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Inhalation of Corticosteroids in Smoking and Non-smoking Asthmatics.

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01400906
First received: July 21, 2011
Last updated: April 10, 2014
Last verified: November 2013
  Purpose

People with asthma suffer from breathlessness because the small tubes (bronchioles) that carry air in and out of the lungs become inflamed and narrow. Steroids reduce the inflammation, and are commonly used to control asthma, but they do not work well in some asthmatics, particularly those who smoke.

This study is done to find out more about why smokers with asthma do not benefit from steroid treatment. In this study, the effect of Flixotide (fluticasone propionate), a steroid widely used to treat asthma, is tested in smokers and non-smokers with mild asthma.

16 smokers and 16 non-smokers, aged 18−55 years will be enrolled in this study.

Subjects will take each of the following treatments:

  • 100 micrograms Flixotide twice daily for 7 days;
  • 500 micrograms Flixotide twice daily for 7 days; and
  • placebo (dummy medicine) twice daily for 7 days.

Study design: subjects will have a screening visit (over 2 days), and will take part in 3 treatment periods (which are separated by interval of at least 14 days); a follow-up visit is scheduled 7 days after the last intake of study treatment.

The order in which order the subjects will take the treatments is defined at random. Total study duration: about 11 weeks.

To test the effects of Flixotide, the subject's responses to :

  • an inhaled allergen test
  • a PC20 methacholine test
  • blood, urine and sputum PD markers will be analysed.

This study will take place in 2 centres: 1 in the United Kingdom and 1 in Belgium. The units will recruit participants by advertising (newspaper, radio, and websites), word of mouth, from volunteer databases, and via the centres' websites.


Condition Intervention Phase
Asthma
Drug: 100 micrograms Fluticasone propionate
Drug: 500 micrograms Fluticasone propionate
Drug: lactose powder
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Official Title: A Randomized, Double Blind, Placebo-controlled Three-way Crossover Study in Mild Asthmatics to Evaluate the Effect of Smoking Status on the Attenuation by Inhaled Corticosteroids of the Allergen-induced Asthmatic Response.

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Late Asthmatic Response (LAR) - Smokers: Absolute Change From Saline in Minimum Forced Expiratory Volume in One Second (FEV1) Between 4-10 Hours (Hrs) After Allergen Challenge on Day 6 of Each Treatment Period [ Time Frame: Day 6 of each treatment period (up to 11 weeks) ] [ Designated as safety issue: No ]
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants were exposed to an allergen 1 hr after dosing on Day 6. Minimum FEV1 over 4-10 hours post-allergen challenge is the minimum value of all of the post-saline time points between 4 and 10 hrs post-allergen challenge, inclusive of the 4 hr and 10 hr timepoints (i.e., minimum over 4 hrs, 4.5 hrs, 5 hrs, 5.5 hrs, 6 hrs, 6.5 hrs, 7 hrs, 7.5 hrs, 8 hrs, 8.5 hrs, 9 hrs, 9.5 hrs, and 10 hrs). Absolute change from saline at each time point was calculated as the highest allergen challenge FEV1 value minus the highest saline FEV1 value. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.

  • LAR - Non-smokers: Absolute Change From Saline in Minimum FEV1 Between 4-10 Hours (Hrs) After Allergen Challenge on Day 6 of Each Treatment Period [ Time Frame: Day 6 of each treatment period (up to 11 weeks) ] [ Designated as safety issue: No ]
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants were exposed to an allergen 1 hr after dosing on Day 6. Minimum FEV1 over 4-10 hours post-allergen challenge is the minimum value of all of the post-saline time points between 4 and 10 hrs post-allergen challenge, inclusive of the 4 hr and 10 hr timepoints (i.e., minimum over 4 hrs, 4.5 hrs, 5 hrs, 5.5 hrs, 6 hrs, 6.5 hrs, 7 hrs, 7.5 hrs, 8 hrs, 8.5 hrs, 9 hrs, 9.5 hrs, and 10 hrs). Absolute change from saline at each time point was calculated as the highest allergen challenge FEV1 value minus the highest saline FEV1 value. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.

  • LAR - Smokers: Absolute Change From Saline in Weighted Mean (WM) FEV1 Between 4-10 Hrs Following Post-treatment Allergen Challenge on Day 6 of Each Treatment Period [ Time Frame: Day 6 of each treatment period (up to 11 weeks) ] [ Designated as safety issue: No ]
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants were exposed to an allergen 1 hour after dosing on Day 6. The WM FEV1 was derived by calculating the area under the curve, and then dividing the value by the relevant time interval. LAR WM FEV1 was measured at 4 hrs, 4.5 hrs, 5 hrs, 5.5 hrs, 6 hrs, 6.5 hrs, 7 hrs, 7.5 hrs, 8 hrs, 8.5 hrs, 9 hrs, 9.5 hrs, and 10 hrs post-allergen challenge on Day 6. Absolute change from saline at each time point was calculated as the highest allergen challenge FEV1 value minus the highest saline FEV1 value. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.

