Pharmacokinetics of Inhaled Monodisperse Fluticasone Propionate

• Sponsor: Imperial College London (Other)
• Overall Status: Completed
• CT.gov ID: NCT00692978
• Collaborator: (none)
• Enrollment: 30
• Locations: 2
• Arms: 2
• Actual Duration (Months): 35
• Patients Per Site: 15
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Asthma is most effectively treated by delivering inhaled drugs from an inhaler (puffer) directly into the lungs. Inhaled steroids are used in asthmatic patients to dampen down lung inflammation, which unchecked, can often lead to patient symptoms. Inhalers deliver a mist containing particles of lots of different sizes (like hairsprays). Medical puffers used by patients produce a 'coarse' mist of drug particles, which have the potential for side effects, as different sized particles will reach different parts of the airways and include; the mouth, the throat, the windpipe, and the bloodstream (all places we do not want the inhaled drug to go - and can give rise to important side effects)and, the lungs (where we do want the drug to 'deposit').

Our aim in this study is to test an inhaled steroid by giving it to subjects as a 'fine' mist containing drug particles of nearly all one size using a research nebuliser (a Spinning Top Aerosol Generator). We shall use small, intermediate and large drug particle mists. We aim to find out how much of the drug goes to the blood stream for each particle mist and compare it with the standard puffers used in routine clinical practice.

We hope this study will provide information to the rationale that by improving the efficiency of drug delivery (by changing drug particle size) one may improve inhaled drug delivery and ultimately, clinical patient benefit.

Healthy volunteers and asthmatic patients will be recruited at the Royal Brompton Hospital London. The study is funded by GlaxoSmithKline, Research & Development, U.K.

Condition or Disease	Intervention/Treatment	Phase
Healthy; Asthma	Drug: Fluticasone Propionate_1.5; Drug: Fluticasone Propionate_3; Drug: Fluticasone Propionate_6; Drug: FP From Active 250 ug MDI Inhaler	Phase 4

Detailed Description

The clinical trial is to investigate the pharmacokinetic effects (that is how much drug is in the blood) of Fluticasone Propionate (Flixotide), a commonly used steroid drug that is inhaled in patients with asthma. We will use standard clinical Flixotide Nebules that are used with clinical nebulisers (machines used in hospital and at home - to deliver drug to patients with asthma). Current clinical nebulisers deliver a 'coarse' mist of drug, which has the potential for side effects and this is an important consideration with steroids. These Flixotide nebules will be used to deliver the drug (fluticasone propionate) as monodisperse aerosol clouds (that is the drug will be delivered as a 'fine' mist cloud to patients). In order to deliver the drug as a monodisperse aerosol, the Flixotide Nebules will be used with a spinning top aerosol (a large research nebuliser machine)which is able to selectively generate aerosol clouds that have a fine mist. A fine mist cloud leads to less deposition in the throat of the patients and a greater control of the inhaled drug reaching the lungs, and fine mist drug clouds have the potential to reduce side effects. We will also compare this to the use of a standard routine clinical dose of a Flixotide metered-dose inhaler ( a 'press and breathe' inhaler) with a spacer (plastic bubble on the end of an inhaler) delivered to patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Intervention Model Description: Two groups (asthma and healthy) go through different particle size of monodisperse aerosol treatmentsTwo groups (asthma and healthy) go through different particle size of monodisperse aerosol treatments
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: The Pharmacokinetics of Inhaled Fluticasone Propionate Delivered as Monodisperse Aerosols
• Actual Study Start Date: Aug 1, 2008
• Actual Primary Completion Date: Jul 3, 2011
• Actual Study Completion Date: Jul 3, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Asthma Asthma patients	Drug: Fluticasone Propionate_1.5; Dose 50 micrograms (total dose), Monodisperse aerosol with particle size of drug 1.5 micros, inhaled; Drug: Fluticasone Propionate_3; Dose 50 micrograms (total dose), Monodisperse aerosol with particle size of drug 3.0 microns, inhaled; Drug: Fluticasone Propionate_6; Dose 50 micrograms (total dose), Monodisperse aerosol with particle size of drug 6.0 microns, inhaled; Drug: FP From Active 250 ug MDI Inhaler; Monodisperse aerosols inhaled of Fluticasone Propionate at 250micrograms dose with active MDI inhaler
Active Comparator: Healthy volunters Healthy participants	Drug: Fluticasone Propionate_1.5; Dose 50 micrograms (total dose), Monodisperse aerosol with particle size of drug 1.5 micros, inhaled; Drug: Fluticasone Propionate_3; Dose 50 micrograms (total dose), Monodisperse aerosol with particle size of drug 3.0 microns, inhaled; Drug: Fluticasone Propionate_6; Dose 50 micrograms (total dose), Monodisperse aerosol with particle size of drug 6.0 microns, inhaled; Drug: FP From Active 250 ug MDI Inhaler; Monodisperse aerosols inhaled of Fluticasone Propionate at 250micrograms dose with active MDI inhaler

