Airway Effects of Tiotropium in Patients With COPD

• Sponsor: Imperial College London (Other)
• Overall Status: Completed
• CT.gov ID: NCT02683668
• Collaborator: Boehringer Ingelheim (Industry)
• Enrollment: 44
• Location: 1
• Arms: 3
• Actual Duration (Months): 23
• Patients Per Site Per Month: 1.9

Study Details

Study Description

Brief Summary

The aim of the study is 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. Comparisons will be made between Tiotropium Handihaler 18 micrograms once daily and Tiotropium Respimat 5 micrograms once daily

Condition or Disease	Intervention/Treatment	Phase
COPD; LUNG DISEASES, OBSTRUCTIVE	Combination Product: Handihaler-Tiotropium 18 mcg untrained; Combination Product: Handihaler-Tiotropium 18 mcg trained; Combination Product: Respimat-Tiotropium 5 mcg trained	Phase 3

Detailed Description

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. 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. Small airways are less than 2mm in diameter. 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.

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).

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 that allow an increase in the total lung deposition of drug (~52%) and also the potential for penetration to treat the small and large airways in patients with COPD; that is targeting the whole airway tree.

RESEARCH AIM & HYPOTHESIS The aim is 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. The investigators will compare Tiotropium Handihaler 18 micrograms once daily with Tiotropium Respimat 5 micrograms once daily.

The investigators 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 is more distal airway targeting necessary? This doesn't necessarily mean targeting the acinar/alveolar beyond the terminal bronchioles, but just a little bit deeper into the distal conducting airway. This can be achieved with Respimat.

Study Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Each volunteer get all treatment in a same sequenceEach volunteer get all treatment in a same sequence
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Targeting of the Small Airways in Patients With COPD: Airway Effects of Tiotropium - Respimat vs Handihaler
• Actual Study Start Date: Feb 1, 2016
• Actual Primary Completion Date: Jan 1, 2018
• Actual Study Completion Date: Jan 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Handihaler-Tiotropium 18 mcg untrained Patients receiving Handihaler who have not been trained (real-life use) for over 3 months on its use. Here the investigators want to see that if patients have on-going symptoms but are on Handihaler-Tiotropium 18mcg 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	Combination Product: Handihaler-Tiotropium 18 mcg untrained; We are looking at the untrained used of Handihaler
Experimental: Handihaler-Tiotropium 18 mcg trained 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. Here the investigators want to see what happens AFTER proper inhaler technique training on large and small airways lung function and also symptoms or exercise limitation (determined by CAT score)	Combination Product: Handihaler-Tiotropium 18 mcg trained; We are looking at the trained use of Handihaler after 14 days treatment
Experimental: Respimat-Tiotropium 5 mcg trained 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. Here the investigators want to see what happens 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). The investigators 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.	Combination Product: Respimat-Tiotropium 5 mcg trained; we are looking at the trained use of Respimat after 14 days treatment

Outcome Measures

Primary Outcome Measures

1. Peripheral Airways Resistance (R5-R20) [6 months]

   Peripheral airways resistance measured by impulse oscillometry (IOS). Specific frequencies relate to different levels: a frequency of 5 hertz (Hz) provides values for total airway resistance (R5) and reactance (X5); a 20Hz frequency gives a value for central or large airway resistance (R20); and if one subtracts the value of central airway resistance from that for total airway resistance (i.e. R5-R20), this provides a measure of peripheral or small airways resistance.

Secondary Outcome Measures

1. Sacin [14 days]

   After treatment Impulse Oscillometry parameter. Sacin is a gas exchange measures, assessing convectional ventilation heterogeneity in pre acinar/acinar airways.

2. Lung Function FEV1 [14 days]

   After treatment period the lung function parameters FEV1

3. Multi-Breath Washout Test (MBW), Scond [14 days]

   After the treatment period the MBW parameters. Scond is a gas exchange measures, assessing convectional ventilation heterogeneity in peripheral conducting airways.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

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 disease in the elderly population.

4. Have on-going 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.

Exclusion Criteria:

1. Subjects who lack the capacity to consent will not be recruited.

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Asthma Lab, Royal Brompton Hospital	London		United Kingdom	SW36LY

Sponsors and Collaborators

• Imperial College London
• Boehringer Ingelheim

Investigators

• Principal Investigator: Omar Usmani, Imperial College London

Study Documents (Full-Text)

• Study Protocol - Sep 1, 2016
• Statistical Analysis Plan - Sep 1, 2016

More Information

Publications

None provided.

