Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00159341 |
| Other study ID # |
05/Q0404/84 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
September 2005 |
| Est. completion date |
December 2006 |
Study information
| Verified date |
September 2023 |
| Source |
Imperial College London |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This is a clinical research study to assess whether after exhaling a single cigarette smoke
through the nose there are changes in the inflammatory cells and proteins of nasal
secretions.
A single blood sample from each subject will be stimulated with cigarette smoke in the
laboratory to see the effects on inflammatory blood cells.
Comparison of findings between smokers with COPD and "Healthy" smokers will be carried out.
We hypothesize that some subjects have amplified inflammatory response to a single cigarette,
and these will be those subjects who develop chronic obstructive pulmonary disease (COPD)
after decades of smoking. We hope to develop an acute challenge model that relates to the
causation of COPD. When studying the effects of new drugs, these may be detected in small
numbers of patients in a challenge situation, when we would need to study many more
unchallenged patients to demonstrate drug effects. In clinical research on asthma and
allergy, the nasal allergen challenge has been a very successful model, and we hope to
validate a comparable model for COPD.
Description:
Introduction Chronic obstructive pulmonary disease (COPD) is a common respiratory disease
that causes widespread morbidity and mortality, the Global Burden of Disease Study estimating
COPD to be currently the sixth most common cause of death worldwide. Decades of cigarette
smoking is by far the major contributing factor, and this causes a range of respiratory
disorders; including chronic bronchitis, obstructive bronchiolitis, emphysema, and pulmonary
vascular disease. Medical treatment of COPD is largely palliative; involving smoking
cessation, use of inhaled bronchodilators, and long term oxygen therapy for respiratory
failure. Recently, it has been recognised that those smokers who develop COPD have
amplification of inflammation compared with "healthy smokers", and that there is the urgent
need to develop new challenge models to assess why COPD develops in some heavy smokers.
Cigarette Smoke Nasal Challenge Model The nose is an accessible part of the respiratory
system, from which it is possible to obtain tissue exudates and cell brushings in a
non-invasive manner. A comprehensive review of the extensive clinical research experience
with these nasal methodologies has recently been published. There is also the insight that
patients with COPD commonly have inflammation of both the airways and nasal passages, with a
similar type of inflammatory infiltrate in lower and upper airways. In COPD the inflammation
is predominantly involving neutrophils and macrophages, as opposed to the increase in mast
cells and eosinophils characteristic of asthma.
It has long been recognised that there is a strong functional and immunological relationship
between the nose and bronchi, especially in terms of infiltrating leukocytes and inflammatory
mediators when comparing allergic rhinitis and allergic asthma. The upper and lower airways
have related respiratory epithelium and similar responses to allergen challenge.
The nasal and bronchial mucosa of smokers with COPD have been demonstrated to be infiltrated
with CD8+ T lymphocytes and neutrophils. This corresponds to the presence of nasal symptoms
during exacerbations of COPD, and sputum and nasal levels of IL-8 are correlated in COPD.
In order to sample nasal exudates for allergic inflammatory mediators, the classical methods
of nasal lavage are those described by Naclerio et al., the nasal pool method of Greiff et
al., and the use of a Foley's catheter by Grünberg and colleagues. Lavage is performed with
saline at volumes of between 1 and 10ml. The repeatability and validity of different nasal
lavage methods have been compared.
Tommy Sim and colleagues have developed the use of filter paper strips, that are placed on
the turbinates to absorb nasal secretions. The nasal filter paper method has the advantage of
directly sampling nasal secretions which are less diluted and can therefore pick up protein
signals which are below the detection limits of nasal lavage. The matrix or filter paper
method has been used to measure chemokines and cytokines after NAC.
Cells samples may be obtained from the nasal mucosal using small nylon dental flossing
brushes which are gently rotated over the epithelium, and then the attached cells are
dislodged in balanced salt solution. It has been demonstrated that nasal brushing can be used
as an alternative to nasal biopsy [24], whilst nasal brush supernatants can be analysed for
cytokine release [25]. An alternative method is to employ nasal mucosal scrapings using a
plastic curette (Rhinoprobe, Arlington Scientific, Utah). Nasal brushing and scraping causes
some discomfort but does not require local anaesthesia. Nasal biopsy is generally performed
from the lower edge of the inferior turbinate by a specialist. This is a traumatic procedure
that requires careful local anaesthesia, but a specimen of mucosal epithelium with basement
membrane and submucosal tissue is obtained.
Nasal allergen challenge (NAC) is of proven benefit to test novel anti-inflammatory therapy
for allergic rhinitis and asthma.
NAC has advantages over inhaled allergen challenge since it is easier to recruit subjects, it
is less invasive, and repeated tissue samples are readily obtained. Small numbers of patients
can be given even single doses of therapy, and the anti-inflammatory and clinical effects on
NAC responses noted. Using these challenge methods in phase II of drug development for asthma
and allergic rhinitis it is possible to provide an early and reliable "Go/No Go" decision
before embarking on large-scale, long-term and costly phase III studies.
We hope to develop an analogous challenge model for COPD by assessing effects of nasal
challenge with cigarette smoke.
A major challenge is to develop phase IIa clinical pharmacology designs that can be used to
assess anti-inflammatory drugs being developed for COPD. Nasal epithelial and inflammatory
responses to ozone exposure have been much studied [31-39]. Indeed COPD is characterised by
chronic inflammation with an imbalance in oxidant/antioxidant levels, and systemic
inflammation may trigger local exercise-induced oxidative stress.
