Plain English Summary
Background and study aims
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease and currently a leading cause of chronic morbidity (long-term illness) and mortality (death). Inhaled corticosteroids (ICS) belong to the first line treatment for COPD patients; however, there are patients who do not get a significant clinical benefit from ICS. Additionally, ICS overuse results in considerable side effects and economic burden. The aim of this study is to investigate parameters that may help to identify COPD patients that respond better from patients that respond worse to treatment with ICS.
Who can participate?
COPD patients aged 40 and over
What does the study involve?
Participants undergo bronchoscopy, where an instrument called a bronchoscope is threaded through the nose and down the throat to examine the airways and take biopsies (tissue samples). Participants are then divided into two groups based on the area of airway smooth muscle cells (ASMCs). Group A includes patients with ASMC area over 20% and group B includes patients with ASMC area of 20% and lower. All patients are treated for 6 weeks with all three drugs: LAMA (aclidinium), LABA (formoterol) and ICS (budesonide). Patients from each group are then randomly allocated to receive either treatment with LAMA, LABA and ICS (groups A1 and B1) or treatment with LAMA, LABA and placebo (dummy drug) (groups A2 and B2) for 12 months. Participants are followed up at 3, 6, 9 and 12 months, undergo lung function and walking distance tests, and give blood samples and oropharyngeal (throat) swabs.
What are the possible benefits and risks of participating?
Participants receive all tests and treatments for free for the duration of the study (12 months). The risks of the study procedures are considered to be mild. The medication is licensed for use in COPD. Bronchoscopy is a routine test in patients with COPD and the risks of the procedure are minimal. Additional blood samples are taken at the start of the study, scheduled visits and COPD episodes. Oropharyngeal swabs are an established method to take samples and can cause mild discomfort. All other procedures, including lung function and walking distance tests, are standard tests in COPD treatment. The side effects of inhaled steroids are usually mild, such as oral candidiasis (fungal infection in the mouth) and hoarseness. Patients are instructed at each visit how to avoid side effects (e.g. washing the mouth). The study team examine patients for any side effects.
Where is the study run from?
University Hospital Basel (Switzerland)
When is the study starting and how long is it expected to run for?
September 2016 to February 2020
Who is funding the study?
1. University Hospital Basel (Switzerland)
2. AstraZeneca (UK)
Who is the main contact?
Prof. Daiana Stolz
Daiana.Stolz@usb.ch
Trial website
Contact information
Type
Scientific
Primary contact
Prof Daiana Stolz
ORCID ID
Contact details
Petersgraben 4
Basel
4031
Switzerland
+41 (0)61 265 5195
Daiana.Stolz@usb.ch
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
N/A
Study information
Scientific title
Histological, cellular and molecular investigation of steroid responsiveness in chronic obstructive pulmonary disease - the HISTORIC study
Acronym
HISTORIC
Study hypothesis
Chronic obstructive pulmonary disease (COPD) patients with increased airway smooth muscle cell (ASMC) area respond better to inhaled corticosteroids (ICS) and this type of histological analysis can predict steroid responsiveness in COPD patients.
Ethics approval
EKNZ (Ethikkommission Nordwest and Zentralschweiz), 12/12/2016, ref: 2016-01880
Study design
Investigator-initiated and -driven double-blind randomized placebo-controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
No participant information sheet available
Condition
Chronic obstructive pulmonary disease
Intervention
188 patients with COPD, GOLD groups B-D, are recruited within 18 months. Based on the histological analysis of endobronchial biopsies taken by flexible bronchoscopy, patients are divided into two groups. Group A includes patients with ASMC area >20% and group B includes patients with ASMC area ≤20%. All patients follow a run-in period of 6 weeks on open-label triple therapy with LAMA (aclidinium 400 mcg, bid), LABA (formoterol 12 mcg, bid) and ICS (budesonide 400 mcg, bid). Subsequently, patients from each group are randomized (1:1) to receive either:
1. Triple treatment with LAMA, LABA and ICS (groups A1 and B1) or
2. Combined bronchodilator therapy with LAMA and LABA and placebo for ICS (groups A2 and B2)
Randomization will be stratified by group (A vs B), follow a block size of 4. The duration of treatment will be 12 months, with follow-up at 3, 6, 9 and 12 months after randomization.
