The Effects of Salbutamol on Mannitol Induced Cough Responses in Healthy Controls (COMA)

The study aim is to investigate if changes in osmolarity using mannitol challenge can evoke coughing healthy controls with no evidence of bronchoconstriction (PC20>16mg/ml or mannitol PD15 > 635 mg, or < 10% incremental fall in FEV1 between consecutive mannitol doses) and if salbutamol can affect this. This is a double-blind, placebo-controlled analysis in healthy controls assessing the effects of salbutamol on mannitol induced cough.

Study Overview

• Status: Completed
• Conditions: Cough
• Intervention / Treatment: Drug: Salbutamol 5mg/mL; Drug: Sodium Chloride 0.9% Inhl 3Ml

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 and 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.

Effects of Salbutamol (Visit 3 and 4) - For Healthy Control Subjects, Twenty subjects with no evidence of asthma will return for visit 3 and 4. These visits must be at least 24h apart and no longer than 7 days. Health controls 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 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 Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster University
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Cardio-Respiratory Research Lab

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Able to understand and give written informed consent.
2. Male and female volunteers 18 through 65 years of age.
3. No airway hyperresponsiveness as determined by methacholine PC20>16mg/ml or mannitol PD15 > 635 mg, or < 10% incremental fall in FEV1 between consecutive mannitol doses.
4. Fall in FEV1 of ≤ 5% after any mannitol dose during mannitol challenge compared to baseline FEV1 at 0 mg at screening mannitol challenge (Visit 2).
5. Baseline FEV1≥ 80% of the predicted value.
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. Pregnancy or breastfeeding.
5. Use of corticosteroids within 28 days prior to the first study visit.
6. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) within 48 hours of study visits or aspirin with 7 days of study visits
7. Use of antihistamines including those in cold and allergy medications within 72 hours of study visits
8. Use of caffeine-containing products within 4 hours of study visits
9. Use of ACE inhibitors
10. 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.
11. Unwillingness or inability to comply with the study protocol for any other reason

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Healthy Control - Active Arm; Healthy Controls Mannitol-Induced Cough Challenges on Visit 2 to determine elligibility (cough response). Mannitol delivered via inhalation. Dosage: 0, 5, 10, 20, 40 mg capsules. 80 and 160 mg doses delivered with two and four capsules, respectively. Nebulized salbutamol (5mg/mL) given prior to Mannitol-Induced Cough Challenges on Visit 3 or 4.	Drug: Salbutamol 5mg/mL; Nebulized salbutamol given prior to Mannitol-Induced Cough Challenge; Other Names: Ventolin nebuliser
PLACEBO_COMPARATOR: Healthy control - Placebo Arm; Healthy Controls Mannitol-Induced Cough Challenges on Visit 2 to determine elligibility (cough response). Mannitol delivered via inhalation. Dosage: 0, 5, 10, 20, 40 mg capsules. 80 and 160 mg doses delivered with two and four capsules, respectively. Nebulized 0.9% Saline given prior to Mannitol-Induced Cough Challenges on Visit 3 or 4.	Drug: Sodium Chloride 0.9% Inhl 3Ml; Nebulized 0.9% saline given prior to Mannitol-Induced Cough Challenge; Other Names: Placebo Comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary Outcome - Emax	The effect of salbutamol on mannitol induced coughs Emax - the maximum number of coughs at any dose of mannitol.	Through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cough dose response curves	Comparison of mannitol-induced cough dose response curves in normal healthy controls treated with salbutamol compared with placebo.	Through study completion, an average of 1 year
ED50	The effect of salbutamol on mannitol induced coughs E50 - the dose of mannitol causing half the maximal response.	Through study completion, an average of 1 year
C2	Comparison of the mannitol dose causing 2 coughs (C2) in a mannitol induced cough challenge in healthy controls treated with salbutamol compared with placebo.	Through study completion, an average of 1 year
C5	Comparison of the mannitol dose causing 5 coughs (C5) in a mannitol induced cough challenge in healthy controls treated with salbutamol compared with placebo.	Through study completion, an average of 1 year
Cumulative number of coughs	Comparison of the cumulative number of coughs in a mannitol induced cough challenge in healthy controls treated with salbutamol compared with placebo.	Through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: McMaster University

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 30, 2020
• Primary Completion (ACTUAL): December 16, 2021
• Study Completion (ACTUAL): December 16, 2021

Study Registration Dates

• First Submitted: August 17, 2020
• First Submitted That Met QC Criteria: September 24, 2020
• First Posted (ACTUAL): September 25, 2020

Study Record Updates

• Last Update Posted (ACTUAL): June 16, 2022
• Last Update Submitted That Met QC Criteria: June 13, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Cough; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Albuterol
• Other Study ID Numbers: McMaster-COMA-11537

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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