Improving Inhaler Treatment and Small Airways Assessment in Chronic Obstructive Pulmonary Disease (COPD)
Phase: PHASE4
Conditions: CHRONIC OBSTRUCTIVE PULMONARY DISEASE, ASTHMA, HEALTHY SUBJECTS
Sponsor: Imperial College London

 
Short title: Drug Lung Deposition in COPD 
Protocol Version: 1.0; Date 20/10/2011;  
Sponsor Ref: NIHRCDF 
 
 
 
Page 1 of 14 
NRES REC Ethics Number: 12/LO/0004 
Eudra CT:           2011-005544-10                      
 
1
Clinical Study Protocol 
 
NCT01721291 
Full Project Title: 
Improving Inhaler Treatment and Small Airways Assessment in Chronic Obstructive 
Pulmonary Disease 
Chief Investigator (Investigator accepting clinical responsibility): 
Dr Omar S Usmani, MBBS PhD FHEA FRCP 
Airway Disease Section,  
c/o Asthma Lab 
NHLI,  
Imperial College London,  
Dovehouse Street,  
London SW3 6LY, UK;  
Tel: +44 (0)20 7351 8051/8929,  
Fax: +44 (0)20 7351 8937 
 e-mail: o.usmani@imperial.ac.uk   
 
Study Team Investigators: 
 
Ms Sally Meah (Senior Clinical Research Nurse) 
 
 
Informed consent / Undertake experiments / Data collection 
Dr Martyn Biddiscombe  
 
 
 
 
Undertake experiments / Data collection 
Dr James Hull (Clinical Research Fellow) 
 
 
Informed consent 
 
All contactable at the above address of PI (see 1(a)). 
 
 
 
 
 
 

 
Short title: Drug Lung Deposition in COPD 
Protocol Version: 1.0; Date 20/10/2011;  
Sponsor Ref: NIHRCDF 
 
 
 
Page 2 of 14 
NRES REC Ethics Number: 12/LO/0004 
Eudra CT:           2011-005544-10                      
 
2
 
 
1. Background/Rationale for this Study 
Chronic obstructive pulmonary disease (COPD) is a global epidemic affecting ~10% of 
people aged >40years and currently the 5th commonest cause of death worldwide 
[1]. COPD is characteristed by chronic inflammation, but as there are no effective 
anti-inflammatory 
treatments, 
management 
focusses 
on 
using 
inhaled 
bronchodilators for symptomatic control, and short-acting β2-agonists are the drug-
class most commonly used [2,3]. Inhaled medications form the cornerstone in the 
management of COPD patients. Approximately 38 million inhalers are dispensed in 
the UK/year [4]. However, current inhalers used in everyday clinical practice are 
inefficient, where at best, only 20% of the drug reaches the lungs [5]. Inhalers 
overcome their inefficiency and achieve clinical relief by using larger than needed 
drug doses given at the mouth, but importantly the greatly wasted part of the drug 
dose can give rise to adverse side-effects. Such inefficiency would not be accepted in 
other industries; e.g. washing machines that were inefficient and required 80% more 
powder, or inefficient car engines that required more fuel.  
 
The small airways and lung parenchyma are the main sites of disease and airflow 
limitation in COPD [6]. This means the current inhalers in use, that were developed 
to treat asthma predominantly a large airway disease, may not be optimal in treating 
COPD patients. Poor delivery of inhaled bronchodilators to the peripheral airways 
may be a major factor limiting the clinical benefit provided by existing devices.The 
key to successful treatment could be to accurately target drug to the diseased sites.  
 
However, very little is known about the fate of inhaled drug within the lungs of COPD 
patients. Importantly, there are no data on the regional lung deposition of inhaled 
bronchodilator and its relationship to clinical benefit or pulmonary function in COPD, 
mainly because there are inadequate functional parameters to sensitively assess the 
diseased small airways. The Pharmaceutical industry is currently advocating inhaled 
therapy to small airways in COPD with devices that; deliver drug slowly (tiotropium-
Respimat™) [12]; have drug formulations of small particle size (BDP/formoterol-
Fostair™) [13]; or deliver expensive drug in niche areas (e.g. inhaled α1-anti-trypsin 
for emphysema) [32]. There is a real need to actually determine whether targeting 
the regional small airways in COPD patients is indeed important, and what the 
physiological significance and clinical benefit is of small versus large airway targeting.  
 