Outcome Measures

Primary Outcome Measures

1. AUC Fluticasone Propionate (FP) [12 hours]

   The main outcome measure is the concentration of Fluticasone Propionate in blood following inhalation of the dose. This will be found by calculating the area under the curve of concentration versus time 0 and 12 hours.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

Healthy Volunteers

Participants will be included if they meet all of the following inclusion criteria

1. Healthy non smoking participants

2. Male or female aged above 18 years

3. No history of respiratory disease

4. Normal baseline spirometry as predicted for age, sex and height (we have excluded those with abnormal spirometry as this may indicate an underlying lung condition that needs attention, and such participants will be told their result and with their consent, the information will be forwarded to their General Practitioner, as part of the safety and well being of the research participant.

5. No history of allergic disease i.e., a negative skin prick test

6. Participants who are free from significant cardiac, gastrointestinal, hepatic, renal, hematological, neurological and psychiatric disease.

7. Not taking any regular medication that is contraindicated in those about to receive fluticasone propionate (as indicated in the British National Formularly); other than the oral contraceptive pill.

Asthmatics

1. Male or females aged greater than 18 years with a documented history of reversible airways disease responding to beta2-adrenergic therapy.

2. Asthmatic patients who are free from significant cardiac, gastrointestinal, hepatic, renal, hematological, neurological and psychiatric disease.

3. Patients who are stabilized on 500 micrograms or less of inhaled beclomethasone dipropionate or alternative inhaled corticosteroid (budesonide or ciclesonide).

4. Patients who are able and willing to give written informed consent to take part in the study

5. Not taking any regular medication that is contraindicated in those about to receive fluitcasone propionate (as indicated in the British National Formularly); other than the oral contraceptive pill.

Exclusion Criteria:

Healthy Volunteers and Asthmatics

1. Those requiring maintenance oral or parenteral corticosteroid therapy for their airways disease or patients who have ceased maintenance oral or parenteral corticosteroid therapy within the four weeks prior to visit 1

2. Those requiring greater than 500 micrograms of inhaled beclomethasone dipropionate or alternative inhaled corticosteroid (budesonide or ciclesonide).

3. Subjects that have received inhaled or intravenous fluticasone propionate in the last 2 months.

4. Those whose reversible airways obstruction has been unstable in the last four weeks (indicated by any change in their maintenance therapy).

5. Those participants who have had a lower respiratory tract infection in the previous four weeks

6. Those who have donated 450ml blood or more within the previous 1 month.

7. Those who have a history of drug allergy which, in the opinion of the Unit Physician, contraindicates his/her participation in the study.

8. Any evidence of a positive pregnancy urine test for female volunteers or females who are pregnant or lactating or are likely to become pregnant during the trial. Women of child-bearing potential may be included in the study if, in the opinion of the investigator, they are taking adequate contraceptive precautions.

9. Participants with a known or suspected allergy to corticosteroids or any component of the formulations and/or Suspected hypersensitivity to inhaled corticosteroid (this will be asked directly at the screening visit).

10. Any patient with a contraindication to taking an inhaled steroid and specifically FP, listed in the British National Formularly will not be entered into this study

11. Those who have experienced an acute asthma exacerbation requiring emergency room treatment and/or hospitalization within one month of visit 1.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Asthma Lab, Royal Brompton Hospital	London		United Kingdom
2	Department of Nuclear Medicine, Royal Brompton Hospital	London		United Kingdom

Sponsors and Collaborators

• Imperial College London

Investigators

• Principal Investigator: O S Usmani, MD, PhD, Imperial College London

Study Documents (Full-Text)

None provided.