Three year clinical trials involving thousands of patients have found that inhaled
corticosteroids do not affect the accelerated rate loss of lung function in COPD.
Furthermore, ongoing phase III trials with oral phosphodiesterase type 4 (PDE4)inhibitors are
also unconvincing, despite the initial smaller studies looking promising. There is clearly
the compelling need to develop non-invasive biomarkers and clinical challenge models for use
in phase II clinical pharmacology studies to enable reliable assessment of the effects of
anti-inflammatory therapy in COPD.
Use of nasal challenge models coupled to sensitive biomarkers and clinical endpoints could
perhaps be used to establish clinical efficacy of new drugs for COPD in small scale studies.
Novel therapies have the potential to selectively inhibit various cell types and particular
mediators involved in diverse inflammatory diseases. We believe that nasal allergen challenge
has advantages over inhaled challenge: safety, repeat non-invasive sampling.
In the future this will ensure that nasal challenge will play a growing role in clinical
pharmacology assessment of anti-inflammatory therapy. Major efforts are ongoing to develop
nasal challenge models to mimic the inflammation found in COPD, that can be used in clinical
pharmacology assessment of new anti-inflammatory drugs.
Whole Blood Challenge in vitro with Cigarette Smoke We shall stimulate blood samples in the
laboratory in an in vitro manner with a cigarette smoke extract. The cigarette smoke extract
is produced in a fume cabinet ensuring the safety of laboratory personnel. Cigarette smoke
contains many toxic compounds including free radicals and oxidants. Cigarette smoke
conditioned medium (CSCM) is made by bubbling the smoke from burning cigarettes through
buffered salt solution, and this can be used to stimulate cells in vitro. Cigarette smoke
extract has been shown to be cytotoxic to an alveolar type II cell-derived line and this
effect can be blocked by N-acetyl cysteine a scavenger of oxidants. {Hoshino, Mio, et al.
2001 7463 /id}. We have developed methods of assessing neutrophil CD11b upregulation in
response to stimulation with cytokines and chemokines. CD11b is a cell surface receptor on
leukocytes that is mobilised from intracellular stores when cells are stimulated. Surface
CD11b can be measured using fluorescent labelled antibodies and flow cytometry. We have
developed a method of stimulating whole blood with CSCM which produces a 200% increase in
CD11b upregulation after incubation for 20 minutes. This effect is further increased if
plasma is removed from the whole blood prior to stimulation, and the effect can be partially
inhibited by the presence of reduced glutathione. COPD patients and smokers have been shown
to have decreased antioxidant capacity in their plasma. We aim to compare neutrophil
responses to CSCM stimulation in whole blood, and washed blood where the plasma has been
removed, to compare neutrophil responsiveness between COPD patients and smokers and possible
anti-oxidant effects of plasma.
Overview of planned research
Two characterised matched groups of smokers with COPD and "healthy" smokers that do not have
lung disease will be enrolled for this study. Each group will comprise 8 subjects. Each
subject will be required to make 2 visits to the NHLI Clinical Studies Unit as follows:
Visit 1 : Screening During screening, candidates for the study will be fully informed about
the nature of the study and possible AEs. Candidates must read the consent form and sign the
document after the investigator has answered all questions to the candidate's satisfaction.
Further procedures can begin only after the consent form has been signed. Two original
informed consent form copies will be signed by the subject. An original signed consent form
will be retained by the investigator and the second original will be given to the candidate
to take home.
Candidates will be evaluated for entry into the study according to the stated inclusion and
exclusion criteria. The following procedures will be performed to establish each candidate's
general health and qualifications for enrollment into the study:
- Obtain signed, written informed consent
- Record medication history over the past 30 days Record medical history, including
smoking status
- Perform a physical examination of heart, lung and nose
- Pregnancy test for female subjects of child bearing age
- Conduct spirometry and test reversibility
- Review inclusion and exclusion criteria
The investigator will evaluate the results of all examinations including clinical laboratory
tests and will determine each candidate's suitability for the study. When the subject is
suitable for the study, a blood sample (10mls) will be taken for cigarette smoke whole blood
challenge.
Visit 2: Nasal smoke challenge Each subject will be allowed to smoke at least 5 cigarettes
between 9am to 9pm the day before attending the unit, and on the previous 7 days. On the
study day, each patient will be asked to smoke a single cigarette but exhaling through the
nose.
Following this cigarette challenge, we will carry out the following procedures over a period
of 8 hours (pre(x2), 1h, 2h, 3h, 4h,6h and 8h):
1. Nasal lavage consists of washing the nose of 5ml (a teaspoon) of warm salt solution.
This solution is gently passed from a syringe through a hollow "olive" into the end of
the left nostril. The fluid does not enter the sinuses nor pass down the back of the
nose. A total of 2 flushes will be carried out at each timepoints.
2. Nasal filter paper consists of a 7mm x 30mm strips of paper that are gently place inside
the end of the right nostril. They are left there for up to2 minutes until they are
moist with nasal secretions.
3. A cannula will be inserted to enable blood to be taken at the above time points for
serum analysis of cytokines and chemokines.
4. Pregnancy test for female subjects of child bearing age only.
As part of the study, subjects will be informed of the harmful effects of cigarette smoking,
and advised of the need to stop smoking. Subjects will be offered smoking classes to help
them stop smoking. It is anticipated that the study day will be set as the quit date for
subjects.