This research will use different inhaled β2-agonist particle sizes (small, intermediate, 
large) to target drug to different regional anatomical lung region in order to 
determine the ideal site of inhaled drug deposition in COPD patients and, using 
sensitive specialised physiology tests and pharmacokinetic methods, determine 
whether small versus large airways is of clinical benefit to patients. 
 
2. Principal Research Hypothesis / Questions 

 
Short title: Drug Lung Deposition in COPD 
Protocol Version: 1.0; Date 20/10/2011;  
Sponsor Ref: NIHRCDF 
 
 
 
Page 3 of 14 
NRES REC Ethics Number: 12/LO/0004 
Eudra CT:           2011-005544-10                      
 
3
The purpose of the study is whether by improving the efficiency in the lung 
deposition of inhaled bronchodilator drug (by varying the drug aerosol particle size), 
we can improve the physiological breathing responses of patents with COPD. 
 
Q1. What is the lung deposition behaviour of inhaled bronchodilator aerosols of 
different particle size within the airways of patients with chronic obstructive 
pulmonary disease (COPD)? How does this distribution compare to that observed in 
healthy subjects with no lung disease?  
 
Q2. What is the effect of different patient inhalation flows on the lung deposition of 
different sized bronchodilator particles? Is there a specific particle size and 
inhalation flow to achieve optimal lung deposition in COPD patients? 
 
Q3. Does the regional deposition and distribution of inhaled bronchodilator aerosols 
influence the clinical (physiological pharmacodynamic) and systemic (urinary 
pharmacokinetic) responses in COPD patients? 
 
3. Study Design  
This protocol has two studies: Lung DEPOSITION study (in COPD patients and Healthy 
subjects) and Lung PHYSIOLOGY study (in COPD patients and Asthmatics). 
 
Each study (Lung DEPOSITION and Lung PHYSIOLOGY) will be a randomised, double-
blind, cross-over study (6 monodisperse ‘fine-mist’ aerosol treatments, controlled 
against one polydisperse ‘coarse-mist’ pressurised metered dose inhaler (pMDI) 
visit). Treatments will be given as one-off dose-administration. There will be an 
interval of at least 5 days between each study visit.  
 
The Lung DEPOSITION study will involve radiolabelled drug treatments 
(monodisperse aerosols only = 6 visits). All the treatments in the LUNG PHYSIOLOGY 
study will be non-radiolabelled. 
 
4. Study Outcomes 
Primary outcome:  
Lung DEPOSITION study: The primary endpoint for aerosol deposition is penetration index 
(PI) calculated from planar-images, which will indicate differences in regional lung 
deposition as a function of particle size. 
Lung PHYSIOLOGY study: The primary endpoints are multi-breath nitrgen washout 
(MBNW) indices of acinar airways (Sacin) and conducting airways (Scond), which will 
indicate differences in small (and large) airway physiology as a function of particle size. 
Secondary outcomes: 
The secondary outcome measures for both studies are: analysis of the lung physiology 
(MBNW, Impulse oscillometry (IOS), spirometry, body plethysmography) and urine 
pharmacokinetics (urine 0-30minutes, 0-24 hours, 30mins -24 hours)  
 

 
Short title: Drug Lung Deposition in COPD 
Protocol Version: 1.0; Date 20/10/2011;  
Sponsor Ref: NIHRCDF 
 
 
 
Page 4 of 14 
NRES REC Ethics Number: 12/LO/0004 
Eudra CT:           2011-005544-10                      
 
4
5. Study Centre / Number of Patients / Recruitment 
The single-centre study will be carried out at the Asthma Lab, Royal Brompton Hospital 
and National Heart and Lung Institute, London, UK. Patients will be recruited from: 
Asthma Lab NHLI, Respiratory outpatients of the Royal Brompton and Harefield NHS 
Foundation Trust, St Mary’s Hospital part of Imperial College NHS Trust, Local GP Practices 
and from our current patient Asthma Lab database from local GP Practices.   
The study will recruit; 
Lung DEPOSITION study: 12 mild-moderate COPD patients, 12 healthy subjects 
Lung PHYSIOLOGY study: 26 mild-moderate COPD patients, 13 mild-moderate asthmatic 
patients 
 
6. Inclusion criteria  
 
COPD patients, either male or female, over the age of 40 with a clincal diagnosis of COPD 
with airflow obstruction (FEV1/FVC<0.7) and post-bronchodilator FEV1>50% 
predicted, gas trapping (on lung volume testing), and decreased carbon monoxide 
transfer factor.  
 
