Targeting of the Small Airways in Patients With COPD: Airway Effects of Tiotropium - Respimat vs Handihaler
Phase: PHASE3
Conditions: COPD, LUNG DISEASES, OBSTRUCTIVE
Sponsor: Imperial College London

 
 
 
 
 
 
 
 
 
 
 
 
Study Protocol Version 6 (01/09/16) 
TARGETING OF THE SMALL AIRWAYS IN PATIENTS WITH COPD: AIRWAY EFFECTS OF 
TIOTROPIUM – Respimat vs. Handihaler  
 
NCT02683668 
 
 
 
 
 
 
 

Study Protocol Version 6 (01/09/16) 
TARGETING OF THE SMALL AIRWAYS IN PATIENTS WITH COPD: AIRWAY EFFECTS OF 
TIOTROPIUM – Respimat vs. Handihaler 
 
EudraCT No: 2015-001615-13 
REC/IRAS number: 15/LO/0982 
 
OUTLINE OF PROTOCOL FOR PROPOSED TRIAL 
 
For official use: 
Date received _______________ 
Date approved _______________ 
CTA no. ___________________ 
1. ADMINISTRATIVE INFORMATION 
Name of sponsor 
Imperial College London 
Name of funder 
Boehringer Ingelheim 
Name of the investigational medicinal product 
Tiotropium bromide 
Eudract number for proposed trial 
2015-001615-13 
Title: Dr 
Forename/Initials: Omar S 
Surname: Usmani 
Post: Clinical Senior Lecturer and Honorary Consultant in 
Respiratory Medicine 
Chief Investigator responsible for conducting the 
Qualifications: MBBS, MRCP, PhD 
Organisation: Imperial College London, National Heart & Lung 
trial 
Institute and RBH 
Work Address: Guy Scadding Building (c/o Asthma Lab) 
Dovehouse Street, London SW3 6LY 
E−mail: o.usmani@imperial.ac.uk 
Telephone: 0207 351 8051 
Fax: 0207 351 8937 
Name Martyn Biddiscombe 
Telephone 0207 351 8051 
Co-Investigators: 
E-mail m.biddiscombe@imperial.ac.uk 
Name Sally Meah 
Telephone 0207 351 8051 
E-mail sally.meah@imperial.ac.uk 
2. CLINICAL USE 
Medical condition or disease under 
Inhaled Drug Delivery in COPD 
investigation 
Any other medical condition or disease 
No 
under investigation with this product 
3. DATE OF PROTOCOL 
30.03.3015 
OVERVIEW SUBMISSION 
4. TITLE OF CLINICAL TRIAL 
Targeting of the Small Airways in Patients with COPD: Airway 
Effects of Tiotropium – Respimat vs. Handihaler. 
 
 
 
 
 
 
 
 
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1 

Bronchodilator targeting throughout the whole airway tree is 
important in respiratory disease and more so in COPD where the 
disease pathology and airflow physiological limitation arises 
from the small airways. However many drugs do not reach the 
small airways. Respimat is a novel inhaler platform that has 
small particles and a slow inhalation allowing deeper lung drug 
delivery. Small particle ICS and LABA combinations have been 
5. PURPOSE OF CLINICAL TRIAL shown to improve markers of large and small airways that are 
also now being translated into meaningful improvements in 
patients with asthma and COPD [10c]. 
We aim to investigate the effect of tiotropium from different 
devices on a panel of small (IOS, MBNW, DLCO, FVC) and 
large airway (FEV1, PEF) responses in patients with mild- 
moderate COPD. We will compare Tiotropium Handihaler 18 
micrograms once daily with Tiotropium Respimat 5 micrograms 
once daily 
6. DESIGN OF CLINICALTRIAL 
Open label. Sequential 
7. PATIENT POPULATION IN 
Mild-Moderate COPD 
CLINICAL TRIAL 
8.  MAXIMUM NUMBER OF 
N= 44 
PATIENTS TO BE INCLUDED IN 
CLINICAL TRIAL 
COPD 
1) COPD patients with FEV1/FVC <70% predicted. 
2) Mild (GOLD stage I: FEV1 >80% pred.) to moderate (GOLD 
stage II: FEV1 50-80% pred.) 
3) Aged 30 years onwards – there is no upper age limit as we do 
not want to exclude elderly patients as COPD is primarily a 
9. MAIN INCLUSION CRITERIA 
disease in the elderly population. 
IN CLINICAL TRIAL 
4) Have ongoing symptoms or exercise limitation (determined 
by CAT score) 
5) Stable COPD (no chest infection requiring antibiotics and/or 
oral steroids in the past 2 months). 
6) Capable of giving informed consent, which includes 
compliance with the requirements and restrictions listed in the 
consent form. 
 
 
 
 
 
 
 
 
 
 
 
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2 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10. MAIN EXCLUSION 
CRITERIA IN CLINICAL TRIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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COPD 
 
1) We will not recruit subjects who lack the capacity to consent. 
 
2) Current or past diagnosis of asthma. 
 
3) Patients on concurrent oral bronchodilators (theophylline, 
PDE4 inhibitors) will not be included. 
 
4) Patients on other LAMAs will not be included 
 
5) History of any chronic respiratory diseases other than COPD. 
 
6) History of another medical condition, which in the opinion of 
the Unit Physician, contraindicates his/her participation in the 
study. 
 
7) Clinical evidence of heart failure (NYHA class III-IV). 
 
