Objective: To perform a study comparing the efficacy of extra-fine particle HFA-QVAR 200 µg b.i.d. to an equipotent dose of course particle HFA-beclomethasone (HFA-Clenil) 400 µg b.i.d. and with coarse particle HFA-fluticasone (GSK) 250 µg in ex-…
ID
Source
Brief title
Condition
- Bronchial disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary end-parameter is the PD20 small particle adenosine. The co-primary
objective (only in case of non-inferiority of QVAR on the primary objective)
will be: Reduction in peripheral airways resistance (R5-R20) measured with IOS
at the provocative dose of small particle adenosine causing the FEV1 to drop
with 20% (PD20).
Secondary outcome
* Twice daily symptoms (including night-time symptoms) and peakflow (PEF).
* Resistance (R5, R20, R5-R20) and Reactance at 5 Herz (X5) with IOS.
* Lung function (FEF25, FEF50, FEF75, FEF25-75, PEF, FEV1, FEV1/FVC, FVC/SVC
* Body plethysmography (RV (%predicted), TLC, RV/TLC (%), FRC, FRC/TLC (%),
FRC/TLC (%predicted), IC, RV/TLC %predicted).
* Peripheral blood (cell differential counts).
* Delta FVC during PD20 small particle adenosine.
* Questionnaires (Asthma Control Questionnaire (ACQ), Bronchial
Hyperresponsiveness Questionnaire (BHQ), and Clinical COPD Questionnaire
(CCQ).
* Multiple Breath Washout Analysis: Lung Clearance Index, Sacin and Scond
before and after provocation test with AMP and small particle adenosine.
* Genome-wide mRNA and miRNA expression, and DNA methylation in epithelial
cells derived from nasal epithelial brushes.
* inflammatory cytokines and chemokines in nasal lining fluid
Background summary
Rationale: Thus far, most clinical studies investigating the effects of inhaled
corticosteroids (ICS) in asthma have concentrated on non-smoking asthmatics.
However, a considerable proportion of asthma patients smokes. Cigarette smoke
consists of ultra-fine particles with a diameter between 0.1 and 1 µm and
therefore reaches even the smallest airways.1 In line with this, it has been
reported that smoking is associated with small airways dysfunction..2;3 The
latter may help to explain the observation that treatment with course particle
inhaled corticosteroids is less effective in smokers with asthma.4;5 Recently,
extra-fine particle aerosols such as hydrofluoroalkane-beclomethasone
(HFA-QVAR) have become available for the treatment of asthma, which are more
likely to reach the smaller airways. Based on the above, we hypothesize that
extra-fine particle treatment with HFA-QVAR will be superior in improving small
airways dysfunction, especially in ex-smokers and smokers with asthma.
Study objective
Objective: To perform a study comparing the efficacy of extra-fine particle
HFA-QVAR 200 µg b.i.d. to an equipotent dose of course particle
HFA-beclomethasone (HFA-Clenil) 400 µg b.i.d. and with coarse particle
HFA-fluticasone (GSK) 250 µg in ex-smokers and smokers with asthma.
In addition, we aim to investigate the contribution of small airways disease to
the clinical expression of asthma. To this, we will assess the association
between parameters of large and small airway function and symptoms. In
addition, we will assess whether changes in these after the start of
anti-inflammatory treatment or after treatment discontinuation are associated
with changes in asthma symptoms. In addition, we will investigate whether we
can identify specific gene or miRNA expression levels, SNPs, or changes in DNA
methylation status that are associated with parameters of large and small
airway function. Further, we will investigate the effect of treatment on nasal
epithelial gene and miRNA expression profiles as well as DNA methylation status
and whether there are differences between HFA-QVAR and HFA-Fluticasone or
HFA-Clenil in this respect. Finally, we investigate whether discontinuation of
anti-inflammatory treatment (between pre-screening (visit 1) and screening
(visit 2) induces changes nasal epithelial gene and miRNA expression profiles
as well as DNA methylation status into the opposite direction.
Study design
Study design: This study will be an open-label, randomised, three-way
cross-over, two-center study. 20 smokers and 20 ex-smokers with asthma will
receive the following treatments for two weeks:
Intervention
There are three treatment periods of two weeks:
A: 2-week treatment with HFA-QVAR (TEVA) 200 *g b.i.d.
B: 2-week treatment with HFA-Clenil (Chiesi) 400 *g b.i.d.
C: 2-week treatment with HFA-Fluticasone (GlaxoSmithKline) 250 *g b.i.d.
Study burden and risks
*Nasal epithelium collection may cause a temporary nose bleed.
*Blood collection may cause bruising.
*All drugs may cause side effects. The inhaled corticosteroids HFA-QVAR,
HFA-Clenil, and HFA-Fluticasone are medicinal products that have been on the
market for many years in many countries; therefore side effects associated with
each of the compounds and similar to those reported for the other inhaled
corticosteroids may be expected.
Hanzeplein 1
Groningen 9713GZ
NL
Hanzeplein 1
Groningen 9713GZ
NL
Listed location countries
Age
Inclusion criteria
*Males and females with a doctor*s diagnosis of asthma ;*Age between 18 and 65 years;*Current- and ex-smokers with * 5 packyears.;*Drop in FEV1 > 20% after provocation with small particle adenosine < 20 mg at visit 1.
Exclusion criteria
*An asthma exacerbation during the last 6 weeks or upper respiration tract infection during the last 4 weeks prior to inclusion in the study. ;*Severe airway obstruction at visit 1, 2, of 3, i.e. FEV1 < 50% of predicted or < 1.2 liter.;*Maintenance treatment with oral prednisolone.;*Clinically unstable concurrent disease: e.g. hyperthyroidism, diabetes mellitus or other endocrine disease; significant hepatic impairment; significant renal impairment; cardiovascular disease (e.g. coronary artery disease, hypertension, heart failure); gastrointestinal disease (e.g. active peptic ulcer); neurological disease; haematological disease; autoimmune disorders, or other which may impact the evaluation of the results of the study according to investigator*s judgement.;*Ex-smokers who have quit smoking less than 6 months prior to visit 1.;*Pregnant or lactating women. At the first visit 1, a pregnancy test (urine hCG) will be performed in all females.;*Females of childbearing potential without an efficient contraception unless they meet the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels < 40 mIU/mL or use one or more of the following acceptable methods of contraception:;a) Surgical sterilization (e.g. bilateral tubal ligation, hysterectomy).;b) Hormonal contraception (implantable, patch, oral, injectable).;c) Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/cream/suppository.;d) Continuous abstinence.;Periodic abstinence (e.g. calendar, ovulation, symptom-thermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Reliable contraception should be maintained throughout the study and for 30 days after study drug discontinuation.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-005350-39-NL |
| ClinicalTrials.gov | NCT01741285 |
| CCMO | NL42875.042.12 |