diagnosis of COPD, as defined by the American Thoracic Society (ATS)/European 
Respiratory Society (ERS) guidelines and symptoms compatible with COPD for at least 1 year 
prior to screening will be enrolled. 
 
Patients will be seen at approximately 50 sites throughout the European Union. The study 
comprises six visits: screening (visit 1), randomization (visit 2), and weekly visits for 4 weeks 
(visit 3 to visit 6, Week 1 to Week 4). Patients will be screened for eligibility (visit 1), including 
a reversibility test with albuterol/salbutamol between 7 and 14 days before the first dose of study 
medication. 
3.2. 
Treatments 
3.2.1. Treatments Administered 
Patients will be randomized to either RPL554 or placebo. Those assigned to RPL554 will 
receive one of four active strengths, as described in the table below: 
Table 1: RPL554 Doses 
Substance 
Dose Level (mg) 
Concentration (mg/mL) 
RPL554 
0.75 
0.3 
RPL554 
1.5 
0.6 
RPL554 
3.0 
1.2 
RPL554 
6.0 
2.4 
Placebo 
N/A 
N/A 
N/A = Not Applicable 
 
All study medications will be administered twice daily, using a standard jet nebulizer. 
3.2.2. Method of Assigning Patients to Treatment Groups 
At the screening visit, the investigator will assign a unique patient number to each enrolled 
patient. This patient number is made up of three digits unique to each study site and 3 digits for 
each consecutively enrolled patient at the trial site, provided an informed consent form is signed 
by the patient. This number should be entered into the electronic data capture (EDC) system and 
maintained throughout the study. Once the patient meets inclusion and exclusion criteria, the 
study site will request the study medication assignment using the Interactive Response System 
(IXRS). 
3.2.3. Blinding 
This is a randomized, double-blind, placebo-controlled study. Placebo will be similar to 


 
 
Statistical Analysis Plan 
 
Verona Pharma 
RPL554-CO-203 
 
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Author: Eleonora Chiossi 
 
 
 
 
          
      Version: 1.0 
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Version Date: 6 March 2018 
RPL554, except for the omission of the active ingredient. Because a visually matching placebo 
could not be developed, the dosing cup on each nebulizer administered at the study center will 
be obscured with opaque tape to visually blind the study medication.  
3.3. 
Determination of Sample Size 
The standard deviation for peak FEV1 is estimated to be 250 mL. With a 2-sided test at a 5% 
significance level and 80 evaluable patients per group, there will be an 80% power to detect a 
true difference of 111 mL between any two treatments. This detectable limit has been 
considered sufficient to conclusively identify a minimal effective dose of RPL554. Thus 80 
patients per group will be randomized for a total of 400 patients. 
3.4. 
Changes in the Conduct of the Study or Planned Analyses 
x 
The method for analysis the primary efficacy endpoint has been changed from LOCF 
ANCOVA to mixed model for repeated measures (MMRM). The change was led by the 
superiority of MMRM with respect to LOCF in avoiding some type of bias as suggested 
by Siddiqui et al. (Siddiqui O, 2009) 
x 
Introduction of Per Protocol analysis set. This is an analysis set of interest for a phase II 
study. 
3.5. 
Analysis Sets 
All randomized analysis Set: includes all randomized patients 
 
Safety Analysis Set: includes all patients who receive at least one dose of investigational 
product during the study. It is a subset of all randomized analysis set.  
 
Full Analysis Set: includes all randomized patients, who receive at least one dose of 
investigational product during the study and with at least one post/treatment efficacy data 
assessment among spirometry EXACT-PRO questionnaire, SGRQ, TDI PGAC and MRC. It is a 
subset of the safety analysis set.  
 
Per-Protocol Analysis Set: includes all patients who do not have pre-specified major protocol 
deviations which can affect the efficacy outcome or the treatment of the subject (see section 
3.6). It is a subset of the safety analysis set. 
 
 
 
Use of the analysis set 
 
All-
Randomized 
set 
Full Analysis 
Set 
Safety 
Analysis Set 
Per-Protocol 
Analysis Set 
Disposition of patients 
X 
 
 
 
Protocol deviations 
X 
 
 
 
Demographic and other 
baseline characteristics 
X 
 
 
 
Medical history 
X 
 
 
 
Prior and concomitant 
medication 
 
 
X 
 
Treatment compliance and 
extent of exposure 
 
 
X 
 


 
 
Statistical Analysis Plan 
 
Verona Pharma 
RPL554-CO-203 
 
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Author: Eleonora Chiossi 
 
 
 
 
          
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Efficacy: Primary endpoint 
 
X 
 
X 
Efficacy: Secondary 
endpoints 
 
X 
 
X 
Efficacy: Exploratory 
endpoints 
 
X 
 
X 
Safety 
 
 
X 
 
Pharmacokinetic 
 
 
X 
 
The number and percentage of patients within each of these analysis sets will be presented by 
treatment group and overall. 
3.6. 
Major Protocol Deviations 
Major protocol deviations will be defined in a separate document that will be finalized before 
database lock. 
Patients with major protocol deviations will be identified by a clinical review of the data prior to 
database lock to the extent possible in light of restrictions due to blinding of study personnel to 
treatment assignments.  
A summary of major protocol deviations will be presented by treatment group for all 
randomized patients.  
 
3.7. 
General Methodology 
Summary statistics will be presented to give descriptions of patients and an overview of efficacy 
and safety results. All analysis tables will include summaries for all five treatment groups: 
RPL554 0.75 mg BID, RPL554 1.5 mg BID, RPL554 3.0 mg BID, RPL554 6.0 mg BID, 
Placebo BID. Categorical parameters will be summarized with number of observations and 
percentage of patients in each category. Continuous parameters will be summarized using 
number of observations, mean, standard deviation (SD), median, minimum and maximum. 
 
Unless specified otherwise, all statistical tests will be two-sided. All p-values will be rounded to 
three decimal places; p-values less than 0.001 will be presented as ‘<0.001’ and greater than 
0.999 will be presented as ‘>0.999’ in all tables. 
 
All available data from all patients will be listed.  
3.7.1. Baseline 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior 
to study medication start date (including unscheduled assessments). In the case where the last 
non-missing measurement and the study medication start date coincide (and time is either not 
collected or missing), that measurement will be considered pre-baseline, but Adverse Events 
(AEs) and medications commencing on the reference start date will be considered post-baseline. 
3.7.2. End of Study 
This will be visit 6.  
3.7.3. Visit Windows 
No visit windows will be applied in this study and the scheduled assessments will be reported 
and analyzed as per CRF collection. 


 
 
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3.7.4. Duration 
For the purposes of calculating durations expressed in months, a month will be considered as 
one-twelfth of a year, or 365.25 / 12 = 30.4375 days. 
 