8) Unstable respiratory disease in the last four weeks prior to 
the screening visit (indicated by any change in their 
maintenance inhaled therapy or who have had a lower 
respiratory tract infection in the previous four weeks). 
 
9) Evidence of a respiratory exacerbation requiring emergency 
room treatment and/or hospitalisation within four weeks before 
screening. 
 
10) Use of systemic (oral or intravenous) steroids 4 weeks prior 
to inclusion (injectable depot steroids 6 weeks) or more than 3 
periods during the last 12 months. 
 
11) Participants with a known or suspected allergy, sensitivity 
or intolerance to the study drugs (this will be asked directly at 
the screening visit) or patients with a history of another drug 
allergy which, in the opinion of the Unit Physician, 
contraindicates his/her participation in the study. 
 
 
12 Patients with known or suspected cardiac rhythm disorders 
 
13) Patients treated with beta-blockers in the week preceding the 
screening visit and during the study period. 
 
14) Females who are pregnant or lactating or are likely to 
become pregnant during the trial (a urine pregnancy test will be 
performed. Women of childbearing potential may be included in 
the study if, in the opinion of the investigator, they are taking 
adequate contraceptive precautions. 
 
15) Patients who have evidence of alcohol or substance abuse. 
 
16) Participation in another clinical trial with an investigational 
drug in the four weeks preceding the screening visit. 
3

11. PROCEDURES FOR SAFETY 
Direct questioning about medical symptoms at the beginning of 
each study visit (see also ‘Safety’ section and ‘Adverse Events’ 
MONITORING DURING TRIAL 
section below). 
12. CRITERIA FOR 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
WITHDRAWAL OF PATIENTS ON The data to be collected on withdrawn subjects and their follow- 
SAFETY GROUNDS 
up is listed under the ‘Adverse Events’ section (see later). 
13. ROUTE(S) OF 
Inhalation 
ADMINISTRATION (use standard 
terms) 
14 days of handihaler tiotropium 18 micrograms once daily (14 
x 18 micrograms = 252 micrograms total dose tiotropium via 
handihaler device) 
14. MAXIMUM DOSAGE 
And 
ALLOWED (specify daily or total) 
14 days of respimat tiotropium 5 micrograms once daily (14 x 5 
micrograms = 70 micrograms total dose tiotropium via respimat 
device) 
252 + 70 micrograms = 322 maximum dose tiotropium in study 
15. MAXIMUM DURATION OF 
28 days 
TREATMENT OF A SUBJECT 
16. ACTIVE COMPARATOR 
No 
PRODUCT(S) 
17. ON-GOING TRIALS IN 
No 
OTHER EU MEMBER STATES 
18. REGULATORY SUBMISSIONS No 
ON SAFETY GROUNDS 
 
1. BACKGROUND AND RATIONALE (references at end of document) 
Small airways 
 
Patients with asthma and chronic obstructive airways disease (COPD) undergo routine testing of their 
lung function in the diagnosis, progression, management and, response to treatment of their disease [1]. 
Standard lung function obtains measurements based on the forced flow of air moving within the airways. 
Such measurements give a reasonable assessment of disease affecting the large airways, but not an 
accurate estimate of small airways disease [2]. Small airways are less than 2mm in diameter [Fig. 1]. 
However, both asthma and COPD have disease that involves not only the large but also the small airways 
that has important clinical consequences. Indeed, COPD predominantly affects the small airways [3, 3b]. 
 
Silent zone 
 
Figure 1. Small vs. large airways of the lungs. For this reason, the 
small airways of the lungs are often referred to as the ‘silent 
zone’. This is because airways disease in this zone may not be 
detected by standard clinical lung function measures, such as 
spirometry. For example, a recent study showed that small 
airway function became abnormal after only 10 pack-yrs of 
smoking, whereas spirometry became abnormal after 20 pack-
yrs [4]. Also, lung pathology such as airways inflammation & 
narrowing and lung tissue destruction may be well-established 
before patients present with symptoms. This is of particular 
concern in lung transplant recipients where lung rejection often 
 
 
 
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starts with small airways disease, which is difficult to monitor [5]. 
 
Clinical healthcare needs 
 
Better clinical assessments of small airways function and physiology are required. Clinicians need 
information in order to manage small airways disease of the lungs with clinical tests that are non-
invasive, specific and do not expose patients to repeat X-Rays (such as CT scans) or are unpleasant and 
invasive (such as bronchoscopy). Non-invasive lung imaging such as positron emission tomography (PET) 
and magnetic resonance imaging (MRI) have been used, but give poor image resolution of the small 
airways compared to larger airways [Fig. 1]. 
 
Sensitive physiological technologies: IOS and MBNW 
 
Figure 2. Patient set-up for IOS. We have set-up and validated [6, 
7] the impulse oscillometry (IOS) and multi-breath nitrogen 
washout (MBNW) techniques in our lab. These are non-invasive 
physiological instruments that give a sensitive assessment of 
small airways function. They are practical methods of 
measurement that could be used in everyday clinical practice to 
routinely measure small airway function because of ease of 
administration and potentially, production of relatively cheap 
portable devices [8]. IOS [Fig. 2] uses oscillating pressure-flow 
signals of moving air within the lungs to determine peripheral 
lung mechanical parameters [9] which include small airway 
  
resistance and an estimate of lung compliance and air-trapping [Fig. 3], whereas MBNW utilizes the 
exhalation of nitrogen gas from the airways to determine changes in lung ventilation and derive small 
airways indices [10]. Patients are seated and gently breathe for a couple of minutes through the 
machines. Importantly, IOS & MBNW can be comfortably used in children and elderly populations. 
 