Healthy subjects will be non-smokers (or ex-smokers stopped 5 years ago), will have no 
respiratory disease, normal spirometry and be age-matched to the COPD patients.  
 
Asthmatic subjects, either male or female, over the age of 18 with a clincal diagnosis of 
Asthma with airflow obstruction (FEV1/FVC<0.7). 
 
Capable of giving informed consent. 
 
(ii) Exclusion Criteria 
As a result of the medical interview, physical examination or screening investigations, 
the Physician Responsible considers the volunteer unfit for the study. 
 
Oral corticosteroids taken within last month, as this can affect the breathing response 
and signifies that their condition needs to be controlled better. 
 
Current involvement (or involvement in the last 4 weeks) in clinical trials assessing 
investigational medicinal products. 
 
Previous adverse reaction to short or long acting β2 agonist. 
 
Any subject with a contraindication to taking inhaled beta-2 adrenoceptor agonists 
(especially Salbutamol) as listed in the British National Formulary will not be entered 
into this study. 
 

 
Short title: Drug Lung Deposition in COPD 
Protocol Version: 1.0; Date 20/10/2011;  
Sponsor Ref: NIHRCDF 
 
 
 
Page 5 of 14 
NRES REC Ethics Number: 12/LO/0004 
Eudra CT:           2011-005544-10                      
 
5
Those who have experienced an acute respiratory exacerbation requiring 
emergency room treatment and/ or hospitalisation within last four weeks as this 
signifies that their condition needs to be controlled better. 
 
Pregnant or breast-feeding women. 
 
Subjects unable to give Informed Consent. 
 
7. Study Plan and Treatments (see also ‘FLOWCHART’) 
All patients will receive all study treatments in each study. All treatments will be via the 
inhaled route of administration in each study. Treatments (all ‘one-off’ dosing) will only be 
taken while the patient is at the investigator site and there will be no treatments to take 
home with them.  
 
Patients will randomly receive the following treatments (see also page 1 FLOWCHART 
document); 
A) Lung DEPOSITION study  
1. Salbutamol 1.5 micron-sized radiolabelled (*) aerosol particles at 30 micrograms 
single dose delivered via the spinning-top aerosol generator (STAG), inhaled at 
SLOW (20-40 L/min) inhalation by patient. 
2. Salbutamol 3.0 micron-sized radiolabelled (*) aerosol particles at 30 micrograms 
single dose delivered via the STAG, inhaled at SLOW (20-40 L/min) inhalation by 
patient. 
3. Salbutamol 6.0 micron-sized radiolabelled (*) aerosol particles at 30 micrograms 
single dose delivered via the STAG, inhaled at SLOW (20-40 L/min) inhalation by 
patient. 
4. Salbutamol 1.5 micron-sized radiolabelled (*) aerosol particles at 30 micrograms 
single dose delivered via the STAG, inhaled at FAST (>60 L/min) inhalation by 
patient. 
5. Salbutamol 3.0 micron-sized radiolabelled (*) aerosol particles at 30 micrograms 
single dose delivered via the STAG, inhaled at FAST (>60 L/min) inhalation by 
patient. 
6. Salbutamol 6.0 micron-sized radiolabelled (*) aerosol particles at 30 micrograms 
single dose delivered via the STAG, inhaled at FAST (>60 L/min) inhalation by 
patient. 
7. Salbutamol non-radiolabelled aerosol particles at 200 micrograms single dose 
delivered via a pMDI the STAG, inhaled at SLOW (20-40 L/min) inhalation by 
patient. 
A) During the LUNG DEPOSITION study, participants will receive 6 treatments of 'fine-mist' 
monodisperse salbutamol of 1.5, 3.0 and 6µm micron sized  aerosols radiolabelled with 
99MTechnetium that will each be inhaled at a SLOW and a FAST inhalation flow by the 
patient (each treatment 30 microgram dose). Participants will also receive non-
radiolabelled 'coarse-mist' inhaler of salbutamol from a pMDI (200 micrograms 
dose).'Fine-mist' monodisperse salbutamol aerosols will be generated using a spinning-

 
Short title: Drug Lung Deposition in COPD 
Protocol Version: 1.0; Date 20/10/2011;  
Sponsor Ref: NIHRCDF 
 
 
 
Page 6 of 14 
NRES REC Ethics Number: 12/LO/0004 
Eudra CT:           2011-005544-10                      
 
6
top disc aerosol generator (STAG) as previously described by Usmani et al (AJRCCM 
2005). The operator will be blinded to the particle size being administered.  
 