As for duration in days, the calculation will go as follows: 
 
x 
(stop date – start date) + 1 if start date is same as first dose date or later; 
x 
(stop date – start date) if start date is before first dose date. 
3.7.5.  Treatment period 
Treatment period is defined as the time elapsed between the first and last dose intake date plus 1 
day. Assessments will be included in the safety and efficacy analysis if performed during the 
treatment period. 
3.8. 
Handling of Dropouts or Missing Data 
3.8.1. Missing data in efficacy analysis 
MMRM model will be used as a strategy to deal with missing data. 
Last observation carried forward approach (LOCF) will be used a sensitivity analysis of the 
primary endpoint only. 
No other imputation will be applied. 
3.8.2. Missing data in safety analysis 
Any missing safety parameter will be considered missing for purposes of any summary statistics 
and analysis. 
3.8.3. Partial Date Imputation 
Dates are essential for the classification of AEs as treatment-emergent and medications as 
having been taken prior to the start of study medication and/or concomitantly with study 
medication. 
3.8.4. Partial Dates for AEs 
Adverse event start date (references to month are the month of the AE start date): 
1. If only month and year are known and study medication started during that month then set 
start date equal to study medication start date.  
2. If month and year are known and study medication started prior to or after that month then 
set start date equal to 1st day of month. 
3. If only year is known, and it is the same as study medication start year, assume it is the 
study medication start date/year.  If it is different from study medication start year, assume it 
is the first day of the year.   
4. If full start date (i.e. day, month, and year are missing) is unknown impute start date as the 
study medication start date. If imputed start date is greater than stop date, it will be imputed 
as stop date. 


 
 
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3.8.5. Partial Dates for Concomitant Medications 
Concomitant therapy start date (references to month are the month of the concomitant therapy 
start date). Partial date imputation will follow the same pattern as for AEs in section 3.8.4 above. 
 
Concomitant therapy stop date (references to month are the month of the concomitant therapy 
stop date): 
1. If only day is unknown, then set equal to last day of month. 
2. If only year is known, assume it is the last day of the year.   
3. Otherwise (i.e. day, month and year are missing) leave as missing. 
3.9. 
Interim Analyses and Data Monitoring 
There are no planned interim analyses of data from this study.  
3.10. Pooled country/region 
For all analyses, sites will be pooled within countries. This will be detailed and approved prior 
to database lock. 
4. 
Patient disposition, demographic and baseline characteristics, medical history, 
prior and concomitant medications, treatment compliance and exposure 
4.1. 
Patient disposition 
The final patient disposition will be presented by treatment group and overall. The total number 
of patients randomized, treated, completed and discontinued (including reason for 
discontinuation as recorded on the CRF) from the study will be summarized by treatment group 
and overall. The total number of patients prematurely discontinued will be presented overall and 
by visit. If the patient has discontinued between Visit 2 and Visit 3 it will be counted on those 
discontinued up to Week 1, and so on.  
 
4.2. 
Demographic and Other Baseline Characteristics 
Demographics including age, age group, gender, ethnicity and race will be presented by 
treatment group and overall. Also, presented by treatment group and overall are the following 
baseline characteristics: post-bronchodilator FEV1 (both in liters and in percentage of predicted 
normal), post-bronchodilator FVC, FEV1/FVC, FEV1 reversibility test results, duration of 
COPD (from diagnosis to randomization), smoking habits. 
 
Statistical testing will not be performed on these parameters.  
4.3. 
Medical History 
The number and percentage of patients in the SAF with at least one medical condition, diagnosis 
or surgery will be presented by treatment group and overall. Furthermore, the incidence for each 
System Organ Class (SOC) and Preferred Term (PT) will be presented. For each patient, 
multiple events that map to a SOC and PT will be counted only once for incidence counts. 
Events will be in descending frequency of SOC and PT in summaries. A listing of all medical 
history will also be presented. 
 


 
 
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4.4. 
Prior COPD, Prior and Concomitant Medications 
Prior medications are defined as medications taken prior to first study medication dose. 
Concomitant medications are defined as medications with onset dates on or after the first dose of 
study medication, or medications with onset dates prior to first dose of study medication without 
a stop date or with a stop date after first dose of study medication. Partial date imputation for 
medications is described in section 3.8.5. 
 
Prior and concomitant medications will be classified by WHO Drug Dictionary that identifies 
the active ingredient. .  
 
Prior and concomitant medications will be summarized by therapeutic subgroup (ATC level 2), 
active ingredient and treatment group (for prior COPD medications and prior medications the 
overall column will also be presented), displaying frequencies and percentages. The 
denominators for the percentages will be the numbers of patients in each treatment group. 
Medications will be sorted by decreasing order of frequency of the therapeutic subgroup and 
active ingredient within subgroup. 
 
A separate summary of patient taking COPD medications prior to the study by therapeutic class 
will also be presented. COPD medications are identified as those with ‘Indication=’COPD’ on 
the medication log. 
4.4.1. Special grouping of medications 
Special grouping of beta agonist will be done as follows and will replace the ATC2 code 
classification.  
x 
LAMAs 
ATC4=R03BB and active ingredient equal to 
o tiotropium 
o umeclidinium  
o aclidinium  
ATC4=A03AB and active ingredient equal 
o glycopyrronium  
x 
LABAs 
ATC4=R03AC and active ingredient equal to  
o salmeterol 
o formoterol 
o indacaterol 
o olodaterol 
ATC4=R03AK and active ingredient equal to  
o vilanterol and fluticasone furoate 
ATC4=R03AL3 and active ingredient equal to 
o  vilanterol and umeclidinium bromide 


 
 
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o vilanterol, umeclidinium bromide and fluticasone furoate 
x 
Inhaled corticosteroids (ICS) 
ATC4 = R03BA or 
ATC4= R03AK and active ingredient equal 
o beclometasone  
o budesonide  
o flunisolide  
o betamethasone  
o fluticasone  
o triamcinolone  
o mometasone  
o ciclesonide  
o fluticasone furoate  
 
x 
LABA/LAMA 
Active ingredient includes 
o ‘glycopyrronium’ and ‘indacaterol’ 
o ‘olodaterol’ and ‘tiotropium’ 
o ‘aclidinium’ and ‘formoterol’  
o ‘umeclidinium’ and ‘vilanterol’  
x 
LABA/ICS 
Active ingredient includes 
o 
‘budesonide’ and ‘formoterol’ 
o 
‘fluticasone’ and ‘salmeterol’ 
o 
‘fluticasone’ and ‘vilanterol’ 
o 
‘beclomethasone’ and ‘formoterol’ 
o 
‘mometasone’ and ‘formoterol’ 


 
 
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4.5. 
Exposure and compliance 
4.5.1. Treatment Compliance 
Treatment compliance will be summarized by treatment group in 2 ways:  
1. 100*((number of vials dispensed – number of vials returned)/(expected number of vials to 
be taken during study period)) (excluding visit 6 for completers, as the vials will be 
dispensed by the site) 
 
2. 
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. 
4.5.2. Extent of Exposure 
Duration of exposure to study medication will be calculated as follows: 
(Stop date – start date) + 1. 
The mean duration of exposure in days will be summarized by treatment group. Total exposure 
(in mL) will be based on the number of vials dispensed against the number returned (number of 
vials* contents of each vial (in mL)).  
For in-clinic dosing, the RPL554 exposure will be calculated based on the nominal dose. 
 
