Development of Human Nasal Challenge Models With Microbial Constituents and Grass Pollen
Condition: Allergic Rhinitis; Asthma; Latent Tuberculosis
MeSH terms: Tuberculosis; Rhinitis; Latent Tuberculosis; Rhinitis, Allergic
Study type: Interventional

Summary: 
      The investigators propose the development of a range of nasal spray challenge models to study
      the way the nose can respond to different types of nasal challenge that elicit different
      forms of inflammation.

      The investigators will carry out nasal challenge with bacterial and viral components and
      allergens. In this way the nasal upper respiratory tract mucosa is challenged with stimuli of
      the immune system, causing various types of inflammation. Samples will be taken by blotting
      the nostril surface and by scraping off tiny surface samples.

      The nose will be sprayed with a substance that is a single part of a bacteria or virus, or
      with an allergen. The material delivered by nasal spray is of high purity and is sterile,
      containing no live bacteria or viruses. The nasal spray substance contains molecular patterns
      that are recognised as foreign by the immune system, and at the right dose should stimulate
      the immune system, causing mild nasal inflammation. The study employs noninvasive methods of
      sampling using absorptive strips. These strips look and feel like tissue paper, and are
      applied to each nostril for a period of 1 min. A few pinhead-sized tissue samples are taken
      from inside the nose, using a small disposable sterile plastic probe that has a tiny scoop on
      its end. In the nasal lining fluid and tissue samples, measurement will taken of a range of
      molecules and cells that protect against infections and help the immune response.

      By spraying the nose with a challenge agent in this manner, the nasal immune response can be
      assessed, which can help us better understand how the human immune system cells and molecules
      respond to bacteria and viruses. In the future, this may allow the testing of new drugs and
      vaccines, by seeing if they decrease or stop the inflammation after the nasal challenge.
    

Detailed description: 
      STUDY DESIGN AND METHODOLOGY

      The study involves 3 parts with different nasal spray challenges being administered to
      subjects:

        1. Bacterial or viral components, comprising one of the following in a particular patient;

             1. MPLA (monophosphoryl lipid A) resembles bacterial lipopolysaccharide

             2. PolyIC (polyinosinic and cytidylic acids): viral component

             3. PolyICLC (polyIC stabilised with polyLlysine): viral component

             4. Resiquimod: viral mimic

        2. Tuberculin: partially purified protein derivative (PPD) from Mycobacterium bovis, the
           bacteria that causes TB.

        3. Allergen: The nasal spray challenge agent is Timothy grass pollen.

      RECRUITMENT

      The aim is to recruit a total of 174 subjects. Subjects will be identified through
      advertisements in the newspapers, posters on the campus, GP services, outpatients clinics at
      St. Mary's hospital including TB clinics at St. Mary's Hospital. We will gain fully informed
      consent. All data will be managed as per GCP and local Information Governance guidelines.

      NUMBER OF SUBJECTS AND DOSING

      PART 1: Nasal ascending dose challenge with microbial constituents using MPLA, polyIC,
      polyICLC and resiquimod. This is divided into part A and part B.

      PART 1A (n=32): Incremental Ascending Dose Study based on Tolerability and SAM. 4 cohorts of
      8 healthy volunteers (4 of 8 with allergies to grass pollen, house dust mite, or history of
      hay fever). One cohort for each microbial constituent. Each cohort will be given a nasal
      saline control challenge and three ascending doses of the nasal microbial constituent
      challenge:

        -  10μg of microbial constituent in 100μl of saline

        -  100μg of microbial constituent in 100μl of saline

        -  500μg of microbial constituent in 100μl of saline

      PART 1B (n=64): Single Top Dose with Additional Special Sampling Probe (SSP) and Curettage,
      Single Cohort of up to 16 Healthy Volunteers (8 of 16 allergies to grass pollen, housedust
      mite, history of hay fever). Each subject given saline control and single top dose after
      establishing tolerability & SAM response.

      RESIQUIMOD:

      Part B will see 10μg per nostril being given to 36 volunteers:

      12 allergic asthmatics 12 atopic volunteers 12 non-atopic volunteers

      PART 2: Nasal ascending dose challenge with tuberculin. This is divided into part A and part
      B.

