Enhancement of in-Vitro GC Function in Patients With COPD

NCT ID: NCT00241631

Last Updated: 2019-12-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 49 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-04-30
• Study Completion Date: 2007-08-31

Brief Summary

The investigator wish therefore to continue these studies on theophylline principally by conducting a small clinical pilot study on 20-30 COPD patients in a randomised, double-blind, placebo-controlled, parallel-group study.

Detailed Description

The global burden of COPD - a common and debilitating chronic inflammatory disease that is characterised by the progressive development of airflow limitation (shortness of breath - SOB) and is poorly reversible with currently available drugs -is increasing. Cigarette smoking is strongly linked with the ongoing inflammation; inflammation that can continue even when the patient has stopped smoking. The severity of airflow limitation (SOB) is correlated with the degree of pulmonary (lung) inflammation.

Histone deacetylases (HDACs)are important molecules in suppressing this pulmonary inflammation. We have recently shown that patients with COPD have a reduction in total HDAC which correlates with the severity of their lung disease.

Corticosteroids (anti-inflammatory treatment) act, at least in part, by recruitment of these HDACs to the site of active inflammatory gene transcription (which reduces the production of inflammatory molecules) and are widely used in COPD in patients with severe disease. Unfortunately, in COPD, inhaled corticosteroids seem to have little effect on the underlying inflammation (though in a selective group of patients with COPD they do reduce the number of infections a patient may have by a small amount).

Theophylline has been used in the treatment of asthma and COPD for over 70 years, but its use has recently declined. Data so far obtained in primary cells (cells from patients used in the laboratory) from COPD patients suggests that low dose theophylline (~5mg/l) should be effective in restoring steroid sensitivity in patients with COPD (and hence reduce inflammation thus improving SOB).

Conditions

COPD

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Placebo

Inhaled Theophylline placebo capsule, then placebo, then active Theophylline

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

Theophylline

Intervention Type: DRUG

Theophylline placebo capcule

Steroid

Inhaled Theophylline placebo capsule, then Fluticasone Propionate 500 ug bid, then active Theophylline

Group Type: ACTIVE_COMPARATOR

Fluticasone Propionate

Intervention Type: DRUG

500 u

Theophylline

Intervention Type: DRUG

Theophylline placebo capcule

Interventions

Fluticasone Propionate

500 u

Intervention Type: DRUG

placebo

Intervention Type: DRUG

Theophylline

Theophylline placebo capcule

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

Patients with an FEV1 < 30% tend to have more severe symptom limitation and generally (though not always) find participation in a clinical trial involving 4 visits to the clinic difficult. Their airway disease is also generally less responsive to therapeutic intervention and as a consequence finding measurements which show changes to these therapeutic interventions is more difficult.

COPD patients

• All participants will be classified to Stage 2-3 of the GOLD (Global initiative for Obstructive Lung Disease) guidelines
• Male or female, aged 45-80 years (according to GOLD guidelines)
• 30% < FEV1 < 80% predicted
• FEV1/FVC < 70%
• Cigarette exposure of >10 pack-years#
• With or without chronic symptoms (cough, sputum production, dyspnea).
• Steroid therapy will be stopped before run-in, but long acting bronchodilators are acceptable.
• The participants are able to give informed consent # The smoking history should include both the number smoked, for how long, and an estimate of total pack-years of smoking. One pack of 20 cigarettes smoked per day for 1 year = one pack year. Total pack years = No. cigarettes smoked per day/20 x no. years of smoking

Exclusion Criteria

Any history or evidence of asthma

• Pregnancy, breast-feeding or planned pregnancy during the study. Fertile women not using acceptable contraceptive measures, as judged by the investigator
• Hospital admission with respiratory infection within the last 6 months
• Upper respiratory infection within the last 4 weeks
• Participants who have received research medication within the previous one month
• Participants unable to give informed consent
• Any mental condition rendering the participant unable to understand the nature, scope and possible consequences of the study
• Known or suspected hypersensitivity to study therapy or excipients
• Participants with significant or unstable ischemic heart disease, arrhythmia, cardiomyopathy, heart failure, uncontrolled hypertension as defined by the investigator, or any other relevant cardiovascular disorder as judged by the investigator
• Any current respiratory tract disorders other than COPD, which is considered by the investigator to be clinically significant
• Any significant disease or disorder (e.g. gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, major physical impairment) or abnormality laboratory tests which, in the opinion of the investigator, may either put the participant at risk because of inclusion in the study, or may influence the results of the study, or the participants ability to take part in the study

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Mitsubishi Tanabe Pharma Corporation

INDUSTRY

Sponsor Role: collaborator

Medical Research Council

OTHER_GOV

Sponsor Role: collaborator

Imperial College London

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

ian adcock, PhD

Role: PRINCIPAL_INVESTIGATOR

Imperial College London

Locations

Windsor chest clinic KEVII Hospital

Windsor, Berks, United Kingdom

Countries

United Kingdom

References

Ito K, Ito M, Elliott WM, Cosio B, Caramori G, Kon OM, Barczyk A, Hayashi S, Adcock IM, Hogg JC, Barnes PJ. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med. 2005 May 12;352(19):1967-76. doi: 10.1056/NEJMoa041892.

Reference Type: BACKGROUND

PMID: 15888697 (View on PubMed)

Ford PA, Durham AL, Russell RE, Gordon F, Adcock IM, Barnes PJ. Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD. Chest. 2010 Jun;137(6):1338-44. doi: 10.1378/chest.09-2363. Epub 2010 Mar 18.

Reference Type: RESULT

PMID: 20299628 (View on PubMed)

Kirkham PA, Whiteman M, Winyard PG, Caramori G, Gordon F, Ford PA, Barnes PJ, Adcock IM, Chung KF. Impact of theophylline/corticosteroid combination therapy on sputum hydrogen sulfide levels in patients with COPD. Eur Respir J. 2014 May;43(5):1504-6. doi: 10.1183/09031936.00131513. Epub 2014 Feb 13. No abstract available.

Reference Type: DERIVED

PMID: 24525446 (View on PubMed)

Other Identifiers

mitHDAC#1

Identifier Type: -

Identifier Source: org_study_id