RhinosinusitisPhase 2NCT01132781
Theophylline in Rhinitis
A Phase 2 study testing Theophylline (Intervention Group) in people with Rhinosinusitis and Asthma, run by University of East Anglia at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 16 to 65 years
- Conditions the study is for
- Rhinosinusitis, Asthma, Allergic Rhinitis
- What is being tested?
- Theophylline (Intervention Group)
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 28 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- May 2010to Jun 2012
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 to 65 years
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
University of East Anglia
Norwich, Norfolk, NR47TJ
About this study
Official title: The Effect of Theophylline in Patients With Allergic Rhinitis
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.
Read the 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.
- Conditions
- Rhinosinusitis, Asthma, Allergic Rhinitis
- Being tested
- Theophylline (Intervention Group), Placebo (Placebo Group)
- Keywords
- rhinosinusitis, asthma, allergic rhinitis, theophylline
- Medical subject headings
- Rhinosinusitis, Asthma, Rhinitis, Allergic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Theophylline (Intervention Group)Drug
200 mg twice daily of slow release theophylline
Placebo (Placebo Group)Drug
200 mg twice daily of placebo drug
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | 200mg twice daily of placebo drug Receives: Drug: Placebo (Placebo Group) |
| 200mg theophylline | Active comparator | 200mg twice daily of slow release theophylline Receives: Drug: Theophylline (Intervention Group) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 18 weeks
Secondary outcomes (9)
The difference in domiciliary average total nasal symptom score
Measured: 18 weeks
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.
Measured: 18 weeks
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.
Measured: 18 weeks
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.
Measured: 18 weeks
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.
Measured: 18 weeks
Serum theophylline concentration at the end of both placebo or active treatment periods.
Measured: 18 weeks
Serum urea and electrolyte concentration at the both placebo or active treatment periods
Measured: 18 weeks
Drug related adverse effects
Measured: 18 weeks
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.
Measured: 18 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 May 2010 (estimated)
- Study startMay 2010
- Primary completionJun 2012
- Study completionJun 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for RhinosinusitisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 28 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of East Anglia
- Sponsor type
- University, hospital or other
- Collaborators
- Clinical Research and Trials Unit (Norfolk & Norwich University Hospital, UK)
- Responsible party
- Sponsor
- Investigators
- Andrew M Wilson, Principal investigator, University of East Anglia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01132781
- Sponsor's protocol ID
- 2007ENT03
- Other IDs
- 2007-004642-32
- Status last verified
- Aug 2012
- First submitted
- 26 May 2010
- Last updated
- 23 Aug 2012
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 23 Aug 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Theophylline in Patients With Allergic Rhinitis
- ClinicalTrials.gov ID
- NCT01132781
- Acronym / sponsor ID
- 2007ENT03
- Conditions
- Rhinosinusitis, Asthma, Allergic Rhinitis
- Keywords
- rhinosinusitis, asthma, allergic rhinitis, theophylline
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 28 participants (actual)
- Lead sponsor
- University of East AngliaUniversity, hospital or other
- Collaborators
- Clinical Research and Trials Unit (Norfolk & Norwich University Hospital, UK)
- Study start
- May 2010
- Primary completion
- Jun 2012 (actual)
- Study completion
- Jun 2012 (actual)
- First posted
- 28 May 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: Placebo (Placebo Group)200mg twice daily of placebo drug |
| 200mg theophylline | Active comparator | Drug: Theophylline (Intervention Group)200mg twice daily of slow release theophylline |
Who may qualify
- Ages
- 16 to 65 years
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (9 listed)
- 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
Key exclusion criteria (17 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Theophylline (Intervention Group)200 mg twice daily of slow release theophylline | Drug | 200mg theophylline |
| Placebo (Placebo Group)200 mg twice daily of placebo drug | Drug | Placebo |
Primary outcome
Difference in total nasal symptom score
Time frame: 18 weeks
The primary endpoint will be the difference in total nasal symptom score between active and placebo treatment periods measured at the clinic
9 secondary outcomes
The difference in domiciliary average total nasal symptom score
Time frame: 18 weeks
The difference in nasal peak inspiratory flow at clinic visit
Time frame: 18 weeks
The difference in domiciliary nasal peak inspiratory flow
Time frame: 18 weeks
The difference in Sino-Nasal Outcomes Test (SNOT) -22 questionnaire
Time frame: 18 weeks
Secondary Analysis
Time frame: 18 weeks
Serum theophylline concentration at the end of both placebo or active treatment periods.
Time frame: 18 weeks
Serum urea and electrolyte concentration at the both placebo or active treatment periods
Time frame: 18 weeks
Drug related adverse effects
Time frame: 18 weeks
The difference histone deacetylase activity from epithelial cells obtained from nasal scrapings.
Time frame: 18 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Aug 2012.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Andrew M Wilson principal investigator
University of East Anglia
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Theophylline (Intervention Group) in people with Rhinosinusitis and Asthma, run by University of East Anglia at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Aug 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Difference in total nasal symptom score (time frame: 18 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Aug 2012.