• Responsible Party: Imperial College London
• ClinicalTrials.gov Identifier: NCT02683668
• Other Study ID Numbers: 151C2697
• First Posted: Feb 17, 2016
• Last Update Posted: Nov 12, 2019
• Last Verified: Nov 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Imperial College London: Inhalers; Tiotropium
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Tiotropium Bromide

Study Results

Participant Flow

Recruitment Details	Forty-four subjects (23 male) with mild-to-moderate COPD (GOLD stage I-II, FEV1 67.8% of predicted) using DPI-HandiHaler (18µg tiotropium daily) for at least 3 months, but with ongoing symptoms or exercise limitation (COPD Assesment Test (CAT) score >10) participated in the study. 1 failed to complete

Arm/Group Title	Handihaler-Tiotropium 18 mcg Untrained	Handihaler-Tiotropium 18 mcg Trained	Respimat-Tiotropium 5 mcg Trained
Arm/Group Description	Patients receiving Handihaler who have not been trained (real-life use) for over 3 months on its use. Here the investigators want to see that if patients have on-going symptoms but are on Handihaler-Tiotropium 18mcg 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 Handihaler-Tiotropium 18 mcg untrained: We are looking at the untrained used of Handihaler	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. Here the investigators want to see what happens AFTER proper inhaler technique training on large and small airways lung function and also symptoms or exercise limitation (determined by CAT score) Handihaler-Tiotropium 18 mcg trained: We are looking at the trained use of Handihaler after 14 days treatment	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. Here the investigators want to see what happens 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). The investigators 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. Respimat-Tiotropium 5 mcg trained: we are looking at the trained use of Respimat after 14 days treatment
Period Title: Period 1
STARTED	44	0	0
COMPLETED	44	0	0
NOT COMPLETED	0	0	0
Period Title: Period 1
STARTED	0	44	0
COMPLETED	0	43	0
NOT COMPLETED	0	1	0
Period Title: Period 1
STARTED	0	0	43
COMPLETED	0	0	43
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	All Participant
Arm/Group Description	Patients receiving Handihaler who have not been trained (real-life use) for over 3 months on its use.
Overall Participants	44
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	12 27.3%
>=65 years	32 72.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.1 (8.0)
Sex: Female, Male (Count of Participants)
Female	21 47.7%
Male	23 52.3%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
United Kingdom	44 100%
R5 - R20 (Peripheral Airways Resistance) (kPa/l/s) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kPa/l/s]	0.608 (0.207)

Outcome Measures

1. Primary Outcome

Title	Peripheral Airways Resistance (R5-R20)
Description	Peripheral airways resistance measured by impulse oscillometry (IOS). Specific frequencies relate to different levels: a frequency of 5 hertz (Hz) provides values for total airway resistance (R5) and reactance (X5); a 20Hz frequency gives a value for central or large airway resistance (R20); and if one subtracts the value of central airway resistance from that for total airway resistance (i.e. R5-R20), this provides a measure of peripheral or small airways resistance.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Handihaler-Tiotropium 18 mcg Untrained	Handihaler-Tiotropium 18 mcg Trained	Respimat-Tiotropium 5 mcg Trained
Arm/Group Description	Patients receiving Handihaler who have not been trained (real-life use) for over 3 months on its use. Here the investigators want to see that if patients have on-going symptoms but are on Handihaler-Tiotropium 18mcg 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 Handihaler-Tiotropium 18 mcg untrained: We are looking at the untrained used of Handihaler	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. Here the investigators want to see what happens AFTER proper inhaler technique training on large and small airways lung function and also symptoms or exercise limitation (determined by CAT score) Handihaler-Tiotropium 18 mcg trained: We are looking at the trained use of Handihaler after 14 days treatment	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. Here the investigators want to see what happens 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). The investigators 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. Respimat-Tiotropium 5 mcg trained: we are looking at the trained use of Respimat after 14 days treatment
Measure Participants	44	43	43
Mean (Standard Deviation) [kPa/l/s]	0.608 (0.207)	0.589 (0.169)	0.497 (0.148)