 
 
 
 
COPD, untreated  Tio 
 
 
 
 
 
 
 
 
Tiotropium (- 68%) 
 
 
 
Baseline 
 
 
Figure 3. effect of tiotropim (18μg) on small airway reactance as assessed by IOS. Most recently, we have 
developed specific technique with IOS to distinguish patients with COPD from asthma [10b]. 
 
 
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Therapeutic target 
 
It is clear that the small airways are an important target in the treatment of asthma, COPD and other 
respiratory diseases [10c]. Recent clinical trials have used physiologic measures of small airways such as 
MBNW to assess the intervention of pharmacological treatments such as montelukast [11], inhaled 
tiotropium [12], inhaled corticosteroid formulated with specific ability to penetrate into the distal lung 
 
[13] and also, non–drug interventions such as smoking cessation [14], in the management of patients 
with asthma and COPD. 
 
FEV1 is the standard measurement used to measure drug effects in COPD clinical studies, however it 
does not reflect small airway resistance and may not provide information about lung compliance. IOS 
and plethysmography have been shown to have a higher sensitivity than FEV1 for assessing short acting 
bronchodilator [14b] effects in COPD, and recently these techniques have been shown to sensitively 
differentiate the effect of tiotropium over salmeterol when FEV1 measurements are similar [14c]. 
 
FEV1 is insensitive to small airway changes and to alterations of the lung mechanics. On the contrary, the 
combined use of IOS, MBNW, and plethysmography besides providing information on the “silent zone” 
may also reflect changes of lung mechanics. The use of these methods in the same patients is 
unprecedented and we are confident it will provide valuable physiological and pharmacological data. 
 
Inhaled drug delivery technologies: drug particle size 
 
Figure 4. Drug particles of 1.5µm in lungs Usmani et al AJRCCM 2005. Aerosol drug particle size is the 
most important determinant of where inhaled drug deposits within the lungs. We have developed and 
validated an aerosol particle generator system able to produce therapeutic drug aerosols, all of one 
particle size, for controlled delivery to patients [15]. We have shown that by altering inhaled drug particle 
size, we can direct inhaled drug to different airway regions in the lungs [16, Fig. 4]. Determining the 
optimal particle size of inhaled drug therapy may contribute knowledge towards the development of new 
 
inhalers and drugs that require greater selectivity for treating the small 
airways. 
 
 
Small airway function in vitro 
 
We have developed a way to study the pharmacology of small human 
airways in vitro using precision-cut lung slices and videomicroscopy 
[16b]. Using this technique we have demonstrated the pharmacological 
characterization of indacaterol, a novel once daily inhaled 2 
adrenoceptor agonist, on small airways in human and rat precision-cut 
lung slices. 
 
LAMA’S (tiotropium) in COPD and the Respimat Inhaler 
 
Monotherapy with bronchodilators (LABA or LAMA) are first line therapy in the GOLD guidelines [GOLD]. 
According to the current GOLD guidelines [GOLD, bronchodilators should be used in preference to LABA 
and ICS combinations. 
 
Tiotropium (Spiriva, Boehringer Ingelheim), a long-acting inhaled anticholinergic bronchodilator, 
improves lung function, quality of life, and exercise endurance and reduces exacerbations in patients 
with chronic obstructive pulmonary disease (COPD) [Vogelmeier, C , NEJM 2011; Bateman, Respir Med 
2010; Cooper, CB, Chest 2013; Tashkin, DP, N Engl J Med 2008] Tiotropium is approved and marketed as 
 
 
 
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a dry-powder formulation delivered by means of the HandiHaler inhalation device (at a dose of 18 μg) 
[Boehringer Ingelheim. Summary of Product Characteristics (SPC): Spiriva 18 microgram inhalation 
powder, hard capsule. eMC, 2012] and as an aqueous solution delivered by means of the Respimat 
inhaler (at a dose of 5 μg) in many countries [Summary of Product Characteristics (SPC): Spiriva Respimat 
2.5 microgram solution for inhalation. eMC, 2013]Crossover trials of tiotropium Respimat at a dose of 5 
μg and HandiHaler at a dose of 18 μg for up to 4 weeks have shown similar efficacy, safety, and 
pharmacokinetic profiles. [van Noord, JA, Respir Med 2009; Ichinose, M, Respir Med 2010]. Cross-study 
comparisons have suggested the potential superiority of tiotropium Respimat in terms of COPD 
exacerbations, as compared with HandiHaler [Bateman, Respir Med 2010; Tashkin, DP, N Engl J Med 
2008]. Recently, Tiotropium Respimat at a dose of 5 μg or 2.5 μg had a safety profile and exacerbation 
efficacy similar to those of Tiotropium HandiHaler at a dose of 18 μg in patients with COPD *Wise, NEJM 
2013]. 
 
Respimat Soft MistTM Inhaler (SMI) is a novel inhaler delivering a unique slow-moving Soft MistTM that 
allows gentle inhalation – making it easy to inhale. Importantly it has drug particles that are ~ 2microns 
[16c] that allow an increase in the total lung deposition of drug (~52%) [16d] and also the potential for 
penetration to treat the small and large airways in patients with COPD; that is targeting the whole airway 
tree. 
 
