Theophylline in Rhinitis
Primary Purpose
Rhinosinusitis, Asthma, Allergic Rhinitis
Status
Completed
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Theophylline (Intervention Group)
Placebo (Placebo Group)
Sponsored by
About this trial
This is an interventional treatment trial for Rhinosinusitis focused on measuring rhinosinusitis, asthma, allergic rhinitis, theophylline
Eligibility Criteria
Inclusion Criteria:
- Males or females, aged between 16 and 65 years.
- Weight between 50 and 150 Kg.
- Smokers, non-smokers or ex-smoker.
- Chronic rhinosinusitis as defined as 2 or more symptoms of nasal blockage/congestion, discharge, facial pain or reduction in smell for more than 12 weeks.
- A positive skin prick test or RAST to a perennial allergen
- Patients with a seasonal component to their symptoms can be enrolled out with the relevant pollen season.
- Patients must be receiving intranasal corticosteroids
- Patients will be permitted to receive inhaled short and long acting beta2 agonists or anti-cholinergic drugs, inhaled corticosteroids (up to a dose of 2mg per day BPD equivalent), oral montelukast or oral antihistamines.
- Able to provide written informed consent.
Exclusion Criteria:
- Significant medical, surgical or psychiatric disease that would affect the results of the study in the opinion of the investigator.
- Women who are pregnant or breast feeding
- Patients with previous cardiac problems or significant renal or hepatic impairment
- Upper respiratory tract infection in the last month as defined by yellow or green nasal discharge and increase in the usual nasal symptoms.
- Patients consuming more than the recommended amount of alcohol (14 units per week for women and 21 units per week for men) Inhaled corticosteroids at a dose greater than 2mg beclomethasone dipropionate (BDP) equivalent or oral corticosteroids or oral zafirlukast
- Currently receiving oral theophyllines.
- Previous adverse effects to oral or intravenous theophylline.
Currently any medication known to interact with theophylline including
- Allopurinol
- Macrolide, quinolone or isoniazid
- Fluvoxamine
- Carbamazepine, phenytoin
- Fluconazole or itraconazole
- Barbiturates
- Lithium
- Oestrogens
- Cimetidine
Sites / Locations
- University of East Anglia
Arms of the Study
Arm 1
Arm 2
Arm Type
Placebo Comparator
Active Comparator
Arm Label
Placebo
200mg theophylline
Arm Description
200mg twice daily of placebo drug
200mg twice daily of slow release theophylline
Outcomes
Primary Outcome Measures
Difference in total nasal symptom score
The primary endpoint will be the difference in total nasal symptom score between active and placebo treatment periods measured at the clinic
Secondary Outcome Measures
The difference in domiciliary average total nasal symptom score
The difference in nasal peak inspiratory flow at clinic visit
Nasal inspiratory flow will be measured using an In-check™ flow meter (Clement Clarke International Ltd, Harlow, UK). After blowing their nose, patients will inspire forcefully from residual volume to total lung capacity with their mouth closed. All measurements will be made while in the sitting position with a good seal around a purpose built facemask. The median of 3 readings will be recorded. For the purposes of the diary card data, these measurements will be recorded at 2200hrs. The average of the last 5 days measurements will be used in the analysis.
The difference in domiciliary nasal peak inspiratory flow
Nasal inspiratory flow will be measured using an In-check™ flow meter (Clement Clarke International Ltd, Harlow, UK). After blowing their nose, patients will inspire forcefully from residual volume to total lung capacity with their mouth closed. All measurements will be made while in the sitting position with a good seal around a purpose built facemask. The median of 3 readings will be recorded. For the purposes of the diary card data, these measurements will be recorded at 2200hrs. The average of the last 5 days measurements will be used in the analysis.
The difference in Sino-Nasal Outcomes Test (SNOT) -22 questionnaire
The Sino-Nasal Outcomes Test (SNOT) is a validated disease-specific health-related quality of life instrument. It comprises 22 questions and takes less than 5 minute to complete. It is self administered questionnaire. It will be completed at each study visit.
Secondary Analysis
A secondary analysis will be undertaken to determine whether there is a difference in primary and secondary endpoints (above) between treatment with theophylline and placebo in patients who smoke versus those who do not smoke.
Serum theophylline concentration at the end of both placebo or active treatment periods.
Serum urea and electrolyte concentration at the both placebo or active treatment periods
Drug related adverse effects
The difference histone deacetylase activity from epithelial cells obtained from nasal scrapings.
Nasal scrapings will be taken from the right nostril using a Rhino-probe Nasal Mucosal Curette (Arlington Scientific Inc, Springville, Utah, USA). Two scrapes will be taken under direct vision according to manufacturer's guidelines. These will be taken at visits 3 and 5.