2. Secondary Outcome

Title	Sacin
Description	After treatment Impulse Oscillometry parameter. Sacin is a gas exchange measures, assessing convectional ventilation heterogeneity in pre acinar/acinar airways.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Handihaler-Tiotropium 18 mcg Untrained	Handihaler-Tiotropium 18 mcg Trained	Respimat-Tiotropium 5 mcg Trained
Arm/Group Description	Patients receiving Handihaler who have not been trained (real-life use) for over 3 months on its use. Here the investigators want to see that if patients have on-going symptoms but are on Handihaler-Tiotropium 18mcg 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 Handihaler-Tiotropium 18 mcg untrained: We are looking at the untrained used of Handihaler	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. Here the investigators want to see what happens AFTER proper inhaler technique training on large and small airways lung function and also symptoms or exercise limitation (determined by CAT score) Handihaler-Tiotropium 18 mcg trained: We are looking at the trained use of Handihaler after 14 days treatment	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. Here the investigators want to see what happens 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). The investigators 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. Respimat-Tiotropium 5 mcg trained: we are looking at the trained use of Respimat after 14 days treatment
Measure Participants	44	43	43
Mean (Standard Deviation) [kPa\l\s]	0.333 (0.103)	0.339 (0.119)	0.345 (0.134)

3. Secondary Outcome

Title	Lung Function FEV1
Description	After treatment period the lung function parameters FEV1
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Handihaler-Tiotropium 18 mcg Untrained	Handihaler-Tiotropium 18 mcg Trained	Respimat-Tiotropium 5 mcg Trained
Arm/Group Description	Patients receiving Handihaler who have not been trained (real-life use) for over 3 months on its use. Here the investigators want to see that if patients have on-going symptoms but are on Handihaler-Tiotropium 18mcg 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 Handihaler-Tiotropium 18 mcg untrained: We are looking at the untrained used of Handihaler	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. Here the investigators want to see what happens AFTER proper inhaler technique training on large and small airways lung function and also symptoms or exercise limitation (determined by CAT score) Handihaler-Tiotropium 18 mcg trained: We are looking at the trained use of Handihaler after 14 days treatment	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. Here the investigators want to see what happens 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). The investigators 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. Respimat-Tiotropium 5 mcg trained: we are looking at the trained use of Respimat after 14 days treatment
Measure Participants	44	43	43
Mean (Standard Deviation) [liters]	1.575 (0.483)	1.571 (0.523)	1.651 (0.497)

4. Secondary Outcome

Title	Multi-Breath Washout Test (MBW), Scond
Description	After the treatment period the MBW parameters. Scond is a gas exchange measures, assessing convectional ventilation heterogeneity in peripheral conducting airways.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Handihaler-Tiotropium 18 mcg Untrained	Handihaler-Tiotropium 18 mcg Trained	Respimat-Tiotropium 5 mcg Trained
Arm/Group Description	Patients receiving Handihaler who have not been trained (real-life use) for over 3 months on its use. Here the investigators want to see that if patients have on-going symptoms but are on Handihaler-Tiotropium 18mcg 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 Handihaler-Tiotropium 18 mcg untrained: We are looking at the untrained used of Handihaler	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. Here the investigators want to see what happens AFTER proper inhaler technique training on large and small airways lung function and also symptoms or exercise limitation (determined by CAT score) Handihaler-Tiotropium 18 mcg trained: We are looking at the trained use of Handihaler after 14 days treatment	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. Here the investigators want to see what happens 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). The investigators 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. Respimat-Tiotropium 5 mcg trained: we are looking at the trained use of Respimat after 14 days treatment
Measure Participants	44	43	43
Mean (Standard Deviation) [kPa\l\s]	0.047 (0.042)	0.042 (0.032)	0.036 (0.032)

Adverse Events

Time Frame	12 months
Arm/Group Title	All Participant
Arm/Group Description	Patients receiving Handihaler who have not been trained (real-life use) for over 3 months on its use.
All Cause Mortality
	All Participant
	Affected / at Risk (%)	# Events
Total	0/43 (0%)
Serious Adverse Events
	All Participant
	Affected / at Risk (%)	# Events
Total	0/43 (0%)
Other (Not Including Serious) Adverse Events
	All Participant
	Affected / at Risk (%)	# Events
Total	0/43 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.