Probiotics and Capsaicin Evoked Coughs

Study Overview
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Brief Summary
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Cough in asthma is a very common and troublesome symptom in asthma, which predicts severity and poor prognosis. Previous studies have shown that asthmatics have an exaggerated cough response to capsaicin. Currently available asthma treatment is not designed to target the cough reflex directly, so this presents an unmet need for patients. The treatment being tested in this study is the commercially available over the counter oral probiotic BioGaia® DSM17938. Based on clinical and pre-clinical evidence, it is hypothesized that TRPV1 antagonism with BioGaia® DSM17938 will result in a reduction in capsaicin evoked coughs in patients with asthma.

Detailed Description
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Visit 1: Baseline Screening and Beginning of Treatment Period 1 Subjects will undergo consent, complete history, physical examination, spirometry, capsaicin cough challenge, skin prick testing (allergen and histamine), methacholine challenge, induced sputum and blood sampling. Eligible subjects will then be randomized with matched oral BioGaia DSM17938 and placebo and will be given for the next 4 weeks. Visit 2: End of Treatment Period 1 Subjects will undergo spirometry, capsaicin cough challenge, skin prick testing, methacholine challenge, sputum induction and blood testing. Washout: 28 day washout period prior to Visit 3. Visit 3: Beginning of Treatment Period 2 Subjects wills undergo all the same tests performed in visit 2. Drug/Placebo will be given for the next 28 days. Visit 4: End of Treatment Period 2 Subjects will undergo all the same tests performed in visit 2.

Official Title
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A Double-Blind Randomized Placebo Controlled Trial Investigating the Effects of DSM17938 on Capsaicin Evoked Coughs

Conditions
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Atopic Asthma

Intervention / Treatment
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* Dietary Supplement: BioGaia-DSM17938
* Other: Placebo Comparator: Placebo Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥18 Able to understand and give written informed consent Has a diagnosis of atopic asthma (based on at least one positive skin prick test and Methacholine PC20 ≤16 mg/ml) FEV1 (forced expiratory volume at 1 second) ≥ 70% of predicted Demonstrate a cough response to capsaicin Exclusion Criteria: Subjects who are in a pollen season that affects their asthma Subjects who bronchoconstrict by more than 10% at the end of the full dose capsaicin cough challenge (assess after visit 1) Subjects who do not display evidence of airway hyper-responsiveness (PC20>16mg/ml) (assess after visit 1) Symptoms of upper respiratory tract infection (URTI) in the last 1 month which have not resolved. Lower respiratory tract infection or pneumonia in the last 6 weeks. Current smoker or ex-smoker with ≥10 pack year smoking history and abstinence of ≤6 months Asthma exacerbation in the previous month requiring an increase or start of an ICS (inhaled corticosteroids) or OCS (oral corticosteroids) Any asthma medication with the exception of infrequent (less than twice weekly) short-acting beta-agonist. Subjects who have changed asthma medication within the past 4 weeks prior to screening A previous asthma exacerbation requiring Intensive Care Unit (ICU) admission. Significant other primary pulmonary disorders in particularly; pulmonary embolism, pulmonary hypertension, interstitial lung disease, lung cancer, cystic fibrosis, emphysema or bronchiectasis. Pregnancy or breast-feeding Use of ACE (angiotensin converting enzyme) inhibitors Any centrally acting medication which in the view of the investigator could alter the sensitivity of the cough reflex History of psychiatric illness, drug or alcohol abuse which may interfere in the participation of the trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Participants will have a screening period followed by 28 days treatment with BioGaia DSM17938 or placebo, followed by a washout period and will then crossover to the opposite treatment received in the first part of the study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BioGaia-DSM17938 then Placebo Comparator<br>28 days treatment with BioGaia-DSM17938, followed by 28 days washout and then crossover to 28 days placebo comparator treatment. | Dietary Supplement: BioGaia-DSM17938<br>* 2mL per day (1x10^9 CFU) per day taken orally for 28 days<br>Other: Placebo Comparator: Placebo Control<br>* 2mL per day of placebo formulation taken orally for 28 days<br>|
| Placebo Comparator: Placebo Comparator then BioGaia DSM17938<br>28 days treatment with placebo comparator treatment, followed by 28 days washout and then crossover to 28 days treatment with BioGaia DSM17938. | Dietary Supplement: BioGaia-DSM17938<br>* 2mL per day (1x10^9 CFU) per day taken orally for 28 days<br>Other: Placebo Comparator: Placebo Control<br>* 2mL per day of placebo formulation taken orally for 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Emax | The maximum number of capsaicin evoked coughs | Day 1, Day 30, Day 59 and Day 89 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ED50 (median effective dose) | The dose of capsaicin that evokes at least half the maximum number of coughs | Day 1, Day 30, Day 59 and Day 89 | 
| Dose response | Changes in the capsaicin full dose response curves | Day 1, Day 30, Day 59 and Day 89 | 
| C2 and C5 | Changes in the dose of capsaicin causing 2 coughs (C2) and 5 coughs (C5) | Day 1, Day 30, Day 59 and Day 89 | 
| Responses to histamine | The wheal responses to graded doses of histamine skin prick testing | Day 1, Day 30, Day 59 and Day 89 | 
| Itch Intensity | The intensity of itch after skin prick testing using a modified Borg scale (0-10) | Day 1, Day 30, Day 59 and Day 89 | 
| T-Cell Cytokine | Inhibition of T-Cell cytokine responses to stimulation in blood | Day 1, Day 30, Day 59 and Day 89 | 
| Sputum differential cell counts | Changes in sputum differential cell counts | Day 1, Day 30, Day 59 and Day 89 | 
| PC20 | Changes in methacholine PC20 | Day 1, Day 30. Day 59 and Day 89 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cough, Capsaicin, Probiotics, TRPV1