Following inhalation, participants will be seated in front of a gamma camera and inhaled 
particle distribution will be assessed with planar imaging. Scintigraphic images of the 
posterior thorax, anterior thorax, and lateral oropharynx will be recorded, in sequence, 
with the patient repositioned between views. This will be completed within 5 minutes 
following the aerosol inhalation. Subjects will undergo a krypton-81m ventilation 
transmission scan to define their lung boundary. 
 
Participants will then undergo non-invasive measures of pulmonary function and 
pharyngeal function including; spirometry, impulse oscillometry, and multi-breath 
nitrogen washout test (at 30, 60 and 120 minutes post inhalation); body plethysmography 
(at 60 and 120 minutes); and pharyngometry (at 30 and 120 minutes).  
Participants will be asked to void their urine 30 minutes post inhalation, which we will 
collect a sample of. Participants will also be asked to collect their urine over the next 24 
hours. If there are unable to attend to hand-in their 24-hour urine sample the following 
day, our research staff will collect this 24-hour-urine sample from their house/workplace 
the next day. Urine collected will be frozen prior to analysis. 
 
B) Lung PHYSIOLOGY study  
1. Salbutamol 1.5 micron-sized non-radiolabelled aerosol particles at 15 micrograms 
single dose delivered via the spinning-top aerosol generator (STAG), inhaled at 
SLOW (20-40 L/min) inhalation by patient. 
2. Salbutamol 1.5 micron-sized non-radiolabelled aerosol particles at 30 micrograms 
single dose delivered via the STAG, inhaled at SLOW (20-40 L/min) inhalation by 
patient. 
3. Salbutamol 3.0 micron-sized non-radiolabelled aerosol particles at 15 micrograms 
single dose delivered via the spinning-top aerosol generator (STAG), inhaled at 
SLOW (20-40 L/min) inhalation by patient. 
4. Salbutamol 3.0 micron-sized non-radiolabelled aerosol particles at 30 micrograms 
single dose delivered via the STAG, inhaled at SLOW (20-40 L/min) inhalation by 
patient. 
5. Salbutamol 6.0 micron-sized non-radiolabelled aerosol particles at 15 micrograms 
single dose delivered via the spinning-top aerosol generator (STAG), inhaled at 
SLOW (20-40 L/min) inhalation by patient. 
6. Salbutamol 6.0 micron-sized non-radiolabelled aerosol particles at 30 micrograms 
single dose delivered via the STAG, inhaled at SLOW (20-40 L/min) inhalation by 
patient. 
7. Salbutamol non-radiolabelled aerosol particles at 200 microgram single dose 
delivered via a pMDI the STAG, inhaled at SLOW (20-40 L/min) inhalation by 
patient. 
 

 
Short title: Drug Lung Deposition in COPD 
Protocol Version: 1.0; Date 20/10/2011;  
Sponsor Ref: NIHRCDF 
 
 
 
Page 7 of 14 
NRES REC Ethics Number: 12/LO/0004 
Eudra CT:           2011-005544-10                      
 
7
During the LUNG PHYSIOLOGY study (all treatments non-radiolabelled), participants 
will receive 6 treatments of 'fine-mist' monodisperse salbutamol of 1.5, 3.0 and 6µm 
micron sized  aerosols each at a dose of 15 micrograms and 30 micrograms. Participants 
will also receive non-radiolabelled 'coarse-mist' inhaler of salbutamol from a pMDI (200 
micrograms dose).'Fine-mist' monodisperse salbutamol aerosols will be generated using a 
spinning-top disc aerosol generator (STAG) as previously described by Usmani et al 
(AJRCCM 2005). The operator will be blinded to the particle size being administered.  
 
Following inhalation, participants will  undergo non-invasive measures of pulmonary 
function and pharyngeal function including; spirometery, impulse oscillometry, and multi-
breath nitrogen washout test (at 30, 60 and 120 minutes post inhalation); body 
plethysmography (at 60 and 120 minutes); and pharyngometry (at 30 and 120 minutes).  
 
Participants will be asked to void their urine 30 minutes post inhalation, which we will 
collect a sample of. Participants will also be asked to collect their urine over the next 24 
hours. If there are unable to attend to hand-in their 24-hour urine sample the following 
day, our research staff will collect this 24-hour-urine sample from their house/workplace 
the next day. Urine collected will be frozen prior to analysis. 
 
