Development of a Novel Non-invasive Inflammometry Following Allergen Challenge in Patients With Mild Allergic Asthma

Summary

The goal of this exploratory method-development study is to to establish and evaluate novel non-invasive methods to monitor airway inflammation induced by allergen challenge (both by instillation during bronchoscopy and by inhalation) in patients with mild allergic asthma. The investigator wants to further profile and develop the allergen challenge model by investigating the utility of various non-invasive monitoring methods. The hypothesis of the project is that local inflammatory changes in the lung induced by allergen can be captured by gas-enhanced magnetic resonance imaging (MRI) and analysis of exhaled breath. The validation of cellular outcome measures and non-invasive inflammometry can be used in future clinical trials for proof of concept of novel anti-inflammatory medications. Participants will undergo * methacholine challenge * 2 inhaled allergen challenges * 2 MRI with hyperpolarized xenon and gadolinium based contrast agent * 2 bronchoscopies with bronchoalveolar lavage (BAL) * segmental allergen challenge during the first bronchoscopy * spirometry * skin prick test and skin prick dilution tests * measurement of particles in exhaled air * nasal filter * nasal lavage * sputum induction * peak flow meter tests * exhaled NO (nictric oxide) * blood sampling (in total approx. 190 ml)

Eligibility

Inclusion Criteria:

1. Able and willing to give written informed consent.
2. Male and female subjects aged 18-65 years. Women will be considered for inclusion if they are:

   * Not pregnant, as confirmed by pregnancy test (see assessment schedule), and not nursing.
   * Of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is pre-menarcheal or post-menopausal, with documented proof of hysterectomy or tubal ligation, or meets clinical criteria for menopause and has been amenorrhoeic for more than 1 year prior to the Screening Visit).
   * Of childbearing potential and using a highly effective method of contraception during the entire study (vasectomised partner, sexual abstinence, implants, injectables, combined oral contraceptives, hormonal Intrauterine Devices (IUDs) or double-barrier methods, i.e. any double combination of IUD, condom with spermicidal gel, diaphragm, sponge, and cervical cap).
3. History of mild asthma for at least 12 months prior to the Screening Visit that is well controlled with Short Acting Beta-Adrenergic Stimulator (SABA) only.
4. Body mass index between 18 and 32 kg/m2
5. Normal pulmonary function with forced Expiratory Volume in the first second (FEV1) ≥80% of predicted normal and FEV1/Forced Vital Capacity(FVC) ≥70% at Screening Visit. Calculations will be based on Global Lung Function Initiative (GLI) formula. If the participant fails to meet this criterion on the first measurement, spirometry may be repeated twice.
6. Positive skin prick test (wheal diameter reaction ≥3 mm) for the respective challenge aeroallergen (i.e. tree, weed, grass or house dust mite) at or within 12 months prior to the Screening Visit (if performed and documented at Fraunhofer ITEM).
7. Positive early and late asthmatic response upon incremental inhaled allergen challenge at or prior to the Screening Visit (if performed and documented at Fraunhofer ITEM).
8. Production of adequate sputum with ≥1 x 106 total non-squamous cells at or within 12 month prior to the Screening Visit 1 (if not performed and documented at Fraunhofer ITEM).
9. Nonsmokers with a history of less than 1 pack year having been nonsmokers for at least one year.

Exclusion Criteria:

1. Any clinically relevant abnormal findings in physical examination, clinical chemistry, hematology, urinalysis, vital signs, lung function or ECG at Screening Visit, which, in the opinion of the investigator, may either put the subject at risk because of participation in the study or may influence the results of the study, or the subject's ability to participate in the study.
2. Past or present disease, which as judged by the investigator, may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease, malignancy, hepatic disease, renal disease, hematological disease, neurological disease, metabolic disease (asymptomatic Gilbert's syndrome is allowed), endocrine disease (stable and asymptomatic hypothyroidism with or without hormone replacement therapy (HRT) is allowed), or pulmonary disease (including but not confined to chronic bronchitis, emphysema, tuberculosis, bronchiectasis or cystic fibrosis).
3. Regular intake of any prescribed or over the counter medication. Exceptions include paracetamol for pain relief, contraceptive medication, hormonal replacement therapy, dietary and vitamin supplements.
4. Specific Immunotherapy (SIT) within three years prior to the study.
5. Intake of systemic or inhaled steroids within 4 weeks before Screening Visit 1a.
6. Respiratory tract infection (RTI) within 4 weeks before Screening Visit 1a.
7. Mild to moderate asthma exacerbation within 3 months before Screening Visit 1a.
8. Any history of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest or hypoxic seizures.
9. Suspected hypersensitivity to any ingredients of the medication in line with bronchoscopy (bronchodilators, sedatives and local anesthetics).
10. Conditions or factors, which would make the subject unlikely to be able to undergo bronchoscopy or allergen challenge.
11. Conditions or factors, which would make the subject unlikely to undergo MRI (e.g. due to claustrophobia, cardiac pacemaker, hypersensitivity to MR i.v. contrast imaging agents).
12. Participation in another clinical trial with Investigational Medicinal Product (IMP) 30 days or 5 half-lives, whichever is longer, prior to enrollment.
13. Participation in the observation period of a competing study within 30 days prior to Screening.
14. Segmental allergen challenge three months prior to bronchoscopy.
15. Donation of more than 400 ml of blood the preceding 60 days before screening.
16. History of regular drug or alcohol abuse
17. Risk of non-compliance with study procedures.
18. Suspected inability to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study.

Conditions2

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