2. QUESTIONS THIS STUDY WILL ANSWER 
 
PHASE 1: Effect of Inhaler Training with Handihaler on airway function and symptoms 
If we train patients with the Handihaler properly can we 
 
• 
improve (i) lung function (large and small airway)? 
• 
improve(ii) clinical symptoms (determined by CAT score)? 
 
Mild-moderate COPD [GOLD], established (>1 month) already on HandiHaler- Tiotropium 18 mcg once 
daily but have ongoing symptoms or exercise limitation (determined by CAT score) to be eligible to enter. 
So their clinical state may be due to ‘real-life’ poor inhaler technique (which will be assessed by the 
research observer). Patients receiving Handihaler who have not been trained for over 3 months on its 
use will be recruited. 
 
We will train patients in the optimal use of the Handihaler. 
 
So if we train patients with the Handihaler properly can we improve (i) lung function (large and small 
airway) and (ii) clinical symptoms (determined by CAT score). 
 
Data comparison: Data from Visit 1 will be compared to the Screening Visit data. 
 
PHASE 2: Is the device important in treating the small airways 
 
• 
Does changing the device from a DPI-Handihaler (in a trained patient) to a SMI-Respimat give an 
added advantage to the patient? (keeping the dose of the drug equivalent from each device – that is Tio 
18mcg HH = Tio 5mcg Resp). 
 
• 
That is – is there an added advantage with the device that is observed with a change 
(improvement) in (i) lung function (large and small airway) and (ii) clinical symptoms (determined by CAT 
score). 
 
 
 
 
 
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• Do the properties of the Respimat device with deeper lung deposition (slow velocity and small 
particles) can improve small airway measures (and indeed large airway measures) that might also be 
related to an improvement in symptoms. 
 
Data comparison: Data from Visit 2 will be compared to the Visit 1 data. 
 
 
3 . RESEARCH AIM & HYPOTHESIS 
 
We aim to investigate the effect of tiotropium from different devices on a panel of small (IOS, MBNW, 
DLCO, FVC) and large airway (FEV1, PEF) responses in patients with mild-moderate COPD. We will 
compare Tiotropium Handihaler 18 micrograms once daily with Tiotropium Respimat 5 micrograms once 
daily. 
 
We will identify a COPD cohort with ongoing symptoms or exercise limitation on HandiHaler, as 
proposed. The science behind this is why are people still limited (even if partially as determined using the 
CAT score) and could it be that relatively we need more distal airway targeting (this doesn’t necessarily 
mean acinar/alveolar beyond the terminal bronchioles, but just a little bit more going deeper into the 
distal conducting airway) that can be achieved with Respimat. 
 
4. STUDY DESIGN: (also see study treatment dosing flowchart below) 
Target population: N=44 mild COPD patients. 
Open (as patients can identify inhaler device), Sequential, 3 visits (including screening visit). 
 
Patients on concurrent oral bronchodilators (theophylline, PDE4 inhibitors) will not be included. Patents 
on concurrent LABAs will be allowed. 
 
N=44 Patients: Mild-moderate COPD [GOLD], established (>1 month) already on HandiHaler- Tiotropium 
18 mcg once daily but have ongoing symptoms or exercise limitation (determined by CAT score) 
 
There will be three phases. 
 Phase 0 (Screening visit)

Patients receiving Handihaler who have not been trained (real-life use) for over 3 months on its 
use 
 Phase 1

Patients will be trained in their use of Handihaler-Tiotropium and asked to take 18 mcg once daily 
for 14 days to see if their (i) airway lung function and or (ii) clinical symptoms improve AND THEN 
 Phase 2

Patients will be switched to trained Respimat Tiotropium 5 mcg once daily for 14 days to see if 
their (i) airway lung function and or (ii) clinical symptoms improve. 
 
WHAT HAPPENS AT EACH VISIT? 
(i) Phase 0 - SCREENING VISIT: (DAY 0) 
 
• 
IDENTIFY : Mild-moderate COPD [G.O.L.D], established (>1 month) already on HandiHaler-
Tiotropium 18 mcg once daily but have ongoing symptoms or exercise limitation (determined by 
CAT score) to be eligible to enter 
 
• 
Patient to avoid short acting SABA and SAMA and LABA on day of visit 
 
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8 

 
• 9am Baseline: Lung physiology measurements undertaken in this order; IOS, 
MBNW, Spirometry (FVC) /Body plethysmography (DLCO). 
 
• Patient asked to demonstrate how they use Handihaler with a demonstration device. 
Research observer notes how patient takes Handihaler-Tiotropium to assess good or poor 
inhalation technique /errors. 
 
• Patient receives training in how to use Handihaler correctly until observer satisfied. 
 
 
 
• 
10am Patient takes Handihaler-Tiotropium 18 mcg od in Lab. Research observer notes 
how patient takes Handihaler-Tiotropium. 
 
• 
3hours post dosing: Lung physiology measurements undertaken in this order; IOS, MBNW, 
Spirometry (FVC) /Body plethysmography (DLCO). 
 
Tests: 
 
• 
Small (IOS, MBNW, DLCO, FVC) airways (these will be done on physiology machines of Dr 
Usmani) 
• 
Large (FEV1, PEF) airways (these will be done on physiology machines of Dr Usmani) 
• 
CAT 
score 
 
AIM OF THIS PHASE (0) OF STUDY: Here we want to see that if patients have ongoing symptoms 
but are on Handihaler-Tiotropium what is happening PRIOR to proper inhaler technique training – 
that is their ‘real-life’ use of the inhaler - to their lung function (large and small airways) and also 
symptoms or exercise limitation (determined by CAT score) will already be recorded as entry 
criteria 
 
 
• 
Patient will be asked to take Handihaler-Tiotropium 18 mcg od at 10am every day for 14 
days 
 
 
 
(ii) Phase 1 - VISIT 1 (Day 14) (After 14 days OF HANDIHALER TREATMENT) 
The patient attends the department. 
 