More Information

Publications

• Biddiscombe MF, Barnes PJ, Usmani OS. Generating monodisperse pharmacological aerosols using the spinning-top aerosol generator. J Aerosol Med. 2006 Fall;19(3):245-53.
• Biddiscombe MF, Usmani OS, Barnes PJ. A system for the production and delivery of monodisperse salbutamol aerosols to the lungs. Int J Pharm. 2003 Mar 26;254(2):243-53.
• Usmani OS, Biddiscombe MF, Barnes PJ. Regional lung deposition and bronchodilator response as a function of beta2-agonist particle size. Am J Respir Crit Care Med. 2005 Dec 15;172(12):1497-504. Epub 2005 Sep 28.
• Usmani OS, Biddiscombe MF, Nightingale JA, Underwood SR, Barnes PJ. Effects of bronchodilator particle size in asthmatic patients using monodisperse aerosols. J Appl Physiol (1985). 2003 Nov;95(5):2106-12. Epub 2003 Aug 1.

• Responsible Party: Imperial College London
• ClinicalTrials.gov Identifier: NCT00692978
• Other Study ID Numbers: 08/H0712/63
• First Posted: Jun 6, 2008
• Last Update Posted: Nov 25, 2020
• Last Verified: Nov 1, 2020

• 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: Monodisperse aerosols; Healthy Volunteers; Asthmatics; Pharmacokinetics; Randomized
• Additional relevant MeSH terms: Fluticasone; Xhance

Study Results

Participant Flow

Arm/Group Title	Asthma Patients	Healthy Volunteers
Arm/Group Description	Monodisperse aerosols (MO) inhaled of Fluticasone Propionate (FP) 50micrograms dose	Monodisperse aerosols (MO) inhaled of Fluticasone Propionate (FP) 50micrograms dose
Period Title: FP From Active 250 ug MDI Inhaler
STARTED	15	15
COMPLETED	15	15
NOT COMPLETED	0	0
Period Title: FP From Active 250 ug MDI Inhaler
STARTED	15	15
COMPLETED	15	15
NOT COMPLETED	0	0
Period Title: FP From Active 250 ug MDI Inhaler
STARTED	15	15
COMPLETED	15	15
NOT COMPLETED	0	0
Period Title: FP From Active 250 ug MDI Inhaler
STARTED	15	15
COMPLETED	15	15
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Asthma Patients	Healthy Volunteers	Total
Arm/Group Description	Recruited Asthma patients	Recruited healthy volunteers	Total of all reporting groups
Overall Participants	15	15	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35 (11.8)	35 (10.5)	35 (11)
Sex: Female, Male (Count of Participants)
Female	7 46.7%	10 66.7%	17 56.7%
Male	8 53.3%	5 33.3%	13 43.3%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United Kingdom	15 100%	15 100%	30 100%