5. 
Efficacy Endpoints 
5.1. 
Primary Efficacy Endpoint 
x Change from baseline FEV1 to peak FEV1 (over 3 hours) at Week 4  
o Baseline is defined as the FEV1 pre-dose assessment (-15 minutes) collected at Visit 2 
o Peak FEV1 at Week 4 is defined as the maximum post-dose value among the 30 
minutes, 1, 2 and 3 hour assessments collected at Visit 6 (Week 4).  
5.2. 
Secondary Efficacy Endpoints 
x 
Change from baseline FEV1 to morning trough FEV1 at Week 1, 2, 3 and 4 
x 
Change from baseline FEV1 to average FEV1 (over 12 hours) at Day 1 and at Week 4 
x 
Change from baseline FEV1 to average FEV1 (over 3 hours) at Day 1, Week 1, 2, 3, and 
4 
x 
Change from baseline FEV1 to peak FEV1 (over 3 hours) at Day 1, Week 1, 2 and 3 
 
For details on the derivation of the above FEV1endpoints refer to section 5.5.1 
 
x 
Change from baseline in EXACT-PRO E-RS score at Week 4 
x 
Change from baseline in EXACT-PRO Total score at Week 4 
x 
Change from baseline in EXACT-PRO E-RS Breathlessness score at Week 4 
x 
Change from baseline in EXACT-PRO E-RS Cough/Sputum score at Week 4 
x 
Change from baseline in EXACT-PRO E-RS Chest Symptoms score at Week 4 


 
 
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For details on the derivation of the above EXACT-PRO scores refer to section 5.5.2 
 
x 
Change from baseline in the SGRQ-C Total score at Week 4 
x 
Change from baseline in the SGRQ-C Symptoms score at Week 4 
x 
Change from baseline in the SGRQ-C Activity score at Week 4 
x 
Change from baseline in the SGRQ-C Impact score at Week 4 
For details on the derivation of the above SGRQ-C scores refer to section 5.5.3 
 
x 
Change from baseline in MRC breathlessness scales at Week 4 
For details on the MRC scale refer to section 5.5.4 
 
x 
Transition Dyspnea Index (TDI) at week 4 
x 
Patient Global Assessment of Change (PGAC) at Week 4 
x 
Change from baseline (average over the last 7 days of the run-in period) in average daily 
use of rescue medication over the treatment period, and at Week 1, 2, 3 and 4. 
Average daily use of rescue medication is the average of the number of times the rescue 
medications is taken (multiplied by two as two puffs are taken at each administration) 
during the period of time. 
5.3. 
Exploratory Efficacy Endpoints 
x 
Change from baseline in EXACT-PRO E-RS score at Week 1, 2 and 3 
x 
Change from baseline in EXACT-PRO Total score at Week 1, 2 and 3 
x 
Change from baseline in EXACT-PRO E-RS Breathlessness score at Week 1,2 and 3 
x 
Change from baseline in EXACT-PRO E-RS Cough/Sputum score at Week 1,2 and 3 
x 
Change from baseline in EXACT-PRO E-RS Chest Symptoms score at Week 1,2 and 3 
For details on the derivation of the above EXACT-PRO scores refer to section 5.5.2 
 
x 
Change from baseline in the SGRQ-C Total score at Week 2 
x 
Change from baseline in the SGRQ-C Symptoms score at Week 2 
x 
Change from baseline in the SGRQ-C Activity score at Week 2 
x 
Change from baseline in the SGRQ-C Impact score at Week 2 
For details on the derivation of the above SGRQ-C scores refer to section 5.5.3 
 
x 
Change from baseline in MRC breathlessness scales at Week 2 
For details on the MRC scale refer to section 5.5.4 
 
x 
Transition Dyspnea Index at week 2 
x 
Patient Global Assessment of Change (PGAC) at Week 2 
x 
COPD exacerbation  
o Patient with one adverse event with MedDRA Preferred Term=’COPD 
exacerbation’ and use of systemic steroids (ATC2=H02) from AE date of onset 
for at least three days 
x 
Change in peak FEV1 (over 12 hours) from Day 1 (single dose) to Week 4 (steady state) 
5.4. 
Selected secondary endpoints  
The following secondary endpoints are of particular clinical interest and will undergo further 


 
 
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sensitivity analyses like subgroup analyses. 
x 
Change from baseline FEV1 to peak FEV1 (over 3 hours) at Week 4  
x 
Change from baseline FEV1 to morning trough FEV1 at Week 4  
x 
Change from baseline FEV1 to average FEV1 (over 12 hours) at Week 4  
5.5. 
Efficacy Endpoints details 
5.5.1. Pulmonary Function Tests 
 
Baseline FEV1 is defined as the FEV1 pre-dose assessment (-15 minutes) collected at Visit 2. 
 
Peak FEV1 (over 3 (12) hours) is defined as the maximum post-dose value among the values 
collected up to 3 (12) hours. 
 
Morning trough FEV1 is defined as the last pre-dose value at the visit under analysis 
 
Average FEV1 (over 3 (12) hours) is defined as the Area under the curve AUC0-3 (AUC0-12) of 
the FEV1 values collected during the visit under analysis, divided by the length of the time (in 
hours) interval of interest. The AUC is calculated using the trapezoidal rule. 
Parameters will be calculated over 3 hours (at Day 1 and Week 1 to 4) and over 12 hours (Day 1 
and Week 4). 
If patient miss hour 2 and 3 then the AUC 0-3 is set to missing. If patient miss hour 8 and 12 
then AUC 0-12 is set to missing. 
 
Censoring of value after rescue medications: before derivation of endpoints, within each visit, 
the spirometry data collected after the use of rescue medications (either Albuterol / Salbutamol 
or Ipratropium as collected on the CRF) will be censored (i.e.: considered as missing) 
5.5.2. Symptom Diary [EXACT-PRO] 
Once patients provide answers to all 14 questions on the ePRO, the device produces a score for 
each of three subscales: breathlessness, cough/sputum and chest symptoms. In addition to the 
subscale scores, a total score (covering all 14 questions) and a score for the E-RS part (11 
questions) together with the subscores will be obtained.  
 
The average over the week 1, 2, 3 and 4 will be used as timepoint values, while the one over the 
week just prior to randomization (visit 2) will be used as baseline. If less than 4 days are 
available, the average over that week is set to missing. 
 
Scoring will be performed as described in Appendix 2: EXACT-PRO and E-RS Scoring 
Instructions . 
 