8. Study Procedures (see also ‘FLOWCHART’) 
Lung volume tests: 
Spirometry/Reversibility is a type of lung function test that involves breathing into a 
mouthpiece. It measures the amount of air that can be exhaled in one second as well 
as the total volumeof air in th elungs. The results provide information on lung 
volumes and on their function. This test takes ~2 minutes. Reversibility is a test that 
measures how easily the air tubes open up when they are given a reliever inhaler 
(bronchodilator) such as Salbutamol. 
 
‘Body Box’ (Plethysmography) is a type of lung function test. Subjects will be asked to 
sit in a see-through plastic, airtight box (the size of a large ‘lift’ or ‘elevator’), where 
they will breathe gently and normally. The movement of their chest will be detected 
by the machine which will calculate the volumes of their lungs and pressures 
(‘resistance’) of the airway tubes. This test takes ~5 to 10 minutes. 
 
Acoustic Pharyngometry. This test uses sound waves (similar to a ship’s 
ultrasonic−sonar) to measure the dimensions of the throat. The test takes 1 minute. 
 
Small airways tests:  
Impulse Oscillometry (IOS) measurements. Subjects will be asked to breathe gently 
and comfortably through a mouthpiece while wearing nose clips. The mouthpiece is 
connected to a loudspeaker which generates sound and pressure waves (a bit like a 
ship or submarine’s sonar waves), which go into the lungs and are reflected back up 
to the mouth. A computer calculates the pressures (‘resistance’) in the air tubes. This 
test takes ~2 minutes. 
 

 
Short title: Drug Lung Deposition in COPD 
Protocol Version: 1.0; Date 20/10/2011;  
Sponsor Ref: NIHRCDF 
 
 
 
Page 8 of 14 
NRES REC Ethics Number: 12/LO/0004 
Eudra CT:           2011-005544-10                      
 
8
Multiple Breath Nitrogen Washout (MBNW). Subjects will breathe gently and 
comfortably through a mouthpiece, which is connected to a blowing machine which 
measures nitrogen. From the gas breathed out, we can estimate how narrow the 
small airways and large air tubes are. This test takes ~10 minutes 
 
Lung imaging: (in the LUNG DEPOSITION study only) 
Inhalation of Krypton Gas. We will subjects to inhale a few breaths of Krypton gas. 
This takes 2 minutes at most and there is no taste or unpleasant feeling.  
Planar Gamma Camera Imaging. We will subjects to be seated upright on a chair in 
front of the gamma-camera for 5 minutes after inhaling the treatment, during which 
time an image of their lungs will be taken 
 
Urine tests: 
We will ask subjects to provide a sample of their urine at 30 minutes after inhaling 
the treatment, to assess how much of the inhaled treatment has deposited in the 
lungs and then reached the rest of the body. After finishing this Study Visit and 
leaving the Department, we will ask subjects to collect their urine into a container 
for the next 24 hours. (We will provide subjects with a suitable collection vessel for 
their urine samples and a larger storage vessel into which they will be able to 
transfer all their urine samples). If subjects are unable to attend to hand-in their 24-
hour urine sample the following day, our research staff will collect this 24-hour-urine 
sample from their house/workplace the next day. 
 
9. Screening and Study Visits 
Screening visit:  
• Informed Consent of every subject will be obtained by one of the Study Team 
Investigators [see section 1(b)] before any study procedures are done 
• The subject’s medical and smoking history, current medications will be 
documented in the hospital notes and case report form  
• Spirometry will be performed at screening to determine eligibility for the study 
and all inclusion (section 6(i)) and exclusion criteria (section 6(ii)) assessed. 
• For eligible subjects, if patients are currently prescribed Salbutamol as their 
‘rescue’ inhaler, then this will be changed to an identical drug called 
Terbutaline, until they complete this research study. This will enable subjects 
to continue using their ‘rescue’ medication as they need it, because our urine 
measurements cannot separate Salbutamol delivered by their own regular 
blue ‘rescue’ puffer, from the Salbutamol we will deliver by our special ‘fine-
mist’ nebuliser in the study. 
Study Visits: 
We will ask patients to abstain from alcohol one day before the Study Visits and for 
24 hours after receiving the study treatment. In the 6 hours before each Study Visit, 
we will also ask patients not to use either their Terbutaline, Salmeterol (also known 
as a Serevent® or Seretide®), Eformoterol (also known as Oxis® or Symbicort®), 
Ipratropium (also known as Atrovent®) or Tiotropium (also known as Spiriva®) (if they 

 
Short title: Drug Lung Deposition in COPD 
Protocol Version: 1.0; Date 20/10/2011;  
Sponsor Ref: NIHRCDF 
 
 
 
Page 9 of 14 
NRES REC Ethics Number: 12/LO/0004 
Eudra CT:           2011-005544-10                      
 
9
are prescribed these), unless patients feel they need them. There will be no change 
or addition to patients’ treatment throughout this study by us. 
There will be a minimum of a 5 day washout period between study periods. 
At the Asthma Lab, subjects will be asked about any adverse effects they may have 
experienced. If so, the necessary action (see Section 10 below) will be undertaken). 
Spirometry will also be done and patients will be required to be within +/-15% of baseline 
Screening values before commencing study medication, to ensure lung variability is 
minimised. 
 
