Enhancement of in-Vitro GC Function in Patients With COPD

Enhancement of In-vitro GC Function in Patients With COPD. A Randomised, Double Blind, Placebo Controlled, Parallel-group Study to Investigate the Effect of Theophylline and Fluticasone on Induced Sputum Cells Obtained Form COPD Patients

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.

Study Overview

• Status: Completed
• Conditions: COPD
• Intervention / Treatment: Drug: placebo; Drug: Theophylline; Drug: Fluticasone Propionate

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).

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Berks
    • Windsor, Berks, United Kingdom, SL4 3DP
      • Windsor chest clinic KEVII Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:Participants with COPD with an FEV1 of 80-30% predicted. This will incorporate the majority of participants with COPD seen within the chest clinic. Patients with an FEV1 > 80% predicted are not generally severe enough to warrant hospital follow up. These patients are also unlikely to have severe enough disease (and therefore airway inflammation) which may be modified by the therapeutic agents we are studying.

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Inhaled Theophylline placebo capsule, then placebo, then active Theophylline	Drug: placebo; Drug: Theophylline; Theophylline placebo capcule
Active Comparator: Steroid; Inhaled Theophylline placebo capsule, then Fluticasone Propionate 500 ug bid, then active Theophylline	Drug: Theophylline; Theophylline placebo capcule; Drug: Fluticasone Propionate; 500 u

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sputum Inflammatory Cell Counts	Supernatant collect, cell pellets count on slides	10 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Interleukin 8 (IL8)	Interleukin 8 (IL8) assessed from sputum	10 weeks
Total Sputum Eosinophils	Total eosinophils cells assessed from sputum	10 weeks

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: Medical Research Council; Mitsubishi Tanabe Pharma Corporation
• Investigators: Principal Investigator: ian adcock, PhD, Imperial College London

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2006
• Primary Completion (Actual): August 1, 2007
• Study Completion (Actual): August 1, 2007

Study Registration Dates

• First Submitted: October 18, 2005
• First Submitted That Met QC Criteria: October 18, 2005
• First Posted (Estimate): October 19, 2005

Study Record Updates

• Last Update Posted (Actual): December 4, 2019
• Last Update Submitted That Met QC Criteria: November 15, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: COPD
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Purinergic Antagonists; Purinergic Agents; Dermatologic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Anti-Allergic Agents; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Theophylline; Fluticasone; Xhance
• Other Study ID Numbers: mitHDAC#1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No