Note that, as the data are collected with an e-diary, there is no possibility of having missing 
items in the questionnaire as the system does not allow the patient to skip items. 
Also note that the EXACT-PRO subscale scores are not endpoints of the study but will be 
summarized for eventual comparison with other published studies 
5.5.3. 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 


 
 
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(baseline), 4 and 6. This is a 14-question, multiple-choice questionnaire that has 2 parts. Part 1 
(questions 1-7) produces the symptoms score, while part 2 (questions 8-14) produces the activity 
and impacts scores. A total score is also produced. Each possible answer to each of the 14 
questions is assigned a weigh as in Appendix 3: SGRQ-C (Jones P. , 2012). The lowest possible 
weight is zero, the highest is 100. A single response is required to each item. With electronic 
collection, it is impossible that there could be multiple responses given to any one item.  
 
The SGRQ-C is scored in 2 steps: 
 
1. Sum the weights for all items with a positive response 
The symptoms component score is obtained by adding the weights for items 1 through 7.  
 
The activity component score is obtained by adding the weights for the positive responses to 
items Questions 9 and 12.  
 
The impacts component score is obtained by adding the weights of items 8, 10, 11, 13 and 14 
in the following way: the weights for all positive responses to items in Questions 10, 11 and 13 
are summed together with the response to the single item that should have been checked/ticked 
in Questions 8 and 14. 
 
2. Calculate the score 
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. 
 
ܵܿ݋ݎ݁ൌͳͲͲ כ ܵݑ݉݉݁݀ݓ݄݁݅݃ݐݏ݂ݎ݋݉݈݈ܽ݌݋ݏ݅ݐ݅ݒ݁݅ݐ݁݉ݏ݅݊ݐ݄ܽݐܿ݋݉݌݋݊݁݊ݐ
ݏݑ݉݋݂݉ܽݔ݅݉ݑ݉ݓ݄݁݅݃ݐݏ݂݋ݎ݈݈ܽ݅ݐ݁݉ݏ݅݊ݐ݄ܽݐܿ݋݉݌݋݊݁݊ݐ 
 
The total score is calculated similarly 
 
ܵܿ݋ݎ݁ൌͳͲͲ כ ܵݑ݉݉݁݀ݓ݄݁݅݃ݐݏ݂ݎ݋݉݈݈ܽ݌݋ݏ݅ݐ݅ݒ݁݅ݐ݁݉ݏ݅݊ݐ݄݁ݍݑ݁ݏݐ݅݋݊݊ܽ݅ݎ݁
ݏݑ݉݋݂݉ܽݔ݅݉ݑ݉ݓ݄݁݅݃ݐݏ݂݋ݎ݈݈ܽ݅ݐ݁݉ݏ݅݊ݐ݄݁ݍݑ݁ݏݐ݅݋݊ܽ݅ݎ݁ 
 
The total score is calculated by summing the weights to all the positive responses in each 
component. 
 
Please note that by “positive items”, it is meant those that show the presence of symptoms, to 
some degree. For example, in question 1 (part 1), all answers (“most days”, “several days” and 
“with chest infections”) except “not at all” would be positive. Another way to identify a positive 
response from a negative one is that a positive response has a nonzero score, unlike a negative 
one. The same definition is true in part 2. With question 8 for example (“How would you 
describe your chest condition”?), the following responses are positive: “the most important 
problem I have”, “causes me a few problems”; an answer of “Causes no problem” would be 
deemed negative as it does not show any signs of symptoms. In question 14 (see Appendix 3: 
SGRQ-C), as another example, any answer except “It does not stop me doing anything I would 
like to do” would be considered positive. 
 
Note that, as the data are collected with an e-diary, there is no possibility of having missing 
items in the questionnaire as the system does not allow the patient to skip items. 
 


 
 
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5.5.4. Medical Research Council (MRC) Breathlessness Scale 
The MRC is the most commonly used, validated scale to assess dyspnea in daily living in 
chronic respiratory diseases (Mahler & Wells, 1988) (Hajiro, et al., 1998). During Visits 2 
(baseline), 4 and 6, patients will be provided with 
 the MRC (shown in Table 2 below) and asked on a grade of 1 to 5 how they would describe 
their levels of breathlessness. 
 
Table 2: MRC Breathlessness Scale 
Grade 
Degree of breathlessness related to activities 
1 
Not troubled by breathlessness except on strenuous exercise  
2 
Short of breath when hurrying on the level or walking up a slight hill  
3 
Walks slower than most people on the level, stops after a mile or so, or stops after 15 minutes 
walking at own pace  
4 
Stops for breath after walking about 100 yds or after a few minutes on level ground  
5 
Too breathless to leave the house, or breathless when undressing  
 
This scale will be summarized at the time points at which it is collected, which are the same as 
SGRQ-C. 
5.5.5. Patient Global Assessment of Change (PGAC) 
At visits 4 and 6, patients will be asked to respond to a PGAC question along the following 
lines: “compared with prior to the study start, how do you feel your breathing is?” Answers are 
expected to use a 1-5 scale, where 1=much worse to 5=much better, with 3= no change. 
Answers will be summarized at visits 4 and 6, when the questionnaire is administered. 
5.5.6. Baseline and Transition Dyspnea Indices (BDI and TDI) 
The BDI and TDI are interviewer-administered ratings of dyspnea severity.  They are based on 
three components that evoke dyspnea in activities of daily living.  
The questionnaires are comprised of 24 items covering 3 domains.  
 
The domains are the following: 
x 
For BDI: Functional impairment, magnitude of task and magnitude of effort. Patients 
are asked to recall during the previous 2 weeks. Each of these components ranges from 
0 to 4. 
The BDI Total Score is the sum of the three domains and can take values from 0 to 12 (12 
meaning no dyspnea) and is only assessed at baseline. The lower the score, the worse the 
dyspnea severity.  
 
x 
For TDI: Change in functional impairment, change in magnitude of task, change in 
magnitude of effort. Each of these components ranges from -3 (major deterioration) to 
+3 (major improvement) 
The TDI assesses the patient perception of the change in dyspnea severity from baseline.  
The TDI total score is the sum of the three TDI domains and can take values from -9 to 9. 
As with the BDI, the lower the TDI score, the more severe the dyspnea.  


 
 
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5.6. 
Efficacy Endpoint Analysis 
5.6.1. General consideration on the analysis of efficacy  
All efficacy analyses will be performed on the Full Analysis Set. Patients will be analyzed 
according to the randomized treatment. All efficacy summaries will present the five treatment 
groups. All data summarized will also be listed. 
 
5.6.2. Analysis of Primary Endpoint 
The primary efficacy analysis parameter is change from baseline FEV1 to peak FEV1 at Week 4 
of treatment. The primary analysis will be based on the full analysis set. 
 
Summary statistics for FEV1 will be presented for baseline, week 4 and change from baseline by 
treatment group on patients with both assessments. 
 