Full Information
NCT ID
NCT01132781
First Posted
May 26, 2010
Last Updated
August 22, 2012
Sponsor
University of East Anglia
Collaborators
Clinical Research and Trials Unit (Norfolk & Norwich University Hospital, UK)
1. Study Identification
Unique Protocol Identification Number
NCT01132781
Brief Title
Theophylline in Rhinitis
Official Title
The Effect of Theophylline in Patients With Allergic Rhinitis
Study Type
Interventional
2. Study Status
Record Verification Date
August 2012
Overall Recruitment Status
Completed
Study Start Date
May 2010 (undefined)
Primary Completion Date
June 2012 (Actual)
Study Completion Date
June 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of East Anglia
Collaborators
Clinical Research and Trials Unit (Norfolk & Norwich University Hospital, UK)
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Allergic rhinitis and asthma are common respiratory diseases, which often coexist. The prevalence of allergic rhinitis in subjects with asthma is up to 80%, and the prevalence of asthma is 3-5 times greater in subjects with rhinitis than healthy controls. The mechanisms of the allergen response in both diseases are parallel to each other, with similar mediator and cellular responses to similar allergens. These observations have led to the suggestion that both diseases are different expressions of one airway disease.We wish to evaluate the effect of low dose theophylline in patients with asthma, given its effects as subtherapeutic concentrations and the propensity to develop adverse events at higher doses.
Detailed Description
The disease modifying treatments for asthma and rhinitis mirror each other. The first line therapy being the topical corticosteroids, for which there is good evidence of superiority over other therapies. They work by altering the transcription of genes involved in the inflammatory process, thereby favourably influencing the synthesis of inflammatory proteins and cytokines. They have been shown to reduce the numbers of inflammatory cells and their inflammatory action. Other disease modifying therapies such as anti-IgE antibodies improve allergic symptoms in both asthma and rhinitis. Theophylline has been used for many years as a treatment for asthma but has not been used to help patients with rhinitis.
Theophylline has been considered a weak bronchodilator for many years. However relatively recently, it was shown to have anti-inflammatory effects in patients with asthma. It reduces eosinophil counts and eosinophilic cationic protein (ECP) concentration in induced sputum of asthmatic patients. The combination of low dose theophylline has greater effects on lung function and asthma severity than high dose inhaled corticosteroids.
Aubier el al have shown, using a nasal allergen challenge model of rhinitis, that 3 weeks treatment with slow release oral theophylline reduced the increase in the concentration of eosinophilic cationic protein (ECP) and the percentage of eosinophils in nasal lavage following the challenge. Furthermore there was a significant reduction in nasal symptoms in those patients treated with theophylline. However theophylline has not previously been evaluated as a therapeutic option in patients with chronic rhinitis in the clinic setting.
Cigarette smoking is a major cause of morbidity in patients with asthma and has been shown to be independently associated with impaired quality of life in asthmatic children. Recent evidence suggests that patients with asthma who smoke are relatively resistant to inhaled or oral corticosteroid therapy, with larger doses being required for clinical benefit. The actual mechanism for this observation is unknown however one hypothesis is that smoking has an effect on histone deacetylase. It is known that theophylline can active histone deacetylase and therefore improve the efficacy of corticosteroids.
Theophylline causes significant adverse effects at high doses. Unfortunately the bronchodilator effect occurs at doses very close to those causing adverse effects. This low therapeutic index for bronchodilation means that therapeutic monitoring is required. However the anti-inflammatory effect of theophylline and the effect of theophylline on histone deacetylase activity occurs at concentrations lower therapeutic level for bronchodilation.
Why have we chosen a dose of 200mg twice daily? In the study by Evans et al which compared low dose inhaled budesonide plus theophylline to high dose inhaled budesonide, greater effects with the theophylline combination were seen in terms of pulmonary function and hyperresponsiveness at serum concentrations of theophylline that were sub therapeutic (8.7mg/ml). Anti-inflammatory effects are seen in patients with chronic obstructive pulmonary disease at theophylline concentrations that are subtherapeutic. There have been studies in patients with asthma that have shown anti-inflammatory effects at in patients with asthma at doses of 250mg twice daily and 200mg twice daily. We wish therefore to evaluate the effect of low dose theophylline in patients with asthma, given its effects as subtherapeutic concentrations and the propensity to develop adverse events at higher doses.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rhinosinusitis, Asthma, Allergic Rhinitis
Keywords
rhinosinusitis, asthma, allergic rhinitis, theophylline
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
Participant
Allocation
Randomized
Enrollment
28 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
200mg twice daily of placebo drug
Arm Title
200mg theophylline
Arm Type
Active Comparator
Arm Description
200mg twice daily of slow release theophylline
Intervention Type
Drug
Intervention Name(s)
Theophylline (Intervention Group)
Intervention Description
200 mg twice daily of slow release theophylline
Intervention Type
Drug
Intervention Name(s)
Placebo (Placebo Group)
Intervention Description
200 mg twice daily of placebo drug
Primary Outcome Measure Information:
Title
Difference in total nasal symptom score
Description
The primary endpoint will be the difference in total nasal symptom score between active and placebo treatment periods measured at the clinic
Time Frame
18 weeks
Secondary Outcome Measure Information:
Title
The difference in domiciliary average total nasal symptom score
Time Frame
18 weeks
Title
The difference in nasal peak inspiratory flow at clinic visit
Description
Nasal inspiratory flow will be measured using an In-check™ flow meter (Clement Clarke International Ltd, Harlow, UK). After blowing their nose, patients will inspire forcefully from residual volume to total lung capacity with their mouth closed. All measurements will be made while in the sitting position with a good seal around a purpose built facemask. The median of 3 readings will be recorded. For the purposes of the diary card data, these measurements will be recorded at 2200hrs. The average of the last 5 days measurements will be used in the analysis.