•Patient to avoid short acting SABA and SAMA and LABA on day of visit 
 
• 
9am Baseline: Lung physiology measurements undertaken in this order; IOS, MBNW, 
Spirometry (FVC) /Body plethysmography (DLCO). 
 
 
• 
Patient is trained for Respimat using Respimat demonstration device until observer 
satisfied. 
 
 
 
 
 
 
 
 
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• 
Patients switched to Respimat-Tiotropium 5 mcg od and instructed to take it at 10am every 
day. Patient takes first dose of Respimat-Tiotropium 5 mcg in the department during visit 1 at 10 
am. 
 
• 
3 hours post dosing: Measurements IOS, MBNW, Spirometry/Body plethysmography 
undertaken 3 hours post-dosing 
 
Tests: 
 
• 
Small (IOS, MBNW, DLCO, FVC) airways (these will be done on physiology machines of Dr 
Usmani) 
• 
Large (FEV1, PEF) airways (these will be done on physiology machines of Dr Usmani) 
• 
CAT 
score 
 
AIM OF THIS PHASE (1) OF STUDY: *So here we want to see what is happening AFTER proper 
inhaler technique training on large and small airways lung function and also symptoms or exercise 
limitation (determined by CAT score) 
 
 
 
 
(iii) Phase 2 - VISIT 2 (DAY 28 OF TIOTROPIUM TREATMENT) 
• 
Patient to avoid short acting SABA and SAMA and LABA on day of visit 
 
• 
On Day 28 of -Tiotropium treatment patient attends lab and performs the following tests 
at 9am: IOS, MBNW, Spirometry/Body plethysmography. 
 
• 
Measurements IOS, MBNW, Spirometry/Body plethysmography undertaken at 10 am. 
 
 
 
AIM OF THIS PHASE (2) OF STUDY: *So here we want to see what is happening AFTER this 
efficient device Respimat (trained) compared to PREVIOUS device Handihaler (trained) on large 
and small airways lung function and also symptoms or exercise limitation (determined by CAT 
score). Here we want to see if the properties of the Respimat device with deeper lung deposition 
(slow velocity and small particles) can improve small airway measures (and indeed large airway 
measures) that might also be related to an improvement in symptoms. 
 
5. PATIENT ELIGIBILITY 
Patients will be eligible for the study if they have COPD and satisfy the following criteria: 
 
Inclusion Criteria 
1) Patients with FEV1/FVC <70% predicted. 
 
2) Mild (GOLD stage I: FEV1 >80% pred.) to moderate (GOLD stage II: FEV1 50-80% pred.) 
 
3) Aged 30 years onwards – there is no upper age limit as we do not want to exclude elderly patients 
as COPD is primarily a disease in the elderly population. 
 
4) Have ongoing symptoms or exercise limitation (determined by CAT score) 
 
 
 
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5) Stable COPD (no chest infection requiring antibiotics and/or oral steroids in the past 2 months). 
 
6) Capable of giving informed consent, which includes compliance with the requirements and restrictions 
listed in the consent form. 
 
Exclusion Criteria 
 
1) We will not recruit subjects who lack the capacity to consent. 
 
2) Current or past diagnosis of asthma. 
 
3) Patients on concurrent oral bronchodilators (theophylline, PDE4 inhibitors) will not be included. 
 
4) Patients on other  LAMAs will not be included 
 
5) History of any chronic respiratory diseases other than COPD. 
 
6) History of another medical condition, which in the opinion of the Unit Physician, contraindicates 
his/her participation in the study. 
 
7) Clinical evidence of heart failure (NYHA class III-IV). 
 
8) Unstable respiratory disease in the last four weeks prior to the screening visit (indicated by any 
change in their maintenance inhaled therapy or who have had a lower respiratory tract infection in the 
previous four weeks). 
 
9) Evidence of a respiratory exacerbation requiring emergency room treatment and/or 
hospitalisation within four weeks before screening. 
 
10) Use of systemic (oral or intravenous) steroids 4 weeks prior to inclusion (injectable depot steroids 6 
weeks) or more than 3 periods during the last 12 months. 
 
11) Participants with a known or suspected allergy, sensitivity or intolerance to the study drugs (this 
will be asked directly at the screening visit) or patients with a history of another drug allergy which, in 
the opinion of the Unit Physician, contraindicates his/her participation in the study. 
 
12 Patients with known or suspected cardiac rhythm disorders 
 
 
13) Patients treated with beta-blockers in the week preceding the screening visit and during the study 
period. 
 
14) Females who are pregnant or lactating or are likely to become pregnant during the trial. Women of 
childbearing potential may be included in the study if, in the opinion of the investigator, they are taking 
adequate contraceptive precautions. 
 
15) Patients who have evidence of alcohol or substance abuse. 
 
16) Participation in another clinical trial with an investigational drug in the four weeks preceding 
the screening visit. 
 