The primary analysis will use a restricted maximum likelihood (REML)–based repeated-
measures approach. The change from baseline FEV1 (at Day 1, Week 1, 2 3 and 4) will be the 
dependent variable. The analyses will include the fixed, categorical effects of treatment, visit, 
and treatment-by-visit interaction as well as the continuous, fixed covariates of baseline value. 
An unstructured (co)variance structure shared across treatment groups will be used to model the 
within-patient errors. If the model does not converge a compound symmetry (co)variance 
structure will be used. The Kenward-Roger approximation will be used to estimate denominator 
degrees of freedom and adjust standard errors. Analyses will be implemented with SAS PROC 
MIXED (see Appendix 4: SAS code for efficacy analysis). The primary comparison will be the 
contrast (difference in least squares mean [LSMEAN]) between treatments at Week 4. 
5.6.2.1. Sensitivity analysis for the primary endpoint 
To check the robustness of the results the following analysis will be performed: 
x 
MMRM analysis excluding the patients with only one on treatment assessment of peak 
FEV1 (over 3 hours) 
x 
analysis of covariance (ANCOVA) will be used on data where missing data will be 
imputed using last observation carried forward (LOCF) method.  
5.6.3. Analyses of Secondary and exploratory Endpoints 
The secondary and exploratory endpoints will be analyzed in the same way as the primary 
endpoint.  
In the analysis of TDI, BDI scores will be used as baseline in the model and the dependent 
endpoint will be the TDI score. 
 
As for PGAC the model will not include the baseline as the score reflect itself a change from 
baseline.  
 
The number of COPD exacerbations and use of rescue medications will be summarized by 
counts and percentages.  
5.6.4. Multiple Comparison Adjustment for the Primary Efficacy Endpoint 
The MMRM model above will test for the significance of treatment effect. Testing will continue 


 
 
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with each of the 4 doses of RPL554 against placebo, starting with the highest dose (6 mg). 
 
To this end, the fixed-sequence testing approach (Maurer et al., 1995; (Westfall & Krishen, 
2001)) will be used. 
 
Let i = 0, 1, …, 4 represent increasing dose levels, 0 denoting placebo. Also, let μi, i = 0, 1, …, 
4, denote the mean change from baseline in peak FEV1 after 4 weeks of treatment for placebo 
and each increasing active dose level, respectively.  The primary null hypotheses are defined as: 
Hi: μj - μ0 = 0 and will be tested against the two-sided alternative Ki: μj - μ0 ≠ 0, j = 1, …, 4.  
 
Finally, let p1, …, p4 denote the marginal p-values obtained from the statistical tests associated 
with H1, …, H4 (obtained from the MMRM model). 
The fixed-sequence testing will begin with the null hypothesis corresponding to the highest dose 
versus placebo. If a statistically significant difference is found at the two-sided α level of 5%, 
the testing will proceed with the next highest dose, and so on. Otherwise, testing stops and the 
remaining null hypotheses are accepted without testing. 
This testing strategy can be written as the following stepwise algorithm: 
x 
Step 1: If p4 ≤ α reject H4 and go to Step 2. Otherwise accept H1, …, H4 and stop. 
x 
Step 2: If p3 ≤ α reject H3 and go to Step 3. Otherwise accept H1, …, H3 and stop. 
x 
Step 3: If p2 ≤ α reject H2 and go to Step 4. Otherwise accept H1 and H2 and stop. 
x 
Step 4: If p1 ≤ α reject H1. Otherwise accept H1. 
The fixed-sequence procedure controls the family-wise error rate in the strong sense because, for 
each null hypothesis, the testing is conditional upon rejecting all hypotheses earlier in the 
sequence (Dmitrienko, et al., 2009). 
5.6.5. Multiple Comparison Adjustment for the Secondary Efficacy Endpoints 
As type I error is only controlled for the primary, secondary endpoints will be considered 
exploratory. Each secondary endpoint will be tested independently and nominally following a 
hierarchical testing of doses like the one used for the primary. Interpretation of the analyses of 
secondary endpoints in the CSR should ensure to consider the dose ranging nature of the study. 
5.6.6. Examination of Subgroups 
The following subgroups will be examined: 
1. Current vs. ex-smokers 
2. Chronic bronchitis vs. no chronic bronchitis at screening 
3. Males vs. females. 
4. Symptoms severity (MRC <2 vs. MRC ≥ 2) at randomization 
5. Age: (≥ 65 vs < 65)  
6. Inhaled corticosteroid use versus no use (use of medications during the last 7 days of run-in 
phase). 
7. By baseline FEV1 (> or <= 50% predicted) 
Subgroup analyses will be performed for the primary and the selected secondary endpoints (see 
5.4). 
The MMRM model will be run on each subgroup separately. 
6. 
Safety Endpoints 
Safety measures that will be collected and investigated include adverse events (AEs), clinical 


 
 
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laboratory tests, vital signs, physical examination and electrocardiograms assessments (ECGs, 
12-Lead and using 24 hour Holter monitors).  
All safety analyses will be performed on the safety analysis set. Patients will be analyzed 
according to the treatment received. All safety summaries will present the five treatment 
groups. 
6.1. 
Adverse Events 
Treatment Emergent Adverse Events (TEAEs) are defined as all AEs which start after the first 
dose of study medication, or start prior to first dose of study medication and worsen, based on 
the investigator assessment of severity, on or after first dose of study medication.   
Adverse events with completely missing onset dates will also be considered as treatment 
emergent.  If any AE records contain only partial dates, these will be handled by imputation, as 
described in Section 3.8.4.  
 
Table summaries will be produced summarizing AEs in the following ways: 
x 
TEAEs 
x 
TEAEs classified by maximum severity 
x 
TEAEs classified with relationship to study medication 
x 
TEAEs leading to study discontinuation 
x 
Serious TEAEs 
x 
Serious TEAEs classified by maximum severity 
x 
Serious TEAEs classified with relationship to study medication 
x 
Serious TEAEs leading to study discontinuation 
x 
TEAEs with outcome death 
 
6.1.1. Analysis of Adverse Events 
Adverse events will be coded using MedDRA version 20 (June 2017). 
 
All AE tables will be summarized by SOC and PT by treatment group, including the number of 
patients for each SOC and PT. Within each patient, multiple records of events mapping to a 
common MedDRA PT and SOC will be condensed into a single AE for incidence counts. 
Adverse Events will be reported by SOC and by PT in decreasing order of the highest active 
dose group of study medication (i.e 6.0 mg). 
 
Listings of patients who discontinue the study for an AE, patients who experience an SAE and 
patients with AEs resulting in death will be presented.  
 
