Condition category
Respiratory
Date applied
10/11/2016
Date assigned
15/11/2016
Last edited
02/10/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

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 measures

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

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

http://www.unispital-basel.ch/das-universitaetsspital/bereiche/medizin/kliniken-institute-abteilungen/pneumologie/

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

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

02/10/2017: IPD sharing statement added. 18/09/2017: Ethics approval details added.