Clinical trial NCT00158847: Modification Of Disease Outcome In COPD
Official title: Modification of Disease Outcome in COPD. Shortterm Versus Longterm Treatment With Inhaled Corticosteroids, Either or Not Combined With a Long-Acting Beta2-Agonist.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Chronic Obstructive Pulmonary Disease
Keywords: COPD inflammation sputum lung function biopsy
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: Academisch Ziekenhuis Groningen
name: The Netherlands Asthma Foundation
name: Netherlands Organisation for Scientific Research
name: GlaxoSmithKline
First posted: 2005-09-12
Enrollment: 200
Sex: ALL
Minimum age (years): 45
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The hypothesis to be tested of this study is that treatment with fluticasone propionate leads to an initial improvement in symptoms, quality of life and lungfunction and a reduction in airways hyperresponsiveness. The continued decline of lungfunction in COPD may not be influenced by longer lasting treatment. Addition of salmeterol will augment the initial benefits of fluticasone without changing the longterm decline in lungfunction.

Detailed description: Aim The primary aim of this study was to investigate whether short-term treatment with inhaled corticosteroids in COPD results in greater improvements in airway pathology, thereby leading to larger clinical benefits, than continuous long-term treatment. To that end, the outcome variables included features of airways inflammation and remodelling as well as clinical symptoms, exacerbations, quality of life, decline in FEV1, bronchial responsiveness, and pharmaco-economics. The secondary aim of the study was to examine the histopathological and clinical benefits of the combined treatment with an inhaled steroid and a long-acting ß2-agonist in COPD.

Methods Patients. Patients with COPD (45-75 yr, \>10 pckyr) not using inhaled steroids for the past 3 months were recruited.

Design. In a prospective, longitudinal, double blind, 4-arm study, the patients were followed during 2.5 years (Figure 1). They were treated with high dose inhaled corticosteroids (500 g fluticasone bid), combined inhaled steroids+long-acting ß2-agonist (500 µg fluticasone+50 µg salmeterol) or placebo for 6 months. Half of the patients in the steroid group continued their treatment with steroids for another 2 years, whereas the other half received placebo. The combination therapy and placebo groups remained unaltered treatment up to 2.5 years.

Measurements. Symptoms, exacerbations, QOL questionnaires and spirometry were monitored every 3 months. Peripheral blood eosinophils, IgE, exhaled NO, bodyplethysmography, CO-diffusion capacity, PC20 methacholine, sputum induction and bronchoscopy were performed at 0, 6, and 30 months. In BAL and induced sputum we are measuring cell differentials and their state of activation. Immunohistochemistry is being performed in bronchial biopsy specimens, staining for markers on infiltrative and resident cells, and morphometric analysis will allow airway remodelling to be quantified, by using a computerized image analysis system. The effects of treatment will be analyzed by relating the observed changes in clinical and pathophysiological outcome, to those in cellular and histological outcome by using linear mixed statistical models.

Eligibility criteria: Inclusion criteria:

* COPD patients with \> 10 pack years.
* Written informed consent.
* Able to complete a diary card.
* At least one of the following symptoms: chronic cough, chronic sputum production, frequent exacerbations, or dyspnoea at exertion.
* Postbronchodilator FEV1 below 90% confidence interval of predicted and postbronchodilator FEV1/FVC below 90% confidence interval of predicted.

Exclusion criteria:

* No oral corticosteroids 3 months prior to the study or maintenance treatment with corticostroids 6 months prior to the study.
* No history of asthma, lung diseases other than COPD, other diseases likely to interfere with the study.