6.2. 
Clinical Laboratory Evaluations 
x 
Change from baseline to Week 1 (Visit 3) in laboratory parameters 
x 
Change from baseline to End of Study (Visit 6) in laboratory parameters 
 
Laboratory parameters to be analyzed are: 
o Hematology: hemoglobin, hematocrit, total white cell count, leukocyte differential count 
and platelet count 
o Biochemistry: 
creatinine, 
total 
bilirubin, 
alkaline 
phosphatase, 
aspartate 
aminotransferase, 
alanine 
transaminase, 
gamma-glutamyl 
transferase, 
lactate 
dehydrogenase, creatine kinase, thyroid stimulating hormone, triiodothyronine and 


 
 
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thyroxine, glucose, potassium, sodium and calcium 
o Urinalysis: leukocytes, blood, ketones, bilirubin, urobilinogen, protein and glucose. 
6.2.1. Analysis of Clinical Laboratory Evaluation 
Descriptive statistics (number of observations, mean, standard deviation, minimum, median and 
maximum values) for collected values and change from baseline will be summarized for clinical 
laboratory tests (hematology, biochemistry and urinalysis) at applicable visits, by treatment 
groups. 
 
Selected laboratory test results will be classified by markedly abnormal criteria as normal or 
abnormal, according to Table 3 below. The number and percentage of patients with markedly 
abnormal laboratory results will be provided. No statistical testing will be performed on 
laboratory data. 
Table 3: Markedly abnormal ranges for clinical laboratory parameters 
Parameter 
Markedly Abnormally High Criteria 
Alanine Amino Transferase (ALT) 
>3 times Upper Limit of Normal 
Range 
Alkaline Phosphatase 
>3 times Upper Limit of Normal 
Range 
Aspartate Amino Transferase 
(AST) 
>3 times Upper Limit of Normal 
Range 
Creatinine 
221 μmol/L 
Gamma Glutamyl Transferase 
(GGT) 
>3 times Upper Limit of Normal 
Range 
Total Bilirubin 
>3 times Upper Limit of Normal 
Range 
 
In addition, abnormal values (relative to the normal range) for hematology and biochemistry will 
be presented by treatment, patient, visit, and parameter in data listings (including all values of a 
parameter if at least one value was abnormal per patient). These listings will include: treatment, 
subject identifier, the laboratory parameter, units, visit number and study day, parameter value, 
an indicator for values outside of the reference range (H or L), the reference range, and an 
indicator for clinically significant out-of-range values.  
All laboratory parameter results will be listed. 
6.3. 
Electrocardiograms 
x 
Change from baseline (pre-dose at Visit 2) to 2-hours post-dose at Day 1, Week 1, Week 2, 
Week 3 and End of study in ECG parameters 
x 
Change from pre-dose to 2-hours post-dose at Week 1, Week 2, Week 3 and End of study in 
ECG parameters 
x 
Clinically significant ECG abnormality during treatment period 
 
ECG parameters to be analyzed are: QTcF Interval (msec), QRS Interval (msec), PR Interval 
(msec), RR (msec)and Heart rate (bpm). 
 
6.3.1.  Analysis of ECG Evaluations 
A 12-lead ECG will be recorded at Baseline and Screening, visits 2, 3, 4, 5 and end of study (or 


 
 
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early termination). The overall ECG investigator interpretations will be summarized using a 
shift table comparing Baseline to time points. The ECG interpretations will be reported as 
“Normal”, “Abnormal NCS (Not Clinically Significant)”, or “Abnormal CS (Clinically 
Significant)”. The denominators for the percentages will be the numbers of patients with ECG 
data at both the baseline and at the time point in question in each treatment group. The 
quantitative parameters listed in 6.3 will be summarized and listed. 
6.3.2. Holter Monitors 
x 
Change from screening to Week 4 in Holter parameters 
 
The following parameter will be summarized:  
Atrial Fibrillation Time in %, Supraventricular, Supraventricular Couplets, Supraventricular 
Runs, Ventricular Single, Ventricular Couplets, Ventricular Runs, Number of RR > 2 seconds 
The number of patients with Supraventricular or Ventricular runs, and the total number of runs 
will be also summarized at Screening and Week 4, presenting also the number of patients who 
had no runs at screening but had run at Week 4. 
 
These parameters will also be listed together with the start and stop of  Holter recording. 
6.4. 
Vital Signs 
x 
Change from baseline (pre-dose at Visit 2) to each post-dose assessment at Day 1, Week 1, 
Week 2, Week 3 and Week 4 in vital signs parameters 
x 
Change from pre-dose to each post-dose assessment at Week 1, Week 2, Week 3 and Week 
4 in vital signs parameters 
 
Blood pressure (systolic and diastolic) and pulse rate will be measured at screening (visit 1) and 
pre-dose, 30 minutes and 1, 2, 4, 6, 8 and 12 hours post-dose at visits 2 and 6. 
 
Blood pressure and pulse rate will be measured at pre-dose and 30 minutes, 1, 2 and 3 hours 
after dosing at visits 3 to 5. 
6.4.1. Analysis of Vital Signs 
Vital signs to be analyzed and presented are body weight, sitting blood pressure (systolic and 
diastolic), sitting pulse rate, and BMI. Vital signs at all study visits and changes from baseline at 
post-baseline visits will be summarized by visit for each treatment group using descriptive 
statistics. 
 
Post-baseline results qualifying as Markedly Abnormal will be summarized by treatment group 
by parameter. Post-baseline markedly abnormal vital signs criteria are defined below:  
 
Table 4: Markedly Abnormal Post-Baseline Vital Signs 
Vital 
Sign 
Parameter 
Abnormally Low 
Abnormally High 
Heart Rate (bpm) 
A decrease from Baseline of 
≥20 to a value ≤50 
An increase from Baseline of 
≥20 to a value ≥110 
Systolic 
blood 
pressure (mmHg) 
A decrease from Baseline of 
≥20 to a value ≤90 
An increase from Baseline of 
≥20 to a value ≥180 
Diastolic 
blood A decrease from Baseline of An increase from Baseline of 


 
 
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pressure (mmHg) 
≥20 to a value ≤50 
≥20 to a value ≥105 
Body weight (kg) 
Loss of ≥ 5% 
Gain of ≥ 5% 
 
Vital sign measurements will be presented by patient, visit and parameter in a data listing. 
 
6.5. 
Physical Findings 
The physical examination will be performed at screening and end of study (or early termination) 
and the results will only be listed. 
6.6. 
Drug induced bronchospasm 
x 
Drug induced bronchospasm, defined as a decrease from pre-dose FEV1 value of > 20% 
within the first hour after dosing. 
6.6.1. Analysis of drug induced bronchospasm 
The number of patients with at least one event of drug induced bronchospasm will be 
summarized by counts and percentage, overall and displayed by spirometry assessment (Day 1 
and Week 1 to 4).  The total number of events will also be displayed. 
7. 
Pharmacokinetic  
x 
Concentration of study medication at pre-dose assessment of Week 1 and Week 4 
x 
Correlation of pre-dose concentration with trough FEV1 at Week 1 and at Week 4 
7.1. 
Analysis of pharmacokinetic 
The concentration of study medication will be summarized at week 1 and 4. The correlation with 
the pre-dose FEV1 value will be presented in a graphical representation. Pearson’s correlation 
and its 95% CI will be presented as well. 
 