 
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17) Contraindication to taking Tiotropium bromide 
 
6. CONCOMITANT THERAPIES 
 
Patients on other LAMAs including oral bronchodilators (theophylline, PDE4 inhibitors) are excluded from 
the trial. Patents on concurrent LABAs will be allowed. 
 
7. STUDY TESTS 
 
 Small (IOS, MBNW, DLCO, FVC) airways (these will be done on the physiology machines of Dr 
Usmani)

 Large (FEV1, PEF) airways (these will be done on the physiology machines of Dr Usmani)
 CAT score

8. DRUG DOSING 
 
The study drugs, Handihaler tiotropium 18 micrograms and Respimat tiotropium 5 micrograms and the 
placebo, for training purposes, will be supplied by Boehringer Ingelheim (Germany) to the Pharmacy of the Royal 
Brompton Hospital where it will be stored until required. Labels will be assigned to study medication and placebo 
in accordance to the protocol and ICH GCP by the Pharmacy of the Royal Brompton Hospital – as final packaged 
medication for each patient. 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. The Pharmacy of the Royal 
Brompton Hospital will dispense the study drugs to the patients. 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. 
 
 
We will give 14 days duration of treatment in order to achieve steady state dosing of Tiotropium drug. 
 
 The first dose will be given in the Hospital but subsequent doses will be taken at home.

 Dosing of the drug will be undertaken at the same time each day (ideally 9am)

 We will undertake measurements 3 hours post dosing (applies only to the dose given in the 
department). The reason we have used 3 hours is to achieve the maximal response 
pharmacologically with Tiotropium in order to elicit differences within Phase 1 of the study 
(device training ) and Phase 2 (device effects) in Study Group 1.

 We will use Handihaler tiotropium 18 micrograms daily which is licensed for use in COPD.
 We will use Respimat tiotropium 5 micrograms daily which is licensed for use in COPD.

9. DRUG SUPPLY AND MANAGEMENT 
 
- 
Drugs will be bought from the Royal Brompton Hospital Pharmacy (Where it has been delivered 
to by Boehringer Ingelheim ). 
- 
Placebos for training will be supplied by Boehringer Ingelheim. 
 
10 . SAMPLE SIZE CALCULATION: PRIMARY ENDPOINT / SECONDARY ENDPOINTS 
The primary endpoint is the Impulse oscillometry measure of IOS R5-R20. 
 
Each subject will act as their own control and assuming the treatment effect (ie the difference R5-R20 
between baseline and 14 days) to be 0.03kPa(L/s) with an SD of 0.05, then 44 subjects will be required 
to achieve the treatment effect at 1% significance and 90% power. 
 
 
 
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ANALYSIS: 
 
The secondary endpoints are small airways (MBNW, DLCO, FVC) and large airways (FEV1, PEF) airways 
physiology and also the CAT score. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11. STUDY TREATMENT DOSING FLOW-CHART 
 
 
 
 
Screening Visit /Day 0 
Visit 1 / Day 14 
Visit 2 / Day 28 
Phase 0: 
Phase 1: 14days 
Phase 2 : 14 days 
Real-life use / 
Trained 
Trained 
Untrained HandiHaler 
HandiHaler (a dry 
RESPIMAT- (a soft 
(a dry powder inhaler)- 
powder inhaler)- 
mist inhaler) 
Tiotropium 18mcg /od 
Tiotropium 18mcg /od 
Tiotropium 5mcg /od 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14 

12. INFORMED CONSENT 
 
Patients will be recruited by a member of Dr Usmani’s team at the Royal Brompton. At this point they 
will receive an information sheet and an appointment will be made for them with the research nurse to 
discuss enrolment into the study. All participants will provide written informed consent. The Informed 
Consent Form will be signed and dated by the participant before entering the study. The Investigator will 
explain the details of the study and again provide a Participant Information Sheet, ensuring that the 
participant has sufficient time to consider participating or not. The Investigator will answer any questions 
that the participant has concerning study participation. 
 
Each participant has the right to withdraw from the trial at any time. In addition, the investigator may discontinue a 
participant from the trial at any time if the investigator considers it necessary for any reason e.g. pregnancy, 
ineligibility 
 
13. TREATMENT DISCONTINUATION CRITERIA 
 
A patient that experiences any serious adverse event (SAE), intolerable adverse event (AE), or becomes 
pregnant must have treatment withdrawn. Patients who fail eligibility criteria must be withdrawn from the 
trial 
 
14. DEFINITION OF END OF TRIAL 
The last visit of the last subject 
15. SAFETY AND ETHICAL CONSIDERATIONS: 
 
Safety of Procedures & Intervention: 
 
i) Lung Function is performed in a safe environment in the RBH Respiratory BRU CRF. Some participants 
may experience transient coughing after performing a forced blowing manoeuvre into the machine, but 
this is often short lived and self-rectifying. 
 
ii) Impulse Oscillometry (IOS)is performed in a safe environment in the RBH Respiratory BRU CRF. There 
are no potential adverse effects associated with IOS. 
 
iii) Multi−Breath Washout Test (MBW) is performed in a safe environment in the RBH Respiratory BRU 
CRF. Participants may experience a slight dryness in their mouth from the breathing test which takes 
approximately 5 minutes. Water will be provided for patients and they will be seated on a comfortable 
chair. 
 
iv) Tiotropium Bromide 
 
Any patient with a contraindication to taking Tiotropium bromide, listed in the British National 
Formularly (BNF) will not be entered into this study. This will form part of the exclusion criteria. 
 
v) Foreseeable A serious adverse event (SAE) for Tiotropium as listed in BNF. 
 