10. Medication/IMP 
Supply of drugs  
The study drugs will be supplied by Royal Free Hospital (RFH), London UK to the Pharmacy 
of the Royal Brompton Hospital where they will be stored and dispensed.  
RFH Pharmacy will assign labels to all study medication in accordance to the protocol and 
ICH GCP. The labels on the packages and unit medication will specify all necessary 
information for a correct identification of the medication boxes and individual medication 
units. 
All study medication accountability will be performed at the Royal Brompton Hospital by 
members of the study team and returned /unused medication will be destroyed by the 
Royal Brompton Hospital Pharmacy at study closure. 
An independent scientific investigator will create a computer generated randomisation 
lists for the study in accordance with the protocol. Code break envelopes will be provided 
with copies of the randomisation code, which will be stored in the RBH Pharmacy.  
 
11. Sample Size and Statistical Analysis 
Determination of sample size 
Aerosol deposition. Based on penetration index (PI) data from my previous particle-size 
deposition study [27],  n=12 subjects will have 97% power (1-β) to detect a clinically 
relevant difference in means of 0.19 for PI, assuming a standard deviation of differences 
of 0.15, using a paired t-test with a 0.05 two-sided significance level (α). We do not have 
previous within patient repeatability data for PI for each individual particle size, as it is 
unethical to expose patients to more radioactivity than is needed. However, our data 
were highly significant (p <0.001) in differences of PI between the three particle sizes (1.5-
, 3-, 6-µm) that correlated with clinically significant differences in bronchodilator 
responses, and we have used the within subject SD data for PI (collectively of all 3 
particles given to each patient), in the sample size calculation.  
 
Small airway physiology. Based on Sacin and Scond data [Verbanck 1999], where MBNW 
responses in COPD and asthma were measured before and after pMDI salbutamol 
(corresponding to ΔFEV1 19% - a clinically important difference), we calculate n=14 
subjects will have 90% power (1-β) to detect a clinically relevant difference in means of 
0.027 for Scond, assuming a standard deviation of differences of 0.022, using a paired t-
test with a 0.05 two-sided significance level (α). Allowing for inherent biological variability 
for repeated measures over time, the reported intraclass correlation of Scond and Sacin is 

 
Short title: Drug Lung Deposition in COPD 
Protocol Version: 1.0; Date 20/10/2011;  
Sponsor Ref: NIHRCDF 
 
 
 
Page 10 of 14 
NRES REC Ethics Number: 12/LO/0004 
Eudra CT:           2011-005544-10                      
 
10
0.84, 0.95 respectively [Verbanck 1999], and so the sample-size required for 
airway physiology analysis in COPD patients is n=26 (Stata-10, Statacorp, Texas, USA).   
 
Statistical methods 
Longitudinal analysis of paired-data will be performed within and between different 
groups. Data from the primary and secondary endpoints will be use to test the null 
hypothesis using two-way parametric analysis of covariance (ANCoVA), with factors 
for subject, treatment period and order. Modified paired t-tests will be undertaken 
using the Bonferroni method to adjust for P values and multiple comparisons 
between the three particle sizes. Lung deposition comparisons will be made to 
assess particle size deposition effects within diseased COPD patients, within healthy 
subjects (HS) and between disease (COPD) and health (HS). Comparisons will be 
made to determine the effects of inhalation flow on regional lung deposition of the 
three particle sizes in COPD and HS. Small airways physiology comparisons will be 
made between monodisperse aerosols of different particle size in COPD patients and 
between monodisperse and polydisperse-MDI aerosols. 
 
12. Adverse Events  
An adverse event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product. An 
undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., 
tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory 
findings). 
 
In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including run-in or wash-out periods, even if no study treatment has been 
administered. 
 
