Theophylline in Rhinitis

Asthma Clinical Trial

Official title:

The Effect of Theophylline in Patients With Allergic Rhinitis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01132781
• Other study ID #: 2007ENT03
• Secondary ID: 2007-004642-32
• Status: Completed
• Phase: Phase 2
• First received: May 26, 2010
• Last updated: August 22, 2012
• Start date: May 2010
• Est. completion date: June 2012

Study information

• Verified date: August 2012
• Source: University of East Anglia
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited Kingdom: National Health Service
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: June 2012
• Est. primary completion date: June 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years to 65 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Allergic Rhinitis
• Asthma
• Rhinitis
• Rhinosinusitis

Intervention

Drug:
• Theophylline (Intervention Group)
200 mg twice daily of slow release theophylline
• Placebo (Placebo Group)
200 mg twice daily of placebo drug

Locations

Country	Name	City	State
United Kingdom	University of East Anglia	Norwich	Norfolk

Sponsors (2)

Lead Sponsor	Collaborator
University of East Anglia	Clinical Research and Trials Unit (Norfolk & Norwich University Hospital, UK)

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	18 weeks	No
Secondary	The difference in domiciliary average total nasal symptom score		18 weeks	No
Secondary	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.	18 weeks	No
Secondary	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.	18 weeks	No
Secondary	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.	18 weeks	No
Secondary	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.	18 weeks	No
Secondary	Serum theophylline concentration at the end of both placebo or active treatment periods.		18 weeks	Yes
Secondary	Serum urea and electrolyte concentration at the both placebo or active treatment periods		18 weeks	Yes
Secondary	Drug related adverse effects		18 weeks	Yes
Secondary	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.	18 weeks	No