Time Frame
18 weeks
Title
The difference in domiciliary nasal peak inspiratory flow
Description
Nasal inspiratory flow will be measured using an In-check™ flow meter (Clement Clarke International Ltd, Harlow, UK). After blowing their nose, patients will inspire forcefully from residual volume to total lung capacity with their mouth closed. All measurements will be made while in the sitting position with a good seal around a purpose built facemask. The median of 3 readings will be recorded. For the purposes of the diary card data, these measurements will be recorded at 2200hrs. The average of the last 5 days measurements will be used in the analysis.
Time Frame
18 weeks
Title
The difference in Sino-Nasal Outcomes Test (SNOT) -22 questionnaire
Description
The Sino-Nasal Outcomes Test (SNOT) is a validated disease-specific health-related quality of life instrument. It comprises 22 questions and takes less than 5 minute to complete. It is self administered questionnaire. It will be completed at each study visit.
Time Frame
18 weeks
Title
Secondary Analysis
Description
A secondary analysis will be undertaken to determine whether there is a difference in primary and secondary endpoints (above) between treatment with theophylline and placebo in patients who smoke versus those who do not smoke.
Time Frame
18 weeks
Title
Serum theophylline concentration at the end of both placebo or active treatment periods.
Time Frame
18 weeks
Title
Serum urea and electrolyte concentration at the both placebo or active treatment periods
Time Frame
18 weeks
Title
Drug related adverse effects
Time Frame
18 weeks
Title
The difference histone deacetylase activity from epithelial cells obtained from nasal scrapings.
Description
Nasal scrapings will be taken from the right nostril using a Rhino-probe Nasal Mucosal Curette (Arlington Scientific Inc, Springville, Utah, USA). Two scrapes will be taken under direct vision according to manufacturer's guidelines. These will be taken at visits 3 and 5.
Time Frame
18 weeks
10. Eligibility
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Males or females, aged between 16 and 65 years.
Weight between 50 and 150 Kg.
Smokers, non-smokers or ex-smoker.
Chronic rhinosinusitis as defined as 2 or more symptoms of nasal blockage/congestion, discharge, facial pain or reduction in smell for more than 12 weeks.
A positive skin prick test or RAST to a perennial allergen
Patients with a seasonal component to their symptoms can be enrolled out with the relevant pollen season.
Patients must be receiving intranasal corticosteroids
Patients will be permitted to receive inhaled short and long acting beta2 agonists or anti-cholinergic drugs, inhaled corticosteroids (up to a dose of 2mg per day BPD equivalent), oral montelukast or oral antihistamines.
Able to provide written informed consent.
Exclusion Criteria:
Significant medical, surgical or psychiatric disease that would affect the results of the study in the opinion of the investigator.
Women who are pregnant or breast feeding
Patients with previous cardiac problems or significant renal or hepatic impairment
Upper respiratory tract infection in the last month as defined by yellow or green nasal discharge and increase in the usual nasal symptoms.
Patients consuming more than the recommended amount of alcohol (14 units per week for women and 21 units per week for men) Inhaled corticosteroids at a dose greater than 2mg beclomethasone dipropionate (BDP) equivalent or oral corticosteroids or oral zafirlukast
Currently receiving oral theophyllines.
Previous adverse effects to oral or intravenous theophylline.
Currently any medication known to interact with theophylline including
Allopurinol
Macrolide, quinolone or isoniazid
Fluvoxamine
Carbamazepine, phenytoin
Fluconazole or itraconazole
Barbiturates
Lithium
Oestrogens
Cimetidine
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrew M Wilson
Organizational Affiliation
University of East Anglia
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of East Anglia
City
Norwich
State/Province
Norfolk
ZIP/Postal Code
NR47TJ
Country
United Kingdom
12. IPD Sharing Statement
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Theophylline in Rhinitis
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