A serious adverse event (SAE) is an AE occurring during any study period (i.e., run-in, 
treatment, wash-out, follow-up), and at any dose of the investigational product, 
comparator or placebo, that fulfils one or more of the following criteria: 
• results in death 
• is immediately life-threatening 
• requires in-patient hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability or incapacity 
• is a congenital anomaly or birth defect 
• is an important medical event that may jeopardise the patient or may require 
medical intervention to prevent one of the outcomes listed above 
 
A distinction should be drawn between serious and severe events. A severe event is a 
major event of its type. The term “severe” is used to indicate the intensity of a specific 
event, while the term “serious” is based on patient/event outcome or action criteria. 

 
Short title: Drug Lung Deposition in COPD 
Protocol Version: 1.0; Date 20/10/2011;  
Sponsor Ref: NIHRCDF 
 
 
 
Page 11 of 14 
NRES REC Ethics Number: 12/LO/0004 
Eudra CT:           2011-005544-10                      
 
11
 
A suspected unexpected serious adverse reaction (SUSAR) is any adverse event with a 
reasonable possibility of a link to the study drug that is both serious and unexpected (i.e. 
not consistent with the information about the study drug in either the SPC or IB). 
 
Procedures for Serious Adverse Event Reporting 
The Chairman of the Ethics Committee, Imperial College Clinical Joint Research Office 
(JRO) and the Sponsoring Consultant will be immediately informed about all serious 
untoward events. 
 
It will be the responsibility of the Principal Investigator and Study Team Investigators to 
report all adverse events (both serious and non-serious). 
 
Depending on the nature of the event, the reporting procedures will be as follows: 
 
▪ All Adverse Events occurring during the clinical investigation will be recorded and 
documented in the relevant section of the Case Report Form (CRF) 
 
▪ Serious Adverse Events will be documented immediately on a standard narrative 
form and will be reported as soon as possible to the Chairman of the Ethics Committee 
and to Senior Administrator. 
 
Expedite Reporting will be performed by the Principal Investigator in case of any 
suspected, unexpected, serious adverse reaction (SUSAR) or in case of other safety issues 
that qualify for expedite reporting, in accordance with the European Directive 
2001/20/EC. 
 
The expedite reporting to the Competent Authority and Ethics Committee will be 
performed as follows: 
- 
fatal or life-threatening SUSAR, will be reported as soon as possible but no later than 7 
calendar days after first knowledge of the minimum criteria for expediting reporting. 
Relevant follow-up information will be completed as soon as possible and sent within 
an additional 8 calendar days. 
- 
non fatal or life-threatening SUSAR, will be reported as soon as possible but no later 
than 15 calendar days after first knowledge of the minimum criteria for expediting 
reporting. 
 
Copy of SAE/SUSAR reporting will be notified by the Principal Investigator to Imperial 
College Clinical Research Office within the same timeframe. 
13. Indemnity 
Indemnity will be provided by Imperial College Indemnity Scheme which has been 
arranged through the Joint Research Office (JRO) at Imperial College. Imperial 
College’s Miller 'no fault' clinical trials policy: number PIMP00511. Public Liability 
cover is also provided for Imperial College under this policy reference number. 

 
Short title: Drug Lung Deposition in COPD 
Protocol Version: 1.0; Date 20/10/2011;  
Sponsor Ref: NIHRCDF 
 
 
 
Page 12 of 14 
NRES REC Ethics Number: 12/LO/0004 
Eudra CT:           2011-005544-10                      
 
12
14. Data Handling & Record Keeping 
Hard copies of participant's trial research files will kept under lock and key in the 
Asthma Laboratory, Royal Brompton Hospital. Access to these will be limited to the 
Respiratory Physician conducting the study (Dr Omar Usmani), Study Team 
Investigators and the Clinical Research Nurse (Ms Sally Meah). All files will have non 
identifiable information, that is, each participant will only be identified by a study 
code and the study codes for each participant will be kept in a separate locked 
cabinet. The Investigators will permit trial-related monitoring, audits, IRB/IEC 
reviews and internal and external regulatory inspection with provision and direct 
access to source documents and data.  
The following has been included in the Consent Form to patients; 
 “By agreeing to take part in this research study you will be allowing certain persons 
to see the information about you. Your information will be looked at to confirm that 
it is correct and that it is related to you and that the study is being carried out 
correctly. This will be done by selected people working for Imperial College and 
organisations acting on behalf of Imperial College London, such as the local ethics 
committee, and the government regulatory authorities. These persons are required 
to maintain the confidentiality of your information. This is to meet legal or regulatory 
requirements for the study and to ensure that we are carrying out this research 
study to recommended guidelines on good research practice. It is intended that the 
collective results and data from the research will be publicly available in an 
anonymous form in peer reviewed scientific journals and conference presentation. 
Maintaining your confidentiality is important to us. Your personal information (for 
example, your gender, age, and the details of your medical conditions) and other 
information (the data collected as part of the study) will be identified by letters and 
numbers (that is, coded). Imperial College London will keep the information and the 
results collected about you in this study in a secure place. Your information will be 
processed electronically (that is, by a computer) or manually and analysed to 
determine the outcome of this study. Imperial College London may use your 
information for other medical/health care purposes related to this study. For this 
purpose only coded information will be used. These data may be used for: 
 