Intervention type
Drug
Phase
Not Applicable
Drug names
Budesonide, aclidinium, formoterol
Primary outcome measure
To compare the differences in the mean decrease of post-bronchodilator FEV1 in milliliters measured using a spirometer at 12 months, between patients with low (≤20%) and high (>20%) ASMC area and according to whether they received ICS or not
Secondary outcome measures
Immediately after the run-in phase, at 3, 6, 9 and 12 months after randomization to compare changes in:
1. Modified Medical Research Council (MMRC) dyspnea scale
2. COPD assessment test (CAT)
3. Health-related quality of life, measured using SF-36, SGRQ
4. Pre and post bronchodilator body plethysmography/DLCO
5. Expiratory FeNO
6. Single and multiple-breath N2 wash-out
7. Forced impulse oscillometry
8. 6-minute walking distance (6MWD)
9. Movement patterns, measured using accelerometry
10. Therapy-related side effects (oral candidiasis, tachycardia, tremor, hoarseness, pneumonia)
11. Exacerbations rate
12. Serum biomarkers
between patients with low (≤20%) and high (>20%) ASMC area and according to whether they received ICS or not
Overall trial start date
01/09/2016
Overall trial end date
29/02/2020
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Age ≥ 40 years
2. COPD, as defined by the GOLD Guidelines and categorization in groups B-D
3. No acute exacerbation of COPD or any respiratory infection requiring medical attention or leading to a change in medication within the last 4 weeks
4. Unchanged respiratory medication regimen within the last 8 weeks
5. At least one exacerbation in the previous year
6. Current or ex-smokers with smoking history of ≥ 10 pack-years
7. Willingness to participate in a longitudinal, cohort study
8. Capability to provide written informed consent
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
64 patients with high ASCM and 88 patients with low ASCM should be included. Considering a 10% loss to follow up, the planned sample size is 188 patients
Participant exclusion criteria
1. Rapid fatal disease (with life expectancy less than 3 months)
2. Pulmonary condition other than COPD as the main respiratory disease
3. Current diagnosis of bronchial asthma
4. Severe immune-suppression including HIV, organ transplantation, ongoing chemotherapy for cancer
5. Pregnancy or breastfeeding
6. Chronic use of oral steroids (> 10 mg per day) for COPD
7. Intolerance or contraindication to aclidinium, formoterol or budesonide
Recruitment start date
01/03/2017
Recruitment end date
30/09/2018
Locations
Countries of recruitment
Switzerland
Trial participating centre
University Hospital Basel
Petersgraben 4
Basel
4031
Switzerland
Sponsor information
Organisation
University Hospital Basel
Sponsor details
Petersgraben 4
Basel
4031
Switzerland
+41 (0)61 265 5195
Daiana.Stolz@usb.ch
Sponsor type
Hospital/treatment centre
Website
Funders
Funder type
Hospital/treatment centre
Funder name
University Hospital Basel
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
AstraZeneca
Alternative name(s)
Funding Body Type
private sector organisation
Funding Body Subtype
corporate
Location
United Kingdom
Results and Publications
Publication and dissemination plan
The findings from this study are expected to be published in peer-reviewed journals. Criteria for authorship will be based on the rules of The Lancet. Authorship rights are based on active contribution to the study, including study design and planning, funding, patients’ recruitment and follow-up, data collection, data analysis and manuscript preparation. Individual contributions and potential conflicts of interest will be specified. All publications containing study related data, e.g. scientific abstracts or manuscripts, shall be revised and approved by the steering committee before submission.
IPD sharing plan
All relevant information regarding the datasets (including all analyses described in the primary and secondary outcome measures) are/will be available upon request from Prof. Daiana Stolz (Daiana.Stolz@usb.ch). Informed consent was obtained from all patients included in the study.
Intention to publish date
01/02/2020
Participant level data
Available on request
Basic results (scientific)
Publication list