Condition category
Respiratory
Date applied
10/01/2011
Date assigned
17/02/2011
Last edited
03/01/2012
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information

Type

Scientific

Primary contact

Dr Lars-Olaf Cardell

ORCID ID

Contact details

Department of Clinical Science
intervention and technology
Karolinska Institutet
Stockholm
14186
Sweden

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

N/A

Study information

Scientific title

The human nasal lipopolysaccharide (LPS) challenge model reflects inflammatory events in the lower airways, illustrated by CXCR2 inhibition of neutrophil recruitment: a placebo-controlled double-blind, cross-over study

Acronym

Study hypothesis

This study aimed to validate a lipopolysaccharide (LPS) nasal challenge model by investigating the effect of CXCR2 inhibitor AZD8309 on neutrophilic inflammation.

Ethics approval

Regionala etikprövningsnämnden Lund approved on the 16th February 2009 (ref: LU2008/698)

Study design

Placebo-controlled double-blind cross-over study

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Neutrophil inflammation in airway disease

Intervention

Study design
This methodology study is a randomised, double-blind, placebo-controlled, two-way crossover study in healthy subjects to assess the effect of AZD8309 on cells and inflammatory biomarkers in nasal lavage and blood after nasal challenge with LPS. The study will comprise of 6 visits; a screening visit (Visit 1), 4 treatment visits (Visits 2 to 5), and a post-study follow-up visit (Visit 6). The healthy subjects will receive 300 mg AZD8309 (oral solution [30 mg/g]) or placebo twice daily for 3 consecutive days. On the third day of dosing (after the fifth dose of study drug, Visits 3 and 5) the subjects will be challenged with 100 µg nasal LPS. The washout period between the LPS challenges will be at least 3 weeks.

Duration of treatment
This study will include a run-in period of less than 3 weeks, followed by Treatment Period 1 (3 days), a washout period of at least 3 weeks, and Treatment Period 2 (3 days). The total duration of the study from Visit 1 (screening) to Visit 6 (follow-up) will be approximately 6 to 12 weeks for an individual subject.

Visit 1 - screening
Visit 1 will be a screening visit where subject informed consent will be obtained, and subject eligibility will be established.

Visits 2, 3, 4 and 5 - treatment
At Visit 2, eligibility criteria will be checked and the subjects will be asked about any AEs prior to dosing. All randomised subjects will also receive a Study Participation Card in Swedish. At Visit 2 and 4, the subjects will be dosed with either AZD8309 or placebo at 08:00 ± 30 minutes and will remain under medical supervision at the study site for at least 1 hour following dosing. Subjects will then be discharged from the study site and will return 7 hours post-dose of study drug for cells and inflammatory biomarker assessments in blood. The subjects will take their second dose of AZD8309 or placebo at home, approximately 12 hours (± 30 minutes) after their first dose. The subjects will continue to dose with AZD8309 or placebo at home (Day 2) at 08:00 ± 30 minutes and 20:00 ± 30 minutes. The following morning (Day 3), at Visit 3 and 5, the subjects will return to the study site and will be dosed with either AZD8309 or placebo at 08:00 ± 30 minutes. One hour after dosing, nasal challenges with LPS will be performed. The subjects will be confined to the study site until 6 hours post-LPS challenge (7 hours post-dose of study drug), and will then be discharged from the study site. The subjects will take their sixth dose of AZD8309 or placebo at home at 20:00 ± 30 minutes. The following morning, the subjects will return to the study site. Various assessments, such as biomarker assessments in nasal lavage and blood, will be performed 24 hours post-LPS challenge. Subjects will then be discharged from the study site.

Visit 6 - follow-up
Visit 6 will be a post-study follow-up visit.

Intervention type

Drug

Phase

Phase I

Drug names

AZD8309, lipopolysaccharide

Primary outcome measures

Neutrophil numbers in nasal lavage, measured 24 hours post-LPS challenge

Secondary outcome measures

1. Other cells in nasal lavage: total leucocytes, macrophages, lymphocytes, eosinophils and epithelial cells, measured 24 hours post-LPS challenge
2. Inflammatory biomarkers in nasal lavage, which may include, but not be restricted to: IL-8, GROa, LTB4 and neutrophil elastase activity, measured 24 hours post-LPS challenge
3. Cells in blood: total leucocytes, neutrophils, monocytes, lymphocytes, basophils and eosinophils, measured 24 hours post-LPS challenge
4. Inflammatory biomarkers in blood, which may include, but not be restricted to: TNFa, high sensitivity CRP, IL-6, IL-8, GROa and serum amyloid A, measured 24 hours post-LPS challenge
5. Safety:
5.1. Incidence and nature of adverse events
5.2. Nasal symptoms (total nasal symptom scores) and nasal airway resistance (peak nasal inspiratory flow)
5.3. Clinically significant abnormalities in pulse, blood pressure, body temperature and liver enzymes (aspartate aminotransferase, alanine aminotransferase and bilirubin)