Taste disturbance, stomatitis, gastro-oesophageal reflux, epistaxis, oropharyngeal candididiasis, 
intestinal obstruction (including paralytic ileus) laryngitis, insomnia, urinary-tract infection, skin infection, 
sinusitis, dental caries, gingivitis, glossaitis, skin ulcer, joint swelling, dry skin. These will not be reported 
as SAE but will be logged appropriately. 
 
 
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 
 
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15 

 
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. 
 
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 
 
An SAE form should be completed and faxed to the Trial Manager/Chief Investigator for all SAEs (or 
AESIs) within 24 hours. The Trial Manager/Chief Investigator should inform the sponsor of all SAEs within 
24 hours of receiving notice. All SAEs should be recorded on the annual safety reports that are sent to 
the MHRA and REC on the anniversary of the date a favourable opinion for the study was given. 
Contact details for reporting SAEs and SUSARs Fax: 0044 207 351 8937, attention Dr Omar Usmani Please 
send SAE forms to: Dr Omar Usmani Tel: 0044 207 351 8051 (Mon to Fri 09.00 – 17.00) 
Contact details for reporting SAEs and SUSARs to the Sponsor Fax: 0203 311 0203 
 
SUSAR reporting 
 
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. In the case of suspected unexpected serious 
adverse reactions, the staff at the site should: 
 
Complete the SAE case report form & send it immediately (within 24 hours, preferably by fax), signed and 
dated to the study coordination centre together with relevant treatment forms and anonymised copies 
of all relevant investigations. 
Or 
 
Contact the study coordination centre and/or the CI as above by phone and then send the completed 
SAE form to the study coordination centre within the following 24 hours as above. 
 
 
 
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The study coordination centre will notify the MHRA, REC and the Sponsor of all SUSARs occurring during 
the study according to the following timelines; fatal and life-threatening within 7 days of notification and 
non-life threatening within 15 days. All investigators will be informed of all SUSARs occurring throughout 
the study. 
 
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. 
 
SUSAR and SAE reporting 
 
Copy of SAE/SUSAR reporting will be notified by the Principal Investigator to the Sponsor’s 
Representative at Imperial College Joint Research Compliance Office (JRCO) within 24 hrs of becoming 
aware of the event. 
 
 
Data Handling and Record Keeping 
 
Hard copies of participant's trial research files will kept under lock and key in the RBH Respiratory BRU 
CRF. Access to these will be limited to the Respiratory Physician conducting the study (Dr Omar Usmani), 
the Co-Investigator (Dr Martyn Biddiscombe) 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 Patient Information Sheet to patients; 
 
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 on 
ClinicalTrials.gov. 
 
Indemnity 
 
Indemnity will be provided by Imperial College Indemnity Scheme which has been arranged through the 
Clinical Research Office at Imperial College. Public Liability cover is also provided for Imperial College 
under this policy reference number. 
 
 
 
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17 

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. STUDY COSTS 
 
PERSONNEL (ICL) 
STUDY 
PHARMACY (RBH) 
-set-up 
-IMP 
management 
fee/month 
-dispensation 
inc. 
reconciliation 
-DRUG COSTS 
RBH CRF COSTS 
- 
room use 
R&D (RBH) 
-set-up 
-per patient RBH Trust 
INFORM DATA MANAGEMENT 
Design,  development  and 
documentation  of  e-CRF 
with monitor/audit in place 
PATIENTS (ICL) 
patient inc travel, food and 
inconvenience 
EQUIPMENT SMALL AIRWAYS 
& SERVICE (ICL) 
IOS and MBNW / annum 
CONFERENCE 
Support to either ERS or 
ATS inclusive 
of economy 
travel, registration, hotel 
- 
Statistical support will be given by Boehringer Ingelheim 
 
- 
Placebo inhalers Handihaler and Respimat will be supplied by Boehringer Ingelheim 
 
Principal Investigator: Dr Omar Usmani 
 
Imperial's Ref No: P53611 
 
 
Study Budget 
GBP 
 
 
STAFF COSTS (salary & on-costs) 
 
 
 
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18 

PI 
£39,658.11 
Researcher (adjust start date June 1st 2015) 
£179,526.97 
DIRECT STUDY CONSUMABLES 
Patient volunteer payments 
£12,740.69 
Consumables 
£2,919.15 
Pharmacy costs 
£6,024.36 
Drug costs 
XXXX 
R&D costs 
£6,625.16 
BRU(Biomedical Research Unit) costs (room hire) 
XXXX 
Travel costs 
£2,038.51 
InForm costs 
£21,842.80 
FACILITIES & EQUIPMENT 
Access charges 
£34,503.47 
Infrastructure costs 
£8,972.65 
TOTAL 
£314,851.87 
 
17. REFERENCES 
1. Pride NB. Tests of forced expiration and inspiration. Clin Chest Med. 2001;22:599-622. 
 
2. Goedhart DM, Zanen P, Lammers JW. Relevant and redundant lung function parameters in discriminating 
asthma from COPD. COPD. 2006;3:33-9. 
 
3. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, 
Paré PD. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 
2004;350:2645-53. 
 
3b. Usmani OS, Barnes PJ. Assessing and treating small airways disease in asthma and chronic obstructive 
pulmonary disease. Ann Med. 2012 Mar;44(2):146-56. 
 
