The human nasal lipopolysaccharide (LPS) challenge model reflects inflammatory events in the lower airways, illustrated by CXCR2 inhibition of neutrophil recruitment
| ISRCTN | ISRCTN46666382 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN46666382 |
| Secondary identifying numbers | N/A |
- Submission date
- 10/01/2011
- Registration date
- 17/02/2011
- Last edited
- 03/01/2012
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Respiratory
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Plain English summary of protocol
Not provided at time of registration
Contact information
Dr Lars-Olaf Cardell
Scientific
Scientific
Department of Clinical Science, intervention and technology
Karolinska Institutet
Stockholm
14186
Sweden
Study information
| Study design | Placebo-controlled double-blind cross-over study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| 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 |
| Study objectives | This study aimed to validate a lipopolysaccharide (LPS) nasal challenge model by investigating the effect of CXCR2 inhibitor AZD8309 on neutrophilic inflammation. |
| Ethics approval(s) | Regionala etikprövningsnämnden Lund approved on the 16th February 2009 (ref: LU2008/698) |
| Health condition(s) or problem(s) studied | 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | AZD8309, lipopolysaccharide |
| Primary outcome measure | 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 study start date | 01/03/2009 |
| Completion date | 31/12/2010 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 18 |
| Key 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 |
| Key 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 |
| Date of first enrolment | 01/03/2009 |
| Date of final enrolment | 31/12/2010 |
Locations
Countries of recruitment
- Sweden
Study participating centre
Department of Clinical Science, intervention and technology
Stockholm
14186
Sweden
14186
Sweden
Sponsor information
AstraZeneca (Sweden)
Industry
Industry
Västra Mälarehamnen 9
Södertälje
SE-151 85
Sweden
| Website | http://www.astrazeneca.se/ |
|---|---|
"ROR" |
https://ror.org/04wwrrg31 |
Funders
Funder type
Industry
AstraZeneca (Sweden)
Government organisation / For-profit companies (industry)
Government organisation / For-profit companies (industry)
- Alternative name(s)
- AstraZeneca PLC, Pearl Therapeutics
- Location
- United Kingdom
Results and Publications
| Intention to publish date | |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not provided at time of registration |
| Publication and dissemination plan | Not provided at time of registration |
| IPD sharing plan |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | results | 01/04/2012 | Yes | No |
