Development of Human Nasal Challenge Models With Microbial Constituents and Grass Pollen

NCT02090374 | Completed Results

• 2 other identifiers: 13SM1837P45058
• Study Type: interventional
• Target: 93
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Allergic Rhinitis; Asthma; Latent Tuberculosis

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

Outcome Measures

Primary Outcomes (1)

• IFN-y Protein Response in Mucosal Lining Fluid

  The primary outcome measure is IFN-y in nasal mucosal lining fluid after nasal challenge

  0, 1, 2, 3, 4, 6, 8 hours post-dose

Study Arms (8)

Poly ICLC dose escalation

EXPERIMENTAL

Poly ICLC nasal challenge dose escalation 10ug, 100ug, 500ug

Other: Poly ICLC

Poly ICLC highest dose

EXPERIMENTAL

Poly ICLC nasal challenge single dose of 1000ug

Other: Poly ICLC

Poly I:C single dose

EXPERIMENTAL

Poly I:C nasal challenge single dose 500ug

Other: Poly I:C

R848 high dose

EXPERIMENTAL

R848 nasal challenge 10ug

Other: R848

R848 low dose

EXPERIMENTAL

R848 nasal challenge low dose 1-2ug (0.02ug/kg)

Other: R848

Grass pollen

EXPERIMENTAL

Timothy grass pollen nasal challenge

Other: Timothy Grass Pollen

Vitamin D supplementation

EXPERIMENTAL

Vitamin D 4000U orally daily

Other: Vitamin D

Tuberculin

EXPERIMENTAL

Tuberculin PPD nasal challenge

Other: Tuberculin

Interventions

Poly ICLC OTHER

Dose escalation: 10ug, 100ug, 500ug Highest dose: 1000ug

Poly ICLC dose escalation; Poly ICLC highest dose

Poly I:C OTHER

Single dose: 500ug

Poly I:C single dose

R848 OTHER

High dose: 10ug Low dose: 1-2ug

Also known as: Resiquimod

R848 high dose; R848 low dose

Timothy Grass Pollen OTHER

Dose: 5000 SQ-U/100µl

Grass pollen

Vitamin D OTHER

4000U orally

Vitamin D supplementation

Tuberculin OTHER

Tuberculin PPD

Tuberculin

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• GENERAL FOR ALL SUBJECTS
• Males and females aged 18 to 60 years
• Current non-smokers for last year, maximum of 10 cigs per month, with a smoking history of \<5 pack years
• Body mass index in the range18-39
• HEALTHY NON-ATOPIC VOLUNTEERS
• Negative skin prick tests to a range of 6 common aeroallergens: cat, dog, grass pollen, tree pollen, house dust mite, fungal spores
• Normal blood eosinophil count.
• ATOPIC SUBJECTS WITH TIMOTHY GRASS POLLEN SENSITIVITY
• A clinical history of seasonal grass pollen allergic rhinitis: sneezing, running and itching nose, nasal drip in the UK grass pollen summer season (May-July).
• Specific allergy confirmed by positive intra-epidermal skin prick test to Timothy grass pollen extract (Soluprick, Phleum pratense; ALK, Horsholm, Denmark), a positive reaction being a raised wheal of diameter \>3mm larger than a negative saline control.
• ASTHMATIC SUBJECTS WITH TIMOTHY GRASS POLLEN SENSITIVITY
• Seasonal grass pollen allergic rhinitis: sneezing, running and itching nose, nasal drip in the UK grass pollen summer season (May-July).
• Specific allergy confirmed by positive intra-epidermal skin prick test to Timothy grass pollen extract (Soluprick, Phleum pratense; ALK, Horsholm, Denmark), a positive reaction being a raised wheal of diameter \>3mm larger than a negative saline control.
• Half the asthmatics have clinical history and diagnosis of asthma, requiring therapy with occasional inhaled beta-agonists, but no inhaled corticosteroids for the past 28 days. Half the asthmatics receive regular combined inhaled corticosteroids and long-acting beta-agonists (ICS/LABA)
• For those asthmatics in the resiquimod (TLR 7/8 agonist) arm:

You may not qualify if:

• GENERAL
• Recent infections in past 14 days before screening: especially upper respiratory tract illnesses (including colds and influenza), sore throats, sinusitis, infective conjunctivitis.
• Lower respiratory tract infection in past 28 days
• Signs or symptoms of significant nasal anatomical defects, hypertrophy of turbinates, major septum deviation, nasal polyposis injury, ulceration or recurrent sinusitis
• Previous nasal or sinus surgery
• Systemic illnesses that might affect nasal immune responses
• Medical therapy other than that permitted for contraception.
• Treatment with local or systemic corticosteroids during the previous 1 month
• Anti-inflammatory therapy: including non-steroidal anti-inflammatory drugs (NSAIDs)
• tuberculosis at any stage in life
• active infectious disease
• cardiovascular diseases
• respiratory (other than hay fever or asthma where specified)
• hepatic, gastrointestinal, renal, endocrine, infective, haematological, autoimmune, rheumatological, neurological, dermatological,
• neoplastic conditions

Sponsors & Collaborators

• Imperial College London: lead

Study Sites (1)

Imperial Clinical Respiratory Research Unit (ICRRU), St Mary's Hospital

Paddington, London, W2 1NY, United Kingdom

Location

Related Publications (7)

• Hansel TT, Johnston SL, Openshaw PJ. Microbes and mucosal immune responses in asthma. Lancet. 2013 Mar 9;381(9869):861-73. doi: 10.1016/S0140-6736(12)62202-8.

