Theophylline in Rhinitis

This study has been completed.
Sponsor:
Collaborator:
Clinical Research and Trials Unit (Norfolk & Norwich University Hospital, UK)
Information provided by (Responsible Party):
University of East Anglia
ClinicalTrials.gov Identifier:
NCT01132781
First received: May 26, 2010
Last updated: August 22, 2012
Last verified: August 2012
  Purpose

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.


Condition Intervention Phase
Rhinosinusitis
Asthma
Allergic Rhinitis
Drug: Theophylline (Intervention Group)
Drug: Placebo (Placebo Group)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Official Title: The Effect of Theophylline in Patients With Allergic Rhinitis

Resource links provided by NLM:


Further study details as provided by University of East Anglia:

Primary Outcome Measures:
  • Difference in total nasal symptom score [ Time Frame: 18 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 18 weeks ] [ Designated as safety issue: No ]
  • The difference in nasal peak inspiratory flow at clinic visit [ Time Frame: 18 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 18 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 18 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 18 weeks ] [ Designated as safety issue: No ]
    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. [ Time Frame: 18 weeks ] [ Designated as safety issue: Yes ]
  • Serum urea and electrolyte concentration at the both placebo or active treatment periods [ Time Frame: 18 weeks ] [ Designated as safety issue: Yes ]
  • Drug related adverse effects [ Time Frame: 18 weeks ] [ Designated as safety issue: Yes ]
  • The difference histone deacetylase activity from epithelial cells obtained from nasal scrapings. [ Time Frame: 18 weeks ] [ Designated as safety issue: No ]
    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.


Enrollment: 28
Study Start Date: May 2010
Study Completion Date: June 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
200mg twice daily of placebo drug
Drug: Placebo (Placebo Group)
200 mg twice daily of placebo drug
Active Comparator: 200mg theophylline
200mg twice daily of slow release theophylline
Drug: Theophylline (Intervention Group)
200 mg twice daily of slow release theophylline

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.

  Eligibility

Ages Eligible for Study:   16 Years to 65 Years
Accepts Healthy Volunteers:   No
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
  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: NCT01132781

Locations
United Kingdom
University of East Anglia
Norwich, Norfolk, United Kingdom, NR47TJ
Sponsors and Collaborators
University of East Anglia
Clinical Research and Trials Unit (Norfolk & Norwich University Hospital, UK)
Investigators
Principal Investigator: Andrew M Wilson University of East Anglia
  More Information

No publications provided

Responsible Party: University of East Anglia
ClinicalTrials.gov Identifier: NCT01132781     History of Changes
Other Study ID Numbers: 2007ENT03, 2007-004642-32
Study First Received: May 26, 2010
Last Updated: August 22, 2012
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: National Health Service

Keywords provided by University of East Anglia:
rhinosinusitis
asthma
allergic rhinitis
theophylline

Additional relevant MeSH terms:
Rhinitis
Rhinitis, Allergic, Perennial
Nose Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Otorhinolaryngologic Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Theophylline
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Asthmatic Agents
Respiratory System Agents
Therapeutic Uses
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Cardiovascular Agents
Purinergic P1 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents

ClinicalTrials.gov processed this record on September 22, 2014