  • LAR - Non-smokers: Absolute Change From Saline in WM FEV1 Between 4-10 Hrs Following Post-treatment Allergen Challenge on Day 6 of Each Treatment Period [ Time Frame: Day 6 of each treatment period (up to 11 weeks) ] [ Designated as safety issue: No ]
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants were exposed to an allergen 1 hour after dosing on Day 6. The WM FEV1 was derived by calculating the area under the curve, and then dividing the value by the relevant time interval. LAR WM FEV1 was measured at 4 hrs, 4.5 hrs, 5 hrs, 5.5 hrs, 6 hrs, 6.5 hrs, 7 hrs, 7.5 hrs, 8 hrs, 8.5 hrs, 9 hrs, 9.5 hrs, and 10 hrs post-allergen challenge on Day 6. Absolute change from saline at each time point was calculated as the highest allergen challenge FEV1 value minus the highest saline FEV1 value. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.


Secondary Outcome Measures:
  • Early Asthmatic Response (EAR): Absolute Change From Saline in Minimum FEV1 and WM FEV1 Between 0-2 Hours (Hrs) After Allergen Challenge on Day 6 of Each Treatment Period [ Time Frame: Day 6 of each treatment period (up to 11 weeks) ] [ Designated as safety issue: No ]
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants were exposed to an allergen 1 hr after dosing on Day 6. Minimum FEV1 over 0-2 hrs post-allergen challenge (Minimum EAR) is the minimum value of all of the post-allergen challenge timepoints up to and including 2 hours post-allergen challenge (i.e., minimum over 5 minutes [min], 10 min, 15 min, 20 min, 30 min, 45 min and 1 hr, 1.5 hrs, and 2 hrs). The WM FEV1 was derived by calculating the area under the curve, and then dividing the value by the relevant time interval. Absolute change from saline at each time point was calculated as the highest allergen challenge FEV1 value minus the highest saline FEV1 value. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.

  • Absolute Change From Baseline in FEV1 Post-dose on Day 1, Day 6 (Prior to Allergen Challenge), and Day 7 [ Time Frame: Baseline, Day 1, Day 6, and Day 7 ] [ Designated as safety issue: No ]
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Baseline FEV1 was measured on Day 1 pre-dose administration. FEV1 was measured on Day 1 post-dose, on Day 6 (prior to allergen challenge), and on Day 7 pre dose administration. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.

  • Provocative Concentration of Methacholine Resulting in a 20% Reduction in FEV1 (PC20) on Day 7 of Each Treatment Period [ Time Frame: Day 7 of each treatment period (up to 11 weeks) ] [ Designated as safety issue: No ]
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants inhaled doubling increments of methacholine until a >=20% decrease in FEV1 from the post-saline value was achieved.

  • Concentration of Exhaled Nitric Oxide (eNO) on Day 6 and Day 7 of Each Treatment Period [ Time Frame: Day 6 and Day 7 of each treatment period (up to 11 weeks) ] [ Designated as safety issue: No ]
    The concentration of eNO was measured on Day 6 pre-dose and on Day 7 post-study medication administration. eNO was measured 3 times at each time point, and all 3 measurements were recorded. The mean of the 3 measurements was calculated and was used in the derivation of summary statistics.

  • Neutrophil and Eosinophil Cell Counts in Induced Sputum on Day 7 of Each Treatment Period [ Time Frame: Day 7 of each treatment period (up to 11 weeks) ] [ Designated as safety issue: No ]
    Sputum induction was performed using hypertonic saline solution to collect an adequate sample of secretions from lungs. The collected sputum was analyzed for neutrophil and eosinophil counts. Sputum induction was performed after methacholine challenge and post-dose administration on Day 7. Zero values are imputed to 0.001 for this analysis. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.


