Mannitol-Induced Cough Challenge in Healthy Controls and Subjects With Mild Allergic Asthma (MICC)

• ClinicalTrials.gov Identifier: NCT03620422
• Recruitment Status: Completed
• First Posted: August 8, 2018
• Last Update Posted: February 17, 2020
• Sponsor: McMaster University
• Collaborators: Pharmaxis; AllerGen NCE Inc.
• Information provided by (Responsible Party): McMaster University

Study Description

Brief Summary:

The study aim is to investigate if changes in osmolarity using mannitol challenge can evoke coughing reproducibly in mild allergic asthmatics compared with healthy controls and if salbutamol can affect this. Phase 1 of this study is a reproducibility analysis of cough dose response to mannitol in a cohort of mild allergic asthmatics and healthy controls. Phase 2 is a double-blind, placebo-controlled analysis in mild allergic asthmatics assessing the effects of salbutamol on mannitol induced cough.

Condition or disease	Intervention/treatment	Phase
Asthma; Cough	Other: Mannitol; Drug: Salbutamol 5mg/mL; Other: Sodium Chloride 0.9% Inhl 3Ml	Not Applicable

Detailed Description:

The study will have a maximum of 4 visits separated by at least 24 hours. The first 2 visits will determine eligibility. All eligible subjects will be invited back for a third visit, and only subjects with mild allergic asthma will be invited back for a fourth visit.

Screening Period (Visits 1 and 2) - For All Subjects Eligible subjects will be identified during the initial screening procedures with measures of spirometry, hyperresponsiveness to methacholine, complete history, physical examination, allergen skin test, and mannitol cough challenge. The screening procedures will be conducted over 2 separate visits.

Reproducibility (Visit 3) - For Healthy Controls Ten normal healthy controls meeting study eligibility will return for visit 3. This visit must be at least 24h after the mannitol test at visit 1. These data will be used for assessing reproducibility of the mannitol induced coughs; Emax and the median effective dose (ED50).

Effects of Salbutamol (Visit 3 and 4) - For Mild Allergic Asthma Subjects Ten subjects with mild allergic asthma will return for visit 3 and 4. These visits must be at least 24h apart and no longer than 7 days. Mild allergic asthmatics will first receive salbutamol 2.5mg or saline placebo via a nebuliser and 15 mins later the forced expiratory volume at one second (FEV1) measured. Subjects will then undergo a mannitol cough challenge exactly like the previous mannitol cough challenges. These data will be used for determining the effects of salbutamol on mannitol-induced bronchoconstriction and cough.

Visit Windows Each visit must be separated by a minimum of 24 hours, and a maximum of 7 days. Study visits can be performed in the morning or afternoon, however for each subject the timing should be consistent with Visits 2 at the same time of day ± 2 hours

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: This is a mechanistic study. The first part of the study (mild allergic asthmatics and healthy controls) is to determine reproducibility of dose responses to mannitol-induced coughs. The second part of the study (mild asthmatics only) is to determine the effect of salbutamol on mannitol-induced coughs. Salbutamol or placebo will be delivered following a mannitol cough challenge in a randomized, double-blind crossover design.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Mannitol-Induced Cough Challenge in Healthy Controls and Subjects With Mild Allergic Asthma
• Actual Study Start Date: January 11, 2019
• Actual Primary Completion Date: January 31, 2020
• Actual Study Completion Date: January 31, 2020