  PMID: 23428115 BACKGROUND

• Chawes BL, Edwards MJ, Shamji B, Walker C, Nicholson GC, Tan AJ, Folsgaard NV, Bonnelykke K, Bisgaard H, Hansel TT. A novel method for assessing unchallenged levels of mediators in nasal epithelial lining fluid. J Allergy Clin Immunol. 2010 Jun;125(6):1387-1389.e3. doi: 10.1016/j.jaci.2010.01.039. Epub 2010 Mar 20. No abstract available.

  PMID: 20304470 BACKGROUND

• Nicholson GC, Kariyawasam HH, Tan AJ, Hohlfeld JM, Quinn D, Walker C, Rodman D, Westwick J, Jurcevic S, Kon OM, Barnes PJ, Krug N, Hansel TT. The effects of an anti-IL-13 mAb on cytokine levels and nasal symptoms following nasal allergen challenge. J Allergy Clin Immunol. 2011 Oct;128(4):800-807.e9. doi: 10.1016/j.jaci.2011.05.013. Epub 2011 Jun 29.

  PMID: 21719078 BACKGROUND

• Scadding GW, Calderon MA, Bellido V, Koed GK, Nielsen NC, Lund K, Togias A, Phippard D, Turka LA, Hansel TT, Durham SR, Wurtzen PA. Optimisation of grass pollen nasal allergen challenge for assessment of clinical and immunological outcomes. J Immunol Methods. 2012 Oct 31;384(1-2):25-32. doi: 10.1016/j.jim.2012.06.013. Epub 2012 Jun 30.

  PMID: 22759401 BACKGROUND

• Ekman AK, Virtala R, Fransson M, Adner M, Benson M, Jansson L, Cardell LO. Systemic up-regulation of TLR4 causes lipopolysaccharide-induced augmentation of nasal cytokine release in allergic rhinitis. Int Arch Allergy Immunol. 2012;159(1):6-14. doi: 10.1159/000335196. Epub 2012 Apr 27.

  PMID: 22555057 BACKGROUND

• Walrath JR, Silver RF. The alpha4beta1 integrin in localization of Mycobacterium tuberculosis-specific T helper type 1 cells to the human lung. Am J Respir Cell Mol Biol. 2011 Jul;45(1):24-30. doi: 10.1165/rcmb.2010-0241OC. Epub 2010 Aug 19.

  PMID: 20724551 BACKGROUND

• Dhariwal J, Kitson J, Jones RE, Nicholson G, Tunstall T, Walton RP, Francombe G, Gilbert J, Tan AJ, Murdoch R, Kon OM, Openshaw PJ, Hansel TT. Nasal Lipopolysaccharide Challenge and Cytokine Measurement Reflects Innate Mucosal Immune Responsiveness. PLoS One. 2015 Sep 14;10(9):e0135363. doi: 10.1371/journal.pone.0135363. eCollection 2015.

  PMID: 26367003 BACKGROUND

MeSH Terms

Conditions

Rhinitis, Allergic; Asthma; Latent Tuberculosis; Hypersensitivity; Rhinitis, Allergic, Seasonal; Inflammation; Respiratory Tract Infections; Tuberculosis; Virus Diseases

Interventions

poly ICLC; Poly I-C; resiquimod; PHLPVI protein, Phleum pratense; Vitamin D; Tuberculin

Condition Hierarchy (Ancestors)

Rhinitis; Nose Diseases; Respiratory Tract Diseases; Respiratory Hypersensitivity; Otorhinolaryngologic Diseases; Hypersensitivity, Immediate; Immune System Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Lung Diseases; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Latent Infection; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Poly C; Polyribonucleotides; Polynucleotides; Nucleotides; Nucleic Acids, Nucleotides, and Nucleosides; Poly I; Secosteroids; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Antigens, Bacterial; Bacterial Proteins; Proteins; Amino Acids, Peptides, and Proteins; Antigens; Biological Factors

Limitations and Caveats

Tuberculin nasal challenge did not proceed to full enrollment due to insufficient numbers of eligible participants. Samples were therefore not assessed for cytokine measurements.

Results Point of Contact

• Title: Professor Trevor Hansel
• Organization: Imperial College London

t.hansel@imperial.ac.uk

+44 (0)20 3312 5733

Study Officials

• Trevor Hansel, FRCPath, PhD

  Imperial College London

  PRINCIPAL INVESTIGATOR

• Peter JM Openshaw, FRCP, PhD, FRSB, FMedSci

  Imperial College London

  STUDY DIRECTOR

• Robin Shattock, PhD

  Imperial College London

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 11, 2014
• First Posted: March 18, 2014
• Study Start: March 1, 2014
• Primary Completion: March 1, 2017
• Study Completion: March 1, 2017
• Last Updated: November 5, 2021
• Results First Posted: November 3, 2021

Record last verified: 2021-11

Locations

GB (1)