 


 
 
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8. 
REFERENCES 
 
Decramer, M., Celli, B., Kesten, S., & al. (2009). Effect of tiotropium on outcomes in patients 
with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified 
subgroup analysis of a randomised controlled trial. Lancet, 1171-1178. 
Dmitrienko, A., Bretz, F., Westfall, P. H., Troendle, J., Wiens, B. L., Tamhane, A. C., & Hsu, J. 
C. (2009). Multiple testing methodology. Multiple Testing Problems in Pharmaceutical 
Statistics. Chapman and Hall/CRC Press, New York. 
Evidera. 
(2014). 
Retrieved 
from 
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/04/WC50018544
3.pdf 
EXACT-PRO 
Initiative. 
(2014, 
October). 
EMA. 
Retrieved 
from 
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/04/WC50018544
4.pdf 
Hajiro, T., Nishimura, K., Tsukino, M., Ikeda, A., Koyama, H., & Uzumi, T. (1998). 
Comparison of discriminative properties among disease-specific questionnaires for 
measuring health-related quality of life in patients with COPD. American Journal of 
Respiratory and Critical Care Medicine, 785-790. 
Jones, 
P. 
(2012, 
April). 
Retrieved 
from 
http://www.healthstatus.sgul.ac.uk/SGRQ_download/sgrq-c-manual-april-2012.pdf 
Jones, P. W., Quirk, F. H., & Baveystock, C. M. (1991). The St George's Respiratory 
Questionnaire. Respiratory Medicine, 25-31. 
Mahler, D. A., & Wells, C. K. (1988). Evaluation of clinical methods for rating dyspnea. Chest, 
580-586. 
Marcus, R., Peritz, E., & Gabriel, K. R. (1976). On Closed Testing Procedures With Special 
Reference to Ordered Analysis of Variance. Biometrika, 655-660. 
Maurer, W., Hothorn, L. A., & Lehmacher, W. (1995). Multiple Comparisons in Drug Clinical 
Trials and Preclinical Assays: A-priori ordered Hypotheses. Testing Principles in 
Clinical and Preclinical Trials (J. Vollmar, editor) STuttgart, Gustav Fisher Verlag, 3-
18. 
Meguro, M., Barley, E. A., Spencer, S., & Jones, P. W. (2007). Development and Validation of 
an Improved, COPD-Specific Version of the St. George Respiratory Questionnaire. 
Chest, 456-463. 
Miller, M. R., & al. (2005). Standardisation of spirometry. European Respiratory Journal, 153-
161. 
SAS Institute, Inc. (1999). SAS Procedures Guide, version 8. Cary, NC: SAS Institute. 
Siddiqui O, H. H. (2009). MMRM vs. LOCF: a comprehensive comparison based on simulation 
study and 25 NDA datasets. Journal of biopharmaceutical statistics, 19(2):227-46. 
Tamhane, A. C., & Logan, B. R. (2002). Multiple Test Procedures for Identifying the Minimum 
Effective and Maximum Safe Doses of a Drug. Journal of the American Statistical 
Association, 293-301. 
Westfall, P. H., & Krishen, A. (2001). Optimally weighted, fixed sequence, and gatekeeping 
multiple testing procedures. Journal of Statistical Planning and Inference 99, 25-40. 
WHO Collaborating Centre for International Drug Monitoring. (1993). WHO Drug Dictionary. 
Uppsala, Sweden (Box 26, S-751-03). 
 
 
 


 
 
 
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9. 
Appendices 
9.1. 
Appendix 1: Schedule of Events 
 
Visit 
Visit 1a Screening 
(Week -2 to -1) 
Visit 
1b 
(Day after 
Visit 1a) 
Visit 
2 
Randomization 
Visit 3 (Week 1  
±1 day) 
Visit 4 (Week 2 
±1 day) 
Visit 
5 
(Week 3 ±1 
day) 
Visit 
6a 
(Day  
before 
Visit 6b) 
Visit 6b End 
of 
Study 
(Week 4 ±1 
day or early 
termination) 
Telephone 
Follow-up (2 
weeks after 
Visit 6b ±3 
days) 
Informed Consent 
Xa 
 
 
 
 
 
 
 
 
Demographics, except body 
weight 
X 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
 
 
 
 
X 
 
Medical/surgical 
& 
disease 
history 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
X 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
X 
 
Nebulization 
inhalation 
training 
 
 
X 
 
 
 
 
 
 
Reversibility test 
X 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
Pregnancy testb 
X 
 
X 
X 
X 
X 
 
X 
 
Viral serology 
X 
 
 
 
 
 
 
 
 
Study medication inhalation 
 
 
Xc 
X 
X 
X 
 
X 
 
Spirometry 
X 
 
Xd 
Xe 
Xe 
Xe 
 
Xd 
 
Prior/concomitant medications 
X 
 
X 
X 
X 
X 
 
X 
 
Vital signs (blood pressure, 
pulse) 
X 
 
Xf 
Xg 
Xg 
Xg 
 
Xf 
 


 
 
 
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Visit 
Visit 1a Screening 
(Week -2 to -1) 
Visit 
1b 
(Day after 
Visit 1a) 
Visit 
2 
Randomization 
Visit 3 (Week 1  
±1 day) 
Visit 4 (Week 2 
±1 day) 
Visit 
5 
(Week 3 ±1 
day) 
Visit 
6a 
(Day  
before 
Visit 6b) 
Visit 6b End 
of 
Study 
(Week 4 ±1 
day or early 
termination) 
Telephone 
Follow-up (2 
weeks after 
Visit 6b ±3 
days) 
ECG (QTcF and heart rate) 
X 
 
Xh 
Xh 
Xh 
Xh 
 
Xh 
 
Laboratory safety tests 
X 
 
 
X 
 
 
 
X 
 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
Administer SGRQ-C,BDI/TDI 
and MRC breathlessness scale 
 
 
Xi 
 
Xi 
 
 
Xi 
 
Administer 
PGAC 
questionnaire 
 
 
 
 
X 
 
 
X 
 
Dispense study medication and 
nebulizer 
 
 
X 
X 
X 
X 
 
 
 
Collect study medication and 
nebulizer 
 
 
 
X 
X 
X 
 
X 
 
Dispense compressor 
 
 
X 
 
 
 
 
 
 
Collect compressor 
 
 
 
 
 
 
 
X 
 
Dispense albuterol/salbutamolj 
X 
 
 
 
 
 
 
 
 
Trough PK blood sample 
 
 
 
X 
 
 
 
X 
 
Place Holter Monitor 
X 
 
 
 
 
 
X 
 
 
Remove Holter Monitork 
 
X 
 
 
 
 
 