Enrollment: 36
Study Start Date: July 2011
Study Completion Date: December 2012
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: 3 periods cross-over study
Each subject will receive each intervention BID during a 7 days period. The treatment periods are separated by 14 days washout. The sequence in which the interventions are administered are at random and double blind.
Drug: 100 micrograms Fluticasone propionate
100 micrograms micronized drug blended with lactose in dry powder inhalator
Other Name: Flixotide
Drug: 500 micrograms Fluticasone propionate
500 micrograms micronized drug blended with lactose in dry powder inhalator
Other Name: Flixotide
Drug: lactose powder
lactose powder in dry powder device : placebo comparator

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • males and females between 18 and 55 years of age inclusive
  • female subject of child-bearing potential and agrees to use one of the contraception methods; or of non-childbearing potential including pre-menopausal females with documented (medical report verification) hysterectomy or double oophorectomy or postmenopausal defined as 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 40 pg/ml (<140 pmol/L) or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
  • male subjects with female partners of child-bearing potential must agree to use a contraception method
  • body weight ≥50 kg and BMI within the range (18.5-35) kg/m2 (inclusive)
  • documented history of bronchial asthma, first diagnosed at least 6 months prior to the first screening visit (according to the BTS guideline 2009), and currently being treated only with prn short-acting inhaled β2-agonist therapy
  • current smokers or non-smokers or ex-smokers
  • pre-bronchodilator FEV1 >70% of predicted at screening
  • sensitivity to methacholine with a provocative concentration of methacholine resulting in a 20 % fall in FEV1 of < 8 mg/ml at screening
  • able to produce acceptable induced sputum samples
  • positive wheal and/or flare reaction (≥ 3 mm relative to negative control) to at least one allergen on skin prick testing at screening or within 12 months of the study start
  • screening allergen challenge must demonstrate that the subject experiences both an early and late asthmatic response.
  • AST, ALT, alkaline phosphatase and bilirubin <=1.5xULN
  • written informed consent
  • able to understand and comply with the study procedures, planned treatment period and other protocol requirements and stated restrictions

Exclusion Criteria:

  • past or present disease (other than asthma)
  • respiratory tract infection and / or exacerbation of asthma within 4 weeks prior the first dose of study drug
  • history of life-threatening asthma
  • symptomatic with hay fever at screening or predicted to have symptomatic hay fever during the time of the study
  • administration of oral or injectable steroids within 5 weeks of the screening visit or intranasal and / or inhaled steroids within 4 weeks of the screening visit
  • unable to abstain from other medication, including non-steroidal anti-inflammatory drugs, anti-depressants, anti-histamines, anti-asthma and anti-rhinitis or hay fever medication, other than short acting β2-agonists and paracetamol (up to 4 gram per day) for the treatment of minor ailments (such as headache) from 14 days before screening until the follow-up visit
  • unable to abstain from short acting β2-agonists as described in the restriction section of the protocol
  • if, after two consecutive administrations of saline, during the allergen challenge at screening, the subject still has a fall of FEV1 of 10%
  • a positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result
  • clinical significant abnormalities in safety laboratory analysis at screening
  • significant abnormality on 12-lead ECG at screening
  • the subject is undergoing an allergen desensitisation therapy. Subjects with a positive pre-study drug/alcohol screen
  • a history of regular alcohol consumption within 6 months of the screening visit
  • a positive test for HIV antibody
  • the subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer)
  • history of being unable to tolerate or complete methacholine and / or allergen challenge test
  • use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication
  • unable to abstain from medication or supplements that significantly inhibit the cytochrome P450 subfamily enzyme CYP3A4, including but not limited to antiretrovirals (protease inhibitors - e.g. ritonavir indinavir, nelfinavir, ritonavir, saquinavir); imidazole and triazole anti-fungals (e.g. ketoconazole, itraconazole) and macrolide antibiotics (e.g. clarithromycin, telithromycin) from screening and throughout the study
  • consumption of red wine, seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose of study medication
  • history of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that contraindicates their participation
  • donation of blood or blood products in excess of 500 mL within a 56 day period
  • pregnant females at screening or prior to dosing
  • lactating females
  • unwillingness or inability to follow the procedures outlined in the protocol
  • subject is mentally or legally incapacitated
  • urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening (for subjects taking part in the non-smokers group of the study)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01400906

Locations
Belgium
GSK Investigational Site
Brussels, Belgium, 1020
United Kingdom
GSK Investigational Site
London, United Kingdom, NW10 7EW
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Publications:

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01400906     History of Changes
Other Study ID Numbers: 114748
Study First Received: July 21, 2011
Results First Received: July 18, 2013
Last Updated: April 10, 2014
Health Authority: Belgium: Federal Agency for Medicinal Products and Health Products

Additional relevant MeSH terms:
Fluticasone
Anti-Allergic Agents
Anti-Asthmatic Agents
Anti-Inflammatory Agents
Autonomic Agents
Bronchodilator Agents
Dermatologic Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Respiratory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014