Nasal LPS Challenge in Healthy Volunteers

September 13, 2023 updated by: Imperial College London

Nasal Lipopolysaccharide (LPS) Challenge in Healthy Volunteers (HVs): Investigation of Tolerability, Dose Response and the Expression Profile of Intercellular Adhesion Molecule-1 (ICAM-1)

The purpose of this study is to develop a nasal challenge model that causes a mild degree of inflammation, without causing any pain or symptoms, but that allows us to measure a variety of proteins in nasal secretions which causes inflammation in the nose. The nasal challenge model involves spraying the nostrils in the form of a fine mist with 4 different doses (1, 10, 30 and 100µg per nostril) of lipopolysaccharide (LPS) including a placebo. LPS is a type of protein which has been carefully purified from the outer cell wall of certain bacteria, is sterile and does not contain live bacteria, and will not cause infection.

The investigators will measure any inflammation in the nose by looking at cells collected by washing the inside of the nose (nasal lavage) and placing small strips of paper in the nasal cavity. The paper absorbs the nasal fluid and the chemicals produced during inflammation and can be extracted from the paper and analysed in the laboratory. The investigators will also be collecting a small amount of nasal epithelium taken by way of a nasal scrape; this is done by using a Rhinoprobe, a small plastic curette which is used to scrape a small piece of lining of the nose. The investigators hope that information obtained from this study will be used in future studies that will test new study drugs designed to treat diseases of the airways and lungs ( like asthma and chronic obstructive pulmonary disease (COPD) and hay fever.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

STUDY DESIGN AND METHODOLOGY This is a single-centre study which will be carried out at the Imperial Clinical Respiratory Research Unit (ICRRU) at St Mary's Hospital in London Paddington.

RECRUITMENT The study will recruit a total of 15 healthy participants.

STUDY VISITS The study will involve a total of 11 outpatients visits. The screening visit is the initial visit where the study is discussed with the participant and written informed consent is obtained by the PI or his designee. This is done prior to performing any study related procedures. The participant will have had the study information sheet for at least 24 hours prior to the visit.

The visit will include the collection of demographic data, height and weight, physical examination by a doctor, medical history, vital signs, body temperature, 12 lead ECG, laboratory assessments (safety bloods) urine drugs of abuse test and pregnancy tests for females. The participant will also be asked to indicate the presence of any nasal symptoms by completing a modified total nasal symptoms score sheet and perform a peak nasal inspiratory flow (PNIF) test.

If eligible, participants will be asked to return for further study visits. Participants will be given 4 different doses of LPS and a placebo in a randomised manner.

There are a total of 5 treatment periods. Each treatment period consists of a 11h visit the first day and a 20 minute visit the following day. There is a total of 12-28 days interval between each treatment period visit.

During the treatment period visits, the study participants will undergo the following study procedures:

  1. Nasal lavage to both nostrils and discard with 5ml of 0.9% saline in order to clean the nose prior to nasal LPS challenge.
  2. Nasal challenge with LPS (placebo, 1,10, 30 or 100µg per nostril)
  3. Nasosorption (right nostril) at -30m, +30m, +1h, then hourly to 10h and 24h
  4. Nasal lavage (left nostril) at -30m, +2h, +4h, +8h, +24h
  5. Nasal scrape (left nostril) at -30m, +3h, +6h, +24h
  6. Modified total nasal symptom score (TNSS) at -30m, +30m, +1h, then hourly to 10h and 24h
  7. Peak nasal inspiratory flow (PNIF) rate at -30m, +2h, +4h, +8h, 24h
  8. Systemic adverse events
  9. Temperature (oral) at -30m, +2h, +4h, +8h
  10. Blood pressure and heart rate at -30m
  11. Females of child bearing potential will have a pregnancy test performed.