Outcome Measures

1. Primary Outcome

Title	AUC Fluticasone Propionate (FP)
Description	The main outcome measure is the concentration of Fluticasone Propionate in blood following inhalation of the dose. This will be found by calculating the area under the curve of concentration versus time 0 and 12 hours.
Time Frame	12 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	FP From Active 250 ug MDI Inhaler Asthma	FP 50ug 1.5um Asthma	FP 50ug 3um Asthma	FP 50ug 6um Asthma	FP From Active 250 ug MDI Inhaler HV	FP 50ug 1.5um HV	FP 50ug 3um HV	FP 50ug 6um HV
Arm/Group Description	Monodisperse aerosols inhaled of Fluticasone Propionate at 250micrograms dose with active MDI inhaler with Asthma participants	Monodisperse aerosols inhaled of Fluticasone Propionate 1.5 microns size at 50micrograms dose with double-dummy placebo MDI inhaler with Asthma patients	Monodisperse aerosols inhaled of Fluticasone Propionate 3 microns size at 50micrograms dose with double-dummy placebo MDI inhaler with Asthma patients	Monodisperse aerosols inhaled of Fluticasone Propionate 6 microns size at 50micrograms dose with double-dummy placebo MDI inhaler with Asthma patients	Monodisperse aerosols inhaled of Fluticasone Propionate at 250micrograms dose with active MDI inhaler with Healthy participants	Monodisperse aerosols inhaled of Fluticasone Propionate 1.5microns size at 50micrograms dose with double-dummy placebo MDI inhaler with Healthy volunteers	Monodisperse aerosols inhaled of Fluticasone Propionate 3microns size at 50micrograms dose with double-dummy placebo MDI inhaler with Healthy volunteers	Monodisperse aerosols inhaled of Fluticasone Propionate 3microns size at 50micrograms dose with double-dummy placebo MDI inhaler with Healthy volunteers
Measure Participants	15	15	15	15	15	15	15	15
Median (Full Range) [pg.h/ml]	188.2	756	978	380.5	172.3	740	934.6	250.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FP From Active 250 ug MDI Inhaler Asthma, FP 50ug 1.5um Asthma, FP 50ug 3um Asthma, FP 50ug 6um Asthma, FP From Active 250 ug MDI Inhaler HV, FP 50ug 1.5um HV, FP 50ug 3um HV, FP 50ug 6um HV
	Comments
	Type of Statistical Test	Equivalence
	Comments	Log transformed parametric ANOVA
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	calculated
	Method	ANOVA
	Comments

Adverse Events

Time Frame	4 months
Arm/Group Title	FP From Active 250 ug MDI Inhaler Asthma		FP 50ug 1.5um Asthma		FP 50ug 3um Asthma		FP 50ug 6um Asthma		FP From Active 250 ug MDI Inhaler Healthy		FP 50ug 1.5um Healthy		FP 50ug 3um Healthy		FP 50ug 6um Healthy
Arm/Group Description	Monodisperse aerosols inhaled of Fluticasone Propionate at 250micrograms dose with active MDI inhaler with Asthma participants		Monodisperse aerosols inhaled of Fluticasone Propionate 1.5 microns size at 50micrograms dose with double-dummy placebo MDI inhaler with Asthma patients		Monodisperse aerosols inhaled of Fluticasone Propionate 3 microns size at 50micrograms dose with double-dummy placebo MDI inhaler with Asthma patients		Monodisperse aerosols inhaled of Fluticasone Propionate 6 microns size at 50micrograms dose with double-dummy placebo MDI inhaler with Asthma patients		Monodisperse aerosols inhaled of Fluticasone Propionate at 250micrograms dose with active MDI inhaler with Healthy participants		Monodisperse aerosols inhaled of Fluticasone Propionate 1.5 microns size at 50micrograms dose with double-dummy placebo MDI inhaler with Healthy participants		Monodisperse aerosols inhaled of Fluticasone Propionate 3 microns size at 50micrograms dose with double-dummy placebo MDI inhaler with Healthy participants		Monodisperse aerosols inhaled of Fluticasone Propionate 6 microns size at 50micrograms dose with double-dummy placebo MDI inhaler with Healthy participants
All Cause Mortality
	FP From Active 250 ug MDI Inhaler Asthma		FP 50ug 1.5um Asthma		FP 50ug 3um Asthma		FP 50ug 6um Asthma		FP From Active 250 ug MDI Inhaler Healthy		FP 50ug 1.5um Healthy		FP 50ug 3um Healthy		FP 50ug 6um Healthy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)
Serious Adverse Events
	FP From Active 250 ug MDI Inhaler Asthma		FP 50ug 1.5um Asthma		FP 50ug 3um Asthma		FP 50ug 6um Asthma		FP From Active 250 ug MDI Inhaler Healthy		FP 50ug 1.5um Healthy		FP 50ug 3um Healthy		FP 50ug 6um Healthy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	FP From Active 250 ug MDI Inhaler Asthma		FP 50ug 1.5um Asthma		FP 50ug 3um Asthma		FP 50ug 6um Asthma		FP From Active 250 ug MDI Inhaler Healthy		FP 50ug 1.5um Healthy		FP 50ug 3um Healthy		FP 50ug 6um Healthy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (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.