Enhancement of in-Vitro GC Function in Patients With COPD

• Sponsor: Imperial College London (Other)
• Overall Status: Completed
• CT.gov ID: NCT00241631
• Collaborator: Mitsubishi Tanabe Pharma Corporation (Industry), Medical Research Council (Other)
• Enrollment: 49
• Location: 1
• Arms: 2
• Actual Duration (Months): 16
• Patients Per Site Per Month: 3.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
COPD	Drug: Fluticasone Propionate; Drug: placebo; Drug: Theophylline	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 49 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Apr 1, 2006
• Actual Primary Completion Date: Aug 1, 2007
• Actual Study Completion Date: Aug 1, 2007

Arms and Interventions

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: Fluticasone Propionate; 500 u; Drug: Theophylline; Theophylline placebo capcule

Outcome Measures

Primary Outcome Measures

1. Sputum Inflammatory Cell Counts [10 weeks]

   Supernatant collect, cell pellets count on slides

Secondary Outcome Measures

1. Interleukin 8 (IL8) [10 weeks]

   Interleukin 8 (IL8) assessed from sputum

2. Total Sputum Eosinophils [10 weeks]

   Total eosinophils cells assessed from sputum

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Windsor chest clinic KEVII Hospital	Windsor	Berks	United Kingdom	SL4 3DP

Sponsors and Collaborators

• Imperial College London
• Mitsubishi Tanabe Pharma Corporation
• Medical Research Council

Investigators

• Principal Investigator: ian adcock, PhD, Imperial College London

Study Documents (Full-Text)

None provided.

More Information

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.

• Responsible Party: Imperial College London
• ClinicalTrials.gov Identifier: NCT00241631
• Other Study ID Numbers: mitHDAC#1
• First Posted: Oct 19, 2005
• Last Update Posted: Dec 4, 2019
• Last Verified: Nov 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Imperial College London: COPD
• Additional relevant MeSH terms: Pulmonary Disease, Chronic Obstructive; Fluticasone; Xhance; Theophylline

Study Results

Participant Flow

Arm/Group Title	Placebo	Steroid
Arm/Group Description	Inhaled Theophylline placebo capsule, then inhaled placebo, then active Theophylline	Inhaled Theophylline placebo capsule, then Fluticasone Propionate 500 ug bid, then active Theophylline
Period Title: Run in (2 Weeks)
STARTED	25	24
COMPLETED	22	21
NOT COMPLETED	3	3
Period Title: Run in (2 Weeks)
STARTED	22	21
COMPLETED	14	16
NOT COMPLETED	8	5
Period Title: Run in (2 Weeks)
STARTED	14	16
COMPLETED	14	16
NOT COMPLETED	0	0
Period Title: Run in (2 Weeks)
STARTED	14	16
COMPLETED	14	16
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Placebo	Steroid	Total
Arm/Group Description	Inhaled Theophylline placebo capsule, then inhaled placebo, then active Theophylline	Inhaled Theophylline placebo capsule, then Fluticasone Propionate 500 ug bid, then active Theophylline	Total of all reporting groups
Overall Participants	14	16	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61 (2.2)	69 (1.9)	65 (2)
Sex: Female, Male (Count of Participants)
Female	3 21.4%	2 12.5%	5 16.7%
Male	11 78.6%	14 87.5%	25 83.3%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United Kingdom	14 100%	16 100%	30 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Using marginal means as results

Arm/Group Title	Placebo	Steroid
Arm/Group Description	Inhaled Theophylline placebo capsule, then inhaled placebo, then active Theophylline	Inhaled Theophylline placebo capsule, then Fluticasone Propionate 500 ug bid, then active Theophylline
Measure Participants	14	16
Mean (95% Confidence Interval) [millions cells/ ml]	5.42	3.89

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Steroid
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Mixed Models Analysis
	Comments

2. Secondary Outcome

Title	Interleukin 8 (IL8)
Description	Interleukin 8 (IL8) assessed from sputum
Time Frame	10 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Steroid
Arm/Group Description	Inhaled Theophylline placebo capsule, then inhaled placebo, then active Theophylline	Inhaled Theophylline placebo capsule, then Fluticasone Propionate 500 ug bid, then active Theophylline
Measure Participants	14	16
Mean (95% Confidence Interval) [ng/mL]	33.3	28.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Steroid
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	calculated
	Method	Mixed Models Analysis
	Comments

3. Secondary Outcome

Title	Total Sputum Eosinophils
Description	Total eosinophils cells assessed from sputum
Time Frame	10 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Steroid
Arm/Group Description	Inhaled Theophylline placebo capsule, then inhaled placebo, then active Theophylline	Inhaled Theophylline placebo capsule, then Fluticasone Propionate 500 ug bid, then active Theophylline
Measure Participants	14	16
Mean (95% Confidence Interval) [millions cells/ml]	0.132	0.053

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Steroid
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	calculated
	Method	Mixed Models Analysis
	Comments

Adverse Events

Time Frame	10 weeks
Arm/Group Title	Placebo		Steroid
Arm/Group Description	Inhaled Theophylline placebo capsule, then inhaled placebo, then active Theophylline		Inhaled Theophylline placebo capsule, then Fluticasone Propionate 500 ug bid, then active Theophylline
All Cause Mortality
	Placebo		Steroid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/16 (0%)
Serious Adverse Events
	Placebo		Steroid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Steroid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		4/16 (25%)
Gastrointestinal disorders
Nausea	0/14 (0%)	0	4/16 (25%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.