NASAL PROCEDURES IN THE STUDY

  1. Nasal washing (nasal lavage): Nasal washings in the nose are carried out by passing a small volume of salt water (saline) fluid into the nose. A nasal adapter shaped like an olive is placed inside the nostril. The participant is then asked to sit forward and the salty water solution (saline) is used to flush in and out of the nose over a one minute period. This procedure is carried out on both nostrils to clean up the nose on the initial study visit and then repeated only on the left nostril on each treatment visit.
  2. Nasal lining fluid absorption (nasosorption or SAM): A small strip of absorbent material, that looks and feels like soft tissue paper, will be used to absorb moisture from the inside surface of the nostril. The special absorptive paper will be placed inside the nostril and left for a period of 2 minutes to absorb the nasal lining fluid before being removed, gently sucking up fluid like blotting paper. Putting the paper into the nose can tickle, and cause your eyes to water a little. However, the nasosorption does not hurt and the investigators method has proved to be well tolerated in babies, children and adults. The paper absorbs the nasal fluid and many substances produced by the nasal cells can then be extracted from the paper and measured in the laboratory.
  3. Nasal scrape (nasal curettage or Rhinoprobe): A small sterile disposable plastic probe will be inserted into the nose and will be gently pressed against the inside surface lining of the nostril. The 3 inch long probe has a tiny scoop on the end, which can barely be see. 24 tiny samples from each nostril (a pinhead, 2mm, of tissue) will be taken from a part of the nose that has a reduced nerve supply to limit any discomfort. Taking this sample does not cause bleeding, but may cause some mild discomfort, and may make the eyes water slightly. The probe will collect nasal cells from the surface of the nostril which will then be sent for analysis. This method has been performed on many adults, children, and babies, and has been very well tolerated.

STATISTICAL ANALYSIS Each of the measures will be summarised descriptively by dose and time using appropriate summary statistics. If appropriate, response variables will be transformed (e.g. log-transformed). Gene expression data will be normalised by house-keeper gene. The TNSS will be calculated by summing the scores of nasal blockage, nasal discharge/rhinorrhoea, nasal burning/itching/pain sensation, and sneezing at each timepoint. Weighted means of symptom scores will be calculated over the time interval 0 to 10h.

TNSS, nasal sniff pressures, nasosorption measures and gene expression data from the nasal scrapes will each be plotted against time, with a separate plot for each subject and measure, and with LPS dose and placebo represented by separate lines on the plots. Summary statistics (e.g. mean +/- 95% confidence intervals or median and interquartile range) for nasal lavage and gene expression data will be plotted by dose against time.

Correlations will be explored using scatter plots for the following measures:

  • Weighted means TNSS vs. maximum TNF-α
  • Weighted means TNSS vs. maximum IL-8
  • Weighted means TNSS vs. maximum s-ICAM-1
  • Maximum ICAM-1 expression vs. maximum TNF-α

Reproducibility of the nasal LPS challenge for ICAM-1 expression and TNF-α will be explored using the following subsets of data:

  • Predose data for each period to explore intra-subject variability. Parameter vs. period number will be plotted with a separate line for each subject to explore whether there is a period effect. Box and whisker plots will also be used to summarise the parameter by period.
  • Placebo period data - Parameter vs time will be plotted with a separate line for each subject to explore whether there is a time-course effect. Box and whisker plots will also be used to summarise the parameter over time.

Box and whisker plots for ICAM-1 expression and TNF-α and dose and time will be presented to investigate whether these measures return to baseline after 24h.

Additional exploratory analyses may be performed to further characterize the expression profile of ICAM following nasal LPS challenge.

Study Type

Interventional

Enrollment (Actual)

15

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
    • London
      • Paddington, London, United Kingdom, W2 1NY
        • Imperial Clinical Respiratory Research Unit (ICRRU), St Mary's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 56 years (Adult)

Accepts Healthy Volunteers

Yes

Description

INCLUSION CRITERIA

  • Males and females aged 18 to 60 years
  • Current non-smokers for last 6 months (<5 cigs per week), with a smoking history of <5 pack years
  • BMI 20-30 kg/m2

EXCLUSION CRITERIA

  • History of allergy
  • Upper airway infection in 2 weeks before screening
  • Lower respiratory tract infection in past 3 months
  • Treatment with local or systemic corticosteroids during previous 2 months
  • Signs or symptoms of chronic rhinitis, hypertrophy of turbinates, major septum deviation, nasal polyposis or recurrent sinusitis
  • Previous nasal or sinus surgery
  • Clinically significant cardiovascular, hepatic, GIT, renal, endocrine, infective, haematological, neurological, dermatological, neoplastic conditions, gastro-oesophageal reflux, depression, TB
  • Participation in a therapeutic drug trial in the prior 30 days.
  • Medical therapy other than that permitted for contraception.
  • Positive pregnancy test
  • Inability or unwillingness to use contraception if the patient is a female of child-bearing age.
  • History of drug abuse or urine test showing evidence of recreational drug abuse

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Nasal LPS spray - placebo

This is a 5-way crossover, randomised, placebo-controlled study.