Overall trial start date

01/03/2009

Overall trial end date

31/12/2010

Reason abandoned

Eligibility

Participant inclusion criteria

1. Provision of informed consent prior to any study specific procedures
2. Be willing and able to comply with study procedures
3. Healthy men or women aged 18 to 50 years (inclusive). Women must be of non-childbearing potential, that is women who are permanently sterilized (hysterectomy and/or bilateral oophorectomy or salpingectomy).
4. Have a body mass index (BMI) between 18 and 30 kg/m2 (inclusive) and minimum body weight of 50 kg
5. A blood neutrophil count above 2.2 x 10^9/L
6. Be non-smokers, or ex-smokers who have not smoked (or used any other nicotine products) in the 12 months preceding Visit 1 with a pack-year history of less than 10

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

18

Participant exclusion criteria

1. Any clinically relevant disease and/or abnormality (past or present), which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or influence the results of the study, or the subject's ability to participate in the study
2. A definite or suspected personal or family history of intolerance or hypersensitivity to drugs and/or their excipients, judged to be clinically relevant by the investigator
3. Surgery or significant trauma within 3 months of Visit 1
4. Symptoms, signs or laboratory findings suggestive of an ongoing infective illness, as judged by the investigator, at Visit 1
5. Current or recurrent atopic symptoms, ie, rhinitis, asthma or conjunctivitis of clinical relevance as judged by the investigator
6. Participation in any clinical study with an investigational drug or new formulation of a marketed drug in the 3 months prior to Visit 1, or participation in a methodology study 1 month prior to Visit 1 (Note: participation is identified as the completion of a treatment-related visit)
7. Donation of blood within 3 months and plasma within 14 days prior to Visit 1
8. Use of any medication (other than hormone replacement therapy [HRT]), including vaccinations or "over-the-counter" medication (e.g., herbal remedies, vitamins or nutritional supplements) within 2 weeks in relation to first administration of study drug (or longer if the medication has a half-life long enough to potentially expose the subject to any significant systemic exposure that may interfere with the objectives of the study or the safety of the subjects), as judged by the investigator. Occasional intake of paracetamol, maximum 1 g 4 times daily (qid), is allowed.
9. Past or present alcohol or drug abuse, as judged by the investigator, or positive drugs of abuse test
10. Positive results on screening tests for serum hepatitis B surface antigen, hepatitis C antibodies and/or human immunodeficiency virus (HIV)
11. A suspected/manifested infection according to World Health Organization (WHO) risk classification 2, 3 or 4
12. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
13. Previous randomisation into the present study
14. Subjects, who in the opinion of the investigator, should not participate in the study
15. Subjects being recently extensively exposed to passive smoking or environmental LPS (eg, swine farms) as judged by the investigator
16. Previous participation in another LPS study during the last 12 months
17. Suspicion of Gilbert's syndrome
18. Structural abnormalities of the nose or nasal disorder symptomatic enough to cause significant nasal obstruction, as judged by the investigator

Recruitment start date

01/03/2009

Recruitment end date

31/12/2010

Locations

Countries of recruitment

Sweden

Trial participating centre

Department of Clinical Science, intervention and technology
Stockholm
14186
Sweden

Sponsor information

Organisation

AstraZeneca (Sweden)

Sponsor details

Västra Mälarehamnen 9
Södertälje
SE-151 85
Sweden

Sponsor type

Industry

Website

http://www.astrazeneca.se/

Funders

Funder type

Industry

Funder name

AstraZeneca (Sweden)

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

1. 2011 results in http://www.ncbi.nlm.nih.gov/pubmed/22192144

Publication citations

  1. Results

    Virtala R, Ekman AK, Jansson L, Westin U, Cardell LO, Airway inflammation evaluated in a human nasal lipopolysaccharide challenge model by investigating the effect of a CXCR2 inhibitor., Clin. Exp. Allergy, 2012, 42, 4, 590-596, doi: 10.1111/j.1365-2222.2011.03921.x.

Additional files

Editorial Notes