X 
 
Dispense symptom e-diary 
X 
 
 
 
 
 
 
 
 


 
 
 
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Visit 
Visit 1a Screening 
(Week -2 to -1) 
Visit 
1b 
(Day after 
Visit 1a) 
Visit 
2 
Randomization 
Visit 3 (Week 1  
±1 day) 
Visit 4 (Week 2 
±1 day) 
Visit 
5 
(Week 3 ±1 
day) 
Visit 
6a 
(Day  
before 
Visit 6b) 
Visit 6b End 
of 
Study 
(Week 4 ±1 
day or early 
termination) 
Telephone 
Follow-up (2 
weeks after 
Visit 6b ±3 
days) 
Review symptom e-diary 
 
 
X 
X 
X 
X 
 
X 
 
Collect symptom e-diary 
 
 
 
 
 
 
 
X 
 
Adverse event questioning 
X 
 
X 
X 
X 
X 
 
X 
X 
Abbreviations: BDI=Baseline Dyspnea Index; ECG=electrocardiogram; ICS=inhaled corticosteroids; MRC=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; TDI=Transition Dyspnea Index 
(a) Informed Consent may be obtained prior to screening visit 
(b) Serum pregnancy test at Visit 1; urine pregnancy test at Visits 2-6 
(c) At Visit 2, study medication is to be administered at the study clinic twice; first, just after randomization and again 12 hours later once all assessments are complete 
(d) Spirometry at Visits 2 and 6 is performed 15 minutes pre-dose, followed by 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose 
(e) Spirometry at Visits 3, 4, and 5 are performed 15 minutes pre-dose, followed by 30 minutes and 1, 2, and 3 hours post-dose 
(f) Vital signs at Visits 2 and 6 are measured pre-dose and 30 minutes, 1, 2, 4, 6, 8, and 12 hours post-dose 
(g) Vital signs at Visits 3, 4, and 5 are measured pre-dose and 30 minutes, 1, 2 and 3 hours post-dose 
(h) ECG at Visits 2 through 6 is performed pre-dose and 2 hours post-dose 
(i) BDI administered at Visit 2, TDI administered at Visits 4 and 6 
(j) A second canister of albuterol/salbutamol may be dispensed during the study if necessary 
(k) Holter is to be removed 24 hours (± 1 hour) after placement 


 
 
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9.2. 
Appendix 2: EXACT-PRO and E-RS Scoring Instructions 
The following instructions are from the user manual for EXACT-PRO, version 7.0 (EXACT-
PRO Initiative, 2014) 
x 
Raw scores are assigned to each item response option as shown in Table 7 below. 
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.  
x 
Sum the item-level raw scores of the 14 EXACT items to form the raw summed score 
x 
For each raw summed score, look up the corresponding EXACT Total score from Table 
6 below. 
 
Notes: 
1. EXACT total scores range from 0 to 100 
2. If the EXACT total score is 0, set to missing. 
3. The Evaluating Respiratory Symptoms (E-RS) part of the EXACT tool consists 
of the first 11 items, broken down as follows (Evidera, 2014): 
a. RS-Breathlessness: items 7, 8, 9, 10 and 11 (score range: 0-17); 
b. RS-Cough & Sputum: items 2, 3 and 4 (score range: 0-11); 
c. RS-Chest Symptoms: items 1, 5 and 6 (score range: 0-12). 
Scoring the domains: 
The following respiratory domains are included in the EXACT measure: Breathlessness, 
Cough/Sputum and Chest Symptoms. 
Items are assigned to specific domains as follows (please note that items 4, 12, 13 and 14 do not 
correspond to a domain and hence, are not used in domain-specific analyses): 
x 
Breathlessness: items 7, 8, 9, 10 and 11 
x 
Cough and Sputum: items 2 and 3 
x 
Chest Symptoms: items 1, 5 and 6 
Score the domains as follows: 
x 
For each day, sum the item-level raw scores of the items comprising the domain to form 
the domain raw summed score. If no diary entry exists for a given day, leave the domain 
raw summed score missing. 
x 
For each domain raw summed score, look up the corresponding EXACT domain score 
from Table 7 
x 
If no diary entry exists for a given day, leave the EXACT domain score missing. 
x 
If the daily EXACT domain score is 0, set it to missing. 
 
 
 


 
 
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Table 5: Annotated EXACT for raw score assignment 
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 
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 


 
 
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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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Table 6: 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 
 
 
 
 


 
 
Statistical Analysis Plan 
 
Verona Pharma 
RPL554-CO-203 
 
Document:U:\My documents\ad hoc\Mark\Final SAP\Verona RPL554-CO-203 SAP v1.0.docx 
Author: Eleonora Chiossi 
 
 
 
 
 
 
 
 
 
 
 
         
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Version Date: 5th March 2018 
Table 7: Raw Summed Score to Scale Score Conversion Table for EXACT Domains 
Domain Raw 
 Summed Score 
Breathlessness 
Domain Score 
Cough & Sputum 
Domain Score 
Chest Symptoms 
Domain Score 
0 
0 
0 
0 
1 
11 
13 
12 
2 
19 
25 
23 
3 
25 
39 
31 
4 
30 
56 
38 
5 
34 
72 
45 
6 
38 
86 
52 
7 
42 
100 
58 
8 
45 
 
65 
9 
48 
 
72 
10 
52 
 
79 
11 
56 
 
88 
12 
60 
 
100 
13 
65 
 
 
14 
71 
 
 
15 
78 
 
 
16 
87 
 
 
17 
100 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
 
Verona Pharma 
RPL554-CO-203 
 
Document:U:\My documents\ad hoc\Mark\Final SAP\Verona RPL554-CO-203 SAP v1.0.docx 
Author: Eleonora Chiossi 
 
 
 
 
 
 
 
 
 
 
 
         
                   Version: 1.0 
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Version Date: 5th March 2018 
9.3. 
Appendix 3: SGRQ-C 
Table 9: 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 
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 


 
 
Statistical Analysis Plan 
 
Verona Pharma 
RPL554-CO-203 
 
Document:U:\My documents\ad hoc\Mark\Final SAP\Verona RPL554-CO-203 SAP v1.0.docx 
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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 
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 


 
 
Statistical Analysis Plan 
 
Verona Pharma 
RPL554-CO-203 
 
Document:U:\My documents\ad hoc\Mark\Final SAP\Verona RPL554-CO-203 SAP v1.0.docx 
Author: Eleonora Chiossi 
 
 
 
 
 
 
 
 
 
 
 
         
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Version Date: 5th March 2018 
 
9.4. 
Appendix 4: SAS code for efficacy analysis 
 
proc mixed data=efficacy; 
class subject trt country visit; 
model outcome= trt visit trt*visit b_fev /ddfm=kr; 
repeated visit/ sub=subject type=un; 
lsmeans trt*visit/ cl diff; 
 
run; 
where outcome is the change from baseline 
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