Arms consists of the following nasal challenges:

placebo, 1, 10, 30 and 100µg LPS.
Other: Nasal LPS spray
LPS solution (250µl) will be prepared at 10, 100, 300 and 1000µg/ml, 100µl is administered to each nostril, both nostrils will be sprayed. The dose per nostril corresponds to 1, 10, 30 and 100µg.
Experimental: Nasal LPS spray 1µg

This is a 5-way crossover, randomised, placebo-controlled study.

Arms consists of the following nasal challenges:

placebo, 1, 10, 30 and 100µg LPS.
Other: Experimental: Nasal LPS spray 1µg
LPS solution (250µl) will be prepared at 10, 100, 300 and 1000µg/ml, 100µl is administered to each nostril, both nostrils will be sprayed.
Experimental: Nasal LPS spray 10 µg

This is a 5-way crossover, randomised, placebo-controlled study.

Arms consists of the following nasal challenges:

placebo, 1, 10, 30 and 100µg LPS.
Other: Experimental: Nasal LPS spray 10 µg
LPS solution (250µl) will be prepared at 10, 100, 300 and 1000µg/ml, 100µl is administered to each nostril, both nostrils will be sprayed.
Experimental: Nasal LPS spray 30 µg

This is a 5-way crossover, randomised, placebo-controlled study.

Arms consists of the following nasal challenges:

placebo, 1, 10, 30 and 100µg LPS.
Other: Experimental: Nasal LPS spray 30 µg
LPS solution (250µl) will be prepared at 10, 100, 300 and 1000µg/ml, 100µl is administered to each nostril, both nostrils will be sprayed.
Experimental: Nasal LPS spray 100 µg

This is a 5-way crossover, randomised, placebo-controlled study.

Arms consists of the following nasal challenges:

placebo, 1, 10, 30 and 100µg LPS.
Other: Experimental: Nasal LPS spray 100 µg
LPS solution (250µl) will be prepared at 10, 100, 300 and 1000µg/ml, 100µl is administered to each nostril, both nostrils will be sprayed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Level of nasal mucosal inter-cellular adhesion molecule-1 (ICAM-1) by gene expression analysis
Time Frame: 8 hours following nasal lipopolysaccharide (LPS) challenge
Measurement of gene expression (mRNA) for inter-cellular adhesion molecule-1 (ICAM-1) in nasal mucosal curettage samples, 8h following nasal lipopolysaccharide (LPS) challenge.
8 hours following nasal lipopolysaccharide (LPS) challenge

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Nasal mucosal lining fluid IL-1beta levels after nasal lipopolysaccharide (LPS) challenge
Time Frame: Up to 8h after nasal LPS challenge
Nasal mucosal IL-1beta levels after LPS challenge (area under curve, 0 to 8h) will be compared to placebo responses (AUC, 0-8h) in nasal mucosal lining fluid
Up to 8h after nasal LPS challenge
Nasal mucosal lining fluid IL-6 levels after nasal lipopolysaccharide (LPS) challenge
Time Frame: Up to 8h after nasal LPS challenge
Nasal mucosal IL-6 levels after LPS challenge (area under curve, 0 to 8h) will be compared to placebo responses (AUC, 0-8h) in nasal mucosal lining fluid
Up to 8h after nasal LPS challenge
Nasal mucosal lining fluid CXCL8 levels after nasal lipopolysaccharide (LPS)
Time Frame: Up to 8h after nasal LPS challenge
Nasal mucosal CXCL8 levels after LPS challenge (area under curve, 0 to 8h) will be compared to placebo responses (AUC, 0-8h) in nasal mucosal lining fluid
Up to 8h after nasal LPS challenge

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Imperial College London

Collaborators

GlaxoSmithKline

Investigators

  • Principal Investigator: Trevor T Hansel, FRCPath, PhD, Imperial College London

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2010

Primary Completion (Actual)

April 1, 2011

Study Completion (Actual)

April 1, 2011

Study Registration Dates

First Submitted

September 19, 2014

First Submitted That Met QC Criteria

November 3, 2014

First Posted (Estimated)

November 5, 2014

Study Record Updates

Last Update Posted (Actual)

September 15, 2023

Last Update Submitted That Met QC Criteria

September 13, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • ICRRU/2010/001
  • 10/H0803/110, ICRRU/2010/001 (Other Grant/Funding Number: CRO1595)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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