Arms and Interventions

Arm	Intervention/treatment
Healthy Controls; Mannitol-Induced Cough Challenges on Visit 2 and 3. Mannitol delivered via inhalation. Dosage: 0, 5, 10, 20, 40 mg capsules. 80 and 160 mg doses delivered with two and four capsules, respectively.	Other: Mannitol; Mannitol-Induced Cough Challenge; Other Name: Aridol
Placebo Comparator: Mild Allergic Asthmatics (Saline); Mannitol-Induced Cough Challenges on Visit 2, 3 and 4. Nebulized placebo (Sodium Chloride 0.9% Inhl 3Ml) given prior to Mannitol-Induced Cough Challenges on Visit 3 or 4. Mannitol delivered via inhalation. Dosage: 0, 5, 10, 20, 40 mg capsules. 80 and 160 mg doses delivered with two and four capsules, respectively.	Other: Mannitol; Mannitol-Induced Cough Challenge; Other Name: Aridol; Other: Sodium Chloride 0.9% Inhl 3Ml; Nebulized 0.9% saline given prior to Mannitol-Induced Cough Challenge; Other Name: Placebo Comparator
Active Comparator: Mild Allergic Asthmatics (Salbutamol); Mannitol-Induced Cough Challenges on Visit 2, 3 and 4. Nebulized salbutamol (5mg/mL) given prior to Mannitol-Induced Cough Challenges on Visit 3 or 4. Mannitol delivered via inhalation. Dosage: 0, 5, 10, 20, 40 mg capsules. 80 and 160 mg doses delivered with two and four capsules, respectively.	Other: Mannitol; Mannitol-Induced Cough Challenge; Other Name: Aridol; Drug: Salbutamol 5mg/mL; Nebulized salbutamol given prior to Mannitol-Induced Cough Challenge; Other Name: Active Comparator

Outcome Measures

Primary Outcome Measures :

1. ED50 dose response curve [ Time Frame: Through study completion, an average of one year ]
   Median effective dose

Secondary Outcome Measures :

1. ED50 (post-bronchodilator) dose response curve [ Time Frame: Through study completion, an average of one year ]
   Median effective dose

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. Able to understand and give written informed consent
2. Male and female volunteers 18 through 65 years of age.
3. Positive skin-prick test to common aeroallergens (mild allergic asthmatic subjects)
4. Asthma as determined by methacholine provocative concentration causing a 20% fall (PC20) ≤16 mg/ml for mild allergic asthmatic subjects; no airway hyperresponsiveness as determined by methacholine PC20>16mg/ml for normal healthy controls.
5. Baseline FEV1 ≥ 70% of the predicted value for mild allergic asthmatic subjects; baseline FEV1≥ 80% of the predicted value for normal healthy controls.
6. Demonstrate cough response to inhaled mannitol

Exclusion Criteria:

1. Current or former smoker with >10-pack-year history
2. Current or previous history of other significant respiratory disease
3. Significant systemic disease, including history of current malignancy or autoimmune disease
4. Asthma exacerbation or upper/lower respiratory tract infection within the previous 8 weeks
5. Pregnancy
6. Use of corticosteroids within 28 days prior to the first study visit.
7. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) within 48 hours of study visits or aspirin with 7 days of study visits
8. Use of antihistamines including those in cold and allergy medications within 72 hours of study visits
9. Chronic use of other medication for treatment of allergic lung disease other than short-acting β2-agonists.
10. Use of caffeine-containing products within 4 hours of study visits
11. Use of Angiotensin converting enzyme inhibitors (ACE inhibitors)
12. Any centrally acting medication which in the view of the investigator could alter the sensitivity of the cough reflex including but not restricted to tricyclic anti-depressants, pregabalin, gabapentin, codeine, tramadol, or any other opioid.
13. Lung disease other than mild to moderate allergic asthma, for mild allergic asthmatic subjects; no lung disease for normal healthy controls.
14. Unwillingness or inability to comply with the study protocol for any other reason.

Contacts and Locations

Locations

Canada, Ontario

McMaster University

Hamilton, Ontario, Canada, L8N 3Z5

Sponsors and Collaborators

McMaster University

Pharmaxis

AllerGen NCE Inc.

Investigators

• Principal Investigator: Gail Gauvreau, PhD; McMaster University

More Information

• Responsible Party: McMaster University
• ClinicalTrials.gov Identifier: NCT03620422
• Other Study ID Numbers: McMaster-MICC4657
• First Posted: August 8, 2018
• Last Update Posted: February 17, 2020
• Last Verified: March 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by McMaster University:

Mannitol; Bronchoconstriction; Airway nerve function; Cough; Diagnostic Test; Osmolarity; Salbutamol

Additional relevant MeSH terms:

Asthma; Cough; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Mannitol; Albuterol; Bronchodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Asthmatic Agents; Respiratory System Agents; Tocolytic Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Adrenergic Agonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Diuretics, Osmotic; Diuretics