Assessment Of Disease Pathology And Key Therapeutic Targets In Severe Asthma

A Study to Assess Disease Pathology and Key Therapeutic Targets in Severe Asthma

To evaluate and compare the expression and change in expression of key severe asthma targets at baseline in mile to moderate asthmatics vs. severe asthmatic subjects.

To evaluate and compare the airway pathology at baseline and changes in airway pathology in relation to asthma severity.

Study Overview

• Status: Terminated
• Conditions: Asthma
• Intervention / Treatment: Drug: Prednisolone; Procedure: Bronchoscopy

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Leicestershire
    • Leicester, Leicestershire, United Kingdom, LE3 9QP
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• History of asthma with exclusion of other significant pulmonary disease.
• Body Mass Index between 19-31 kg.m-2.
• Subjects will be assigned to group 1(mild to moderate) or Group 2 (severe asthmatics) depending on their Lung Function test results.

Exclusion criteria:

• As a result of medical interview, physical examination or screening investigation the physician responsible considers the subject unfit for the study.
• History of drug or other allergy, which, in the opinion of the responsible physician, contra-indicates their participation.
• Subject is female who is pregnant or lactating.
• Currently or planning to take during the study regular medication (including over-the-counter) except for medication allowed in inclusion criteria.
• Having participated within 30 days or 5 half-lives, whichever is longer of the first dose in a study using new molecular entity, or the first dose in any other study investigating drugs or having participated within one month of the first dose in a study with invasive procedures.
• History or current evidence of an upper or lower respiratory infection or symptoms (including common cold) within 2 weeks of baseline assessments.
• History of abnormal bruising or bleeding.
• History of alcohol or drug abuse.
• Doing night-shift work within at least 5 days prior to dosing until completion of the study.
• Anticoagulants except low dose of Aspirin (80 mg per day) (for bronchoscopy).
• Beta blockers except for low dose Atenolol (25 mg/day) or Metoprolol (50 mg/day) (for bronchoscopy).
• Use of Cytochrome P450 inhibitors.
• History of hypersensitivity to any of the following medications: Lidocaine, Fentanyl, Versed, Demerol, Midazolam, Epinephrine, Flumazenil and Naloxone.
• History of hypersensitivity to bronchodilator (such as Albuterol).

In addition, the following additional exclusion criteria must apply to mild to moderate persistent asthmatics on regular inhaled steroids:

• Changed asthma medication within the 4 weeks prior to screening.
• Has had an asthma exacerbation in the previous month.
• Known sensitivity or allergy to prednisolone.
• Current use or use within the previous 3 months of oral corticosteroids.
• Current use of Methotrexate, cyclosporine and PDE inhibitors
• History of tuberculosis, diabetes mellitus, osteoporosis, severe hypertension, glaucoma , severe affective disorder and peptic ulceration.

In addition, the following additional exclusion criteria must apply to severe persistent asthmatics with clinical controlled asthma symptoms:

• Changed asthma medication within the 4 weeks prior to screening.
• Has had an asthma exacerbation in the previous month.
• sensitivity or allergy to prednisolone.
• History of tuberculosis, diabetes mellitus, osteoporosis, hypertension, glaucoma, severe affective disorder and peptic ulceration.
• Current use or use within the previous 4 weeks of oral prednisolone or equivalent of greater than 20mg daily.
• Current use of Methotrexate, cyclosporin.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intermittent mild steroid-naïve asthmatic group; Asymptomatic subjects receiving only beta-agonist inhaler with predicted FEV1 >=80% and normal peak expiratory flow between attacks will be included.	Drug: Prednisolone; Subjects will be administered oral prednisolone at a dose of 0.5 mg/kg, up to a maximum of 40 mg per day for 14 days.; Procedure: Bronchoscopy; All subjects will undergo bronchoscopy assessments which will involve insertion of a standard bronchoscope.
Experimental: Mild to moderate persistent asthmatic group; Subjects with mild to moderate persistent asthma on low to moderate dose of inhaled corticosteroid (200-500 microgram fluticasone propionate daily or equivalent), an FEV1 >= 80% predicted (post-bronchodilator), and less than 20% variability in peak expiratory flow.	Drug: Prednisolone; Subjects will be administered oral prednisolone at a dose of 0.5 mg/kg, up to a maximum of 40 mg per day for 14 days.; Procedure: Bronchoscopy; All subjects will undergo bronchoscopy assessments which will involve insertion of a standard bronchoscope.
Experimental: Severe asthma group; Subjects with severe persistent asthma. They will be on either: high inhaled corticosteroid (CS >=1000 microgram fluticasone daily or equivalent) or on high dose inhaled CS plus oral CS (no more than 20 milligrams predisolone a day). The subjects should have at least one ( if on oral steroids) or two (if only on inhaled steroids) of the following: 1) FEV1<80% and FEV1/FVC ratio <70% 2) more than 25% variability in peak expiratory flow 3) daily symptoms ± nocturnal symptoms 4) severe exacerbations of >= twice a year in at least one of the last two years.	Drug: Prednisolone; Subjects will be administered oral prednisolone at a dose of 0.5 mg/kg, up to a maximum of 40 mg per day for 14 days.; Procedure: Bronchoscopy; All subjects will undergo bronchoscopy assessments which will involve insertion of a standard bronchoscope.
Placebo Comparator: Healthy subjects group; Non-asthmatic and non-smokers with FEV1 > 85% predicted, on no regular medication.	Procedure: Bronchoscopy; All subjects will undergo bronchoscopy assessments which will involve insertion of a standard bronchoscope.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Airway pathology endpoints Target Validation endpoints Biomarker endpoints Clinical endpoints	biomarkers, vital signs, ECG	Through 2 weeks of Prednisolone dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Expression of airway and systemic biomarkers. Relationship between changes in target expression and clinical measures of disease activity. Relationship between steady state plasma exposure of prednisolone and pharmacodynamic biomarkers.	biomarkers	Through 2 weeks of prednisolone dosing.

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Siddiqui S, Shikotra A, Richardson M, Doran E, Choy D, Bell A, Austin CD, Eastham-Anderson J, Hargadon B, Arron JR, Wardlaw A, Brightling CE, Heaney LG, Bradding P. Airway pathological heterogeneity in asthma: Visualization of disease microclusters using topological data analysis. J Allergy Clin Immunol. 2018 Nov;142(5):1457-1468. doi: 10.1016/j.jaci.2017.12.982. Epub 2018 Mar 14.

Study record dates

Study Major Dates

• Study Start (Actual): August 2, 2005
• Primary Completion (Actual): June 6, 2011
• Study Completion (Actual): June 6, 2011

Study Registration Dates

• First Submitted: May 17, 2006
• First Submitted That Met QC Criteria: May 17, 2006
• First Posted (Estimate): May 18, 2006

Study Record Updates

• Last Update Posted (Actual): August 4, 2017
• Last Update Submitted That Met QC Criteria: August 2, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Asthma; biomarkers; bronchoscopy; Prednisolone; Sputum induction
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Prednisolone
• Other Study ID Numbers: RES100769