▪ Administration purposes  
 
▪ Research and development of pharmaceutical products  
 
▪ Diagnostics and medical aids  
 
▪ Statistical analysis  
You have the right to ask the study Doctor about the data being collected on you for 
the study and about the purpose of this data. You have the right to ask the study 
Doctor to allow you to see your personal information and to have any needed 
corrections to it made.  
It is intended that the results of this study will be published in a Medical journal and 
may be presented at Medical conferences in the UK and abroad, but your identity 
will not be revealed, nor will your name appear in any publications, reports or slides, 
produced from the results of this research study. Should you request any 

 
Short title: Drug Lung Deposition in COPD 
Protocol Version: 1.0; Date 20/10/2011;  
Sponsor Ref: NIHRCDF 
 
 
 
Page 13 of 14 
NRES REC Ethics Number: 12/LO/0004 
Eudra CT:           2011-005544-10                      
 
13
information on the publication of this study, the study Doctor will be able to tell 
you where the results are published, when the study is finished. “  
 
It will be the responsibility of the Chief Investigator and Consultant Respiratory 
Physician conducting the study − Dr Omar Usmani, to ensure the well−being of all 
participants and that they are able to contact him for any queries regarding the 
study. Dr Usmani & Ms Sally Meah will also be responsible for the daily management 
and monitoring of the research data and management of the staff involved with the 
research. Dr Usmani & Ms Sally Meah will liaise with the clinical research governance 
office at Imperial College with respect to auditing the research study. Overall 
responsibility for the study lies with the Chief Investigator, Dr Omar Usmani, Clinical 
Senior Lecturer and Honorary Consultant in Respiratory Medicine, National Heart 
and Lung Institute, Imperial College. The project will be registered with the Clinical 
Research Office of Imperial College London and has been registered with 
ClinicalTrials.gov  
15. Publication  
It is hoped that the results and data from the research will be available publicly in 
peer-reviewed publications. Although no specific publications will be produced for 
the research participants, should a participant request feedback on the outcome of 
research towards which they have contributed, this will be provided to them. 
Information about publication arrangements will be included in the participant 
information sheet, as well as a statement regarding information on individual 
requests for feedback on the study results.  
16. Ethics and Amendments to the Protocol 
Ethics review 
The final protocol and the final version of the written informed consent form must be 
approved or given a favorable opinion in writing by an independent ethics committee 
(IEC). The principal investigator(s) is responsible for informing the IEC of any amendment 
to the protocol in accordance with local requirements. The principal investigator(s) must 
also provide the IEC with reports of serious adverse events from the study site as per local 
requirement. 
 
Patient information and consent 
The Principal Investigator(s) will ensure that the patients are given full and adequate oral 
and written information about the nature, purpose, possible risk and benefit of the study. 
Patients must also be notified that they are free to discontinue from the study at any 
time. The patients should be given the opportunity to ask questions and allowed time to 
consider the information provided. The patient’s signed and dated informed consent must 
be obtained before conducting any procedure specifically for the study. 
 
All patients will be requested to provide their informed consent prior to any study-related 
procedures. If the patient is unable to provide written consent immediately, oral consent 
should be witnessed in writing by a patient representative (i.e. legal guardian, 

 
Short title: Drug Lung Deposition in COPD 
Protocol Version: 1.0; Date 20/10/2011;  
Sponsor Ref: NIHRCDF 
 
 
 
Page 14 of 14 
NRES REC Ethics Number: 12/LO/0004 
Eudra CT:           2011-005544-10                      
 
14
accompanying person or hospital staff not directly involved in this study). In this 
case, the patient should sign the written consent as soon as possible, at the latest before 
the end of the study. 
 
The principle investigator(s) must store the original, signed written informed 
consent form and a copy must be given to the patient.