4. Verbanck S, Schuermans D, Meysman M, Paiva M, Vincken W. Noninvasive assessment of airway alterations in 
smokers: the small airways revisited. Am J Respir Crit Care Med. 2004;170:414-9. 
 
5. Van Muylem A, Verbanck S, Estenne M. Monitoring the lung periphery of transplanted lungs. Respir Physiol 
Neurobiol. 2005;148:141-51. 
 
6. Paredi P, Almahdi A, Pride NB, Kharitonov SA, Barnes PJ. Impulse oscillometry is different in asthmatic and COPD 
patients with equally severe airway obstruction as assessed by FEV1. American Thoracic Society Conference 2008. 
Abstract Ref 439. 
 
7. Biddiscombe MF, Verbanck S, Meah SN, Barnes PJ, Usmani OS. Reproducibility of the multiple breath nitrogen 
washout test in healthy subjects. American Thoracic Society Conference 2007. Am J Respir Crit Care Med. 
173:Abstract A604. 
 
8. King GG, Salome CM. Multimodality measurements of small airways disease. Eur Respir J. 2006;27:250-2. 
 
9. Goldman MD, Saadeh C, Ross D. Clinical applications of forced oscillation to assess peripheral airway 
function.Respir Physiol Neurobiol. 2005;148:179-94. 
 
10. Verbanck S, Schuermans D, Noppen M, Van Muylem A, Paiva M, Vincken W. Evidence of acinar airway 
involvement in asthma. Am J Respir Crit Care Med. 1999;159:1545-50. 
 
10b. Paredi P, Goldman M, Alamen A, Ausin P, Usmani OS, Pride NB, Barnes PJ. Comparison of inspiratory and 
expiratory resistance and reactance in patients with asthma and chronic obstructive pulmonary disease. Thorax. 
2010 Mar;65(3):263-7. 
 
10c. Usmani OS. Treating the small airways. Respiration. 2012;84(6):441-53. 
 
 
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11. Zeidler MR, Kleerup EC, Goldin JG, Kim HJ, Truong DA, Simmons MD, Sayre JW, Liu W, Elashoff R, Tashkin DP. 
Montelukast improves regional air-trapping due to small airways obstruction in asthma. Eur Respir J. 2006;27:307- 
 
15. 
 
12. Verbanck S, Schuermans D, Vincken W. Small airways ventilation heterogeneity and hyperinflation in COpd: 
response to tiotropium bromide. Int J Chron Obstruct Pulmon Dis. 2007;2:625-34. 
 
13. Downie SR, Salome CM, Verbanck S, Thompson B, Berend N, King GG. Ventilation heterogeneity is a major 
determinant of airway hyperresponsiveness in asthma, independent of airway inflammation. Thorax. 2007;62:684- 
 
9. 
 
14. Verbanck S, Schuermans D, Paiva M, Meysman M, Vincken W. Small airway function improvement after 
smoking cessation in smokers without airway obstruction. Am J Respir Crit Care Med. 2006;174:853-7. 
 
14b. Assessment of reversibility of airflow obstruction. Van Noord JA1, Smeets J, Clément J, Van de Woestijne KP, 
Demedts M. Am J Respir Crit Care Med. 1994 Aug;150(2):551-4. 
 
14c. Borrill ZL, Houghton CM, Tal-Singer R, Vessey SR, Faiferman I, Langley SJ, Singh D. The use of plethysmography 
and oscillometry to compare long-acting bronchodilators in patients with COPD. Br J Clin Pharmacol. 2008 
Feb;65(2):244-52. 
 
14d. Paredi P, Kharitonov SA, Meah S, Barnes PJ, Usmani OS. A novel approach to partition central and peripheral 
airway nitric oxide. Chest. 2014 Jan;145(1):113-9. 
 
15. Biddiscombe MF, Barnes PJ, Usmani OS. Generating monodisperse pharmacological aerosols using a spinning 
top aerosol generator. J Aerosol Med. 2006;19:245-253. 
 
16. Usmani OS, Biddiscombe MF, Barnes PJ. Regional lung deposition and bronchodilator response as a function of 
β2-agonist particle size. Am J Respir Crit Care Med. 2005;172:1497-1504. 
 
16b. Sturton RG, Trifilieff A, Nicholson AG, Barnes PJ. Pharmacological characterization of indacaterol, a novel once 
daily inhaled 2 adrenoceptor agonist, on small airways in human and rat precision-cut lung slices. J Pharmacol Exp 
Ther. 2008 Jan;324(1):270-5. 
 
16c. Zierenberg B. Optimizing the in vitro performance of Respimat. J Aerosol Med. 1999;12 Suppl 1:S19-24. 
 
16d. Brand P1, Hederer B, Austen G, Dewberry H, Meyer T. Higher lung deposition with Respimat Soft Mist inhaler 
than HFA-MDI in COPD patients with poor technique. Int J Chron Obstruct Pulmon Dis. 2008;3(4):763-70. 
 
17. Houghton CM, Langley SJ, Singh SD, Holden J, Monici Preti AP, Acerbi D, Poli G, Woodcock A. Comparison of 
bronchoprotective and bronchodilator effects of a single dose of formoterol delivered by hydrofluoroalkane and 
chlorofluorocarbon aerosols and dry powder in a double blind, placebo-controlled, crossover study. Br J Clin 
Pharmacol. 2004 Oct;58(4):359-66. 
 
 
SIGNED: 
DR OMAR S USMANI 
  
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR 
01.09.2016 
 
 
 
 
 
 
 
 
 
 
 
 
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