Primary outcomes:
measure: Inflammation: localisation, numbers and profile of neutrophils, eosinophils, macrophages, and CD8+T cells in bronchial biopsy specimens after 6 months and 2.5 years treatment.
Secondary outcomes:
measure: Clinical: symptoms, exacerbations, quality of life, lung function, 6 min walking test. Inflammation: markers in sputum and BAL, profile of epithelial cells, remodeling.
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
Study officials:
affiliation: Leiden University Medical Center
name: Peter J. Sterk, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lapperre TS, Snoeck-Stroband JB, Gosman MM, Stolk J, Sont JK, Jansen DF, Kerstjens HA, Postma DS, Sterk PJ; Groningen and Leiden Universities Corticosteroids in Obstructive Lung Disease Study Group. Dissociation of lung function and airway inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004 Sep 1;170(5):499-504. doi: 10.1164/rccm.200401-112OC. Epub 2004 Jun 1.
citation: Ditz B, Boekhoudt J, Couto N, Brandsma CA, Hiemstra PS, Tew GW, Neighbors M, Grimbaldeston MA, Timens W, Kerstjens HAM, Rossen JWA, Guryev V, van den Berge M, Faiz A. The Microbiome in Bronchial Biopsies from Smokers and Ex-Smokers with Stable COPD - A Metatranscriptomic Approach. COPD. 2022;19(1):81-87. doi: 10.1080/15412555.2022.2033193. Epub 2022 Feb 4.
citation: Faiz A, Imkamp K, van der Wiel E, Boudewijn IM, Koppelman GH, Brandsma CA, Kerstjens HAM, Timens W, Vroegop S, Pasma HR, Boersma WG, Wielders P, van den Elshout F, Mansour K, Steiling K, Spira A, Lenburg ME, Heijink IH, Postma DS, van den Berge M. Identifying a nasal gene expression signature associated with hyperinflation and treatment response in severe COPD. Sci Rep. 2020 Oct 15;10(1):17415. doi: 10.1038/s41598-020-72551-0.
citation: Kunz LI, van't Wout EF, van Schadewijk A, Postma DS, Kerstjens HA, Sterk PJ, Hiemstra PS. Regulation of YKL-40 expression by corticosteroids: effect on pro-inflammatory macrophages in vitro and its modulation in COPD in vivo. Respir Res. 2015 Dec 22;16:154. doi: 10.1186/s12931-015-0314-3.
citation: Snoeck-Stroband JB, Lapperre TS, Sterk PJ, Hiemstra PS, Thiadens HA, Boezen HM, Ten Hacken NH, Kerstjens HA, Postma DS, Timens W, Sont JK; GLUCOLD Study Group. Prediction of Long-Term Benefits of Inhaled Steroids by Phenotypic Markers in Moderate-to-Severe COPD: A Randomized Controlled Trial. PLoS One. 2015 Dec 10;10(12):e0143793. doi: 10.1371/journal.pone.0143793. eCollection 2015.
citation: Kunz LIZ, Postma DS, Klooster K, Lapperre TS, Vonk JM, Sont JK, Kerstjens HAM, Snoeck-Stroband JB, Hiemstra PS, Sterk PJ; GLUCOLD Study Group. Relapse in FEV1 Decline After Steroid Withdrawal in COPD. Chest. 2015 Aug;148(2):389-396. doi: 10.1378/chest.14-3091.
citation: Kunz LI, Strebus J, Budulac SE, Lapperre TS, Sterk PJ, Postma DS, Mauad T, Timens W, Hiemstra PS; GLUCOLD (Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease) Study Group. Inhaled steroids modulate extracellular matrix composition in bronchial biopsies of COPD patients: a randomized, controlled trial. PLoS One. 2013 May 7;8(5):e63430. doi: 10.1371/journal.pone.0063430. Print 2013.
citation: Lapperre TS, Snoeck-Stroband JB, Gosman MM, Jansen DF, van Schadewijk A, Thiadens HA, Vonk JM, Boezen HM, Ten Hacken NH, Sont JK, Rabe KF, Kerstjens HA, Hiemstra PS, Timens W, Postma DS, Sterk PJ; Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease Study Group. Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2009 Oct 20;151(8):517-27. doi: 10.7326/0003-4819-151-8-200910200-00004.
citation: Lapperre TS, Sont JK, van Schadewijk A, Gosman MM, Postma DS, Bajema IM, Timens W, Mauad T, Hiemstra PS; GLUCOLD Study Group. Smoking cessation and bronchial epithelial remodelling in COPD: a cross-sectional study. Respir Res. 2007 Nov 26;8(1):85. doi: 10.1186/1465-9921-8-85.