      PART 2A (n=16): This comprises a total of 16 latent TB (LTB) subjects,This group is
      subdivided into 4 cohorts of 4 subjects according to the dose of the tuberculin being
      administered;

        -  0.1 TU in 100μl, n = 4

        -  1.0 TU in 100μl, n = 4

        -  2.0 TU in 100μl, n = 4

        -  5.0 TU in 100μl, n = 4 Each cohort has only 1 challenge. The starting dose is very low
           at 0.1 TU. If it is well tolerated, the subject will proceed to the next higher dose of
           1.0 TU. If this is also well tolerated, the subject will proceed to the next higher dose
           of 2.0 TU and then to the highest dose of 5.0 TU in this group ensuring the safety of
           subjects at all times.

      PART 2B (N=16): Top dose with additional sampling. This comprises of 16 people in two groups
      (8 healthy volunteers and 8 subjects with latent TB).

      Group 1: Latent TB subject, no. of people = 8 This group will receive the top dose (5-10.0
      TU) of the tuberculin challenge. Out of the 8 subjects in each group, 2 will receive placebo
      (saline dummy spray) and the remaining 6 will be given the tuberculin spray challenge.

      Group 2: Healthy volunteers, no. of people = 8 This group will also receive the top dose
      (5-10.0 TU) of the tuberculin challenge, subject to tolerability. Out of the 8 subjects, 2
      will receive the placebo (saline dummy spray) and the remaining 6 will be given the
      tuberculin spray challenge

      PART 3 (n=46): Nasal Allergen Challenge with Timothy Grass Pollen

      Initially 30 people shall be studied: one group of 12 people have hay fever, one group of 12
      people have asthma with grass pollen allergy, and a group of 6 people are nonallergic and do
      not have asthma. In an additional group,16 people with hay fever shall be studied by taking
      continuous samples of the surface nasal lining fluid using a special sampling probe (SSP)
      following the nasal spray challenge.

        1. Group 1: people with hay fever, n = 12

        2. Group 2: people with allergic asthma, n = 12

        3. Group 3: healthy, nonatopic people, n = 6

        4. Additional Group 4: people with hay fever, n=16

      NASAL PROCEDURES IN THE STUDY

        1. Nasal washing (nasal lavage): At the start of the day, nasal washings in the nose will
           be carried out by passing a small volume of salt water (saline) fluid into the nose.
           This procedure is carried out before other procedures to clean up the nose. The fluid
           obtained from the nasal washings is discarded and not analysed.

        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 our 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.

        4. Special Sampling Probe (SSP): The nasal surface lining fluid may also be collected using
           a special sampling probe or SSP that uses an electrospray to bounce droplets off the
           nasal lining fluid. This will be done by continuously sampling for a few hours from a
           single nostril. When using this special sampling probe (SSP) in people's noses, there is
           a slight tickling sensation while the sample is being taken. This can barely be noticed.

      STATISTICAL ANALYSIS

      The distribution of data will be assessed by the ShapiroWilks test, which determines whether
      the data has a normal (parametric) or non-normal (non-parametric) distribution.

      Normal data will be displayed graphically as:

        -  arithmetic means and standard error of means (SEM)

        -  or means with SDs

        -  or means with confidence intervals (CIs)

      Non-normal data will be displayed graphically as:

      Box-whisker: median, quartiles, range

      For non-normal data the differences from baseline will be measured for active challenge agent
      (at different doses) and placebo at each time point, and the AUC calculated. The differences
      in AUC from placebo (active placebo) are calculated, and the significance tested with the
      nonparametric Wilcoxon signed rank test(single population). Area under the curve (AUC) shall
      be sued over different defined times depending on the nasal challenge agent.
    

Intervention name(s): Poly ICLC; Poly I:C; R848; Timothy Grass Pollen; Vitamin D; Tuberculin
Intervention type(s): Other; Other; Other; Other; Other; Other
Intervention description(s): Dose escalation: 10ug, 100ug, 500ug Highest dose: 1000ug; Single dose: 500ug; High dose: 10ug Low dose: 1-2ug; Dose: 5000 SQ-U/100µl; 4000U orally; Tuberculin PPD
Other intervention name(s): Resiquimod
Intervention MeSH terms: Vitamin D; Poly ICLC
Allocation: Non-Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Allergy; Asthma; Biomarkers; Chemokines; Cytokines; Eosinophil; Gene Expression; Grass pollen; Hay Fever; Human Challenge Study; Inflammation; Innate Immune Response; Lipopolysaccharide; Mucosal Lining Fluid; Nasal; Nasorption; Respiratory; Respiratory Tract Infection; T cells; Tuberculosis; Virus