Moderate to Severe Asthma
Conditions
Keywords
asthma, hypertonic saline
Brief summary
Purpose: To determine if inhaled hypertonic saline (HS) accelerates airway mucociliary clearance (MCC) in well-controlled moderate to severe asthmatics.
Detailed description
Participants: Non-smoking adults with well controlled moderate to severe asthma Procedures (methods): After undergoing a general health screen, participants will undergo a lung transmission scan to create an image of the lungs. In subsequent visits, participants will inhale nebulized radiolabeled aerosol and sit in front of a gamma camera for 2 hours to measure clearance of radiolabeled particles from the lungs (procedure called gamma scintigraphy), which will be used to calculate baseline MCC. Spirometry will be performed before and at regular intervals after HS to assess for clinically significant reductions in lung function. Vital signs and symptom questionnaires will be administered as well. If participants are deemed tolerant to HS (i.e., no clinically significant deterioration in lung function, vital signs, or symptom questionnaire scores), participants will move forward with study visits.
Interventions
DEVICE3% Hypertonic Saline
4 mL of 3% hypertonic saline
DEVICE7% Hypertonic Saline
4 mL of 7% hypertonic saline
DRUGSalbutamol
4 puffs (90 mcg/actuation)
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of North Carolina, Chapel Hill
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
To access the efficacy of inhalation of 3% and 7% hypertonic saline
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-60 of both genders- * Moderate to severe asthma at baseline (determined by Step 3 therapy or greater or by asthma impairment) and well-controlled asthma at the time of enrollment, as determined by NHLBI Expert Panel Report 3 guidelines for diagnosis and treatment of asthma. * Negative pregnancy test for females who are not s/p hysterectomy with oophorectomy. * Forced expiratory volume in 1 sec (FEV1) of at least 70% of predicted for age, sex, height, and race/ethnicity (without use of bronchodilating medications for 12 hours or long acting beta agonists for 24 hours). * Documented COVID-19 vaccination
Exclusion criteria
Subjects who meet any of these criteria are not eligible for enrollment as study participants: 1. Clinical Contraindications: Any chronic medical condition considered by the PI as a contraindication to the study including significant cardiovascular disease, diabetes, chronic renal disease, chronic thyroid disease, history of chronic infections/immunodeficiency, or history of tuberculosis Any acute infection requiring antibiotics within 4 weeks of study. Mental illness or history of drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements. Medications which may impact the results of the study treatment, or may interfere with any other medications potentially used in the study (to include steroids, beta antagonists, non-steroidal anti-inflammatory agents) Active smoking to include e-cigarettes within 1 year of the study, or lifetime of \> 10 pack-years of smoking Allergy/sensitivity to study drugs, or their formulations. History of intubation for asthma Unwillingness to use reliable contraception if sexually active (birth control pills/patch, condoms). Viral upper respiratory tract infection within 4 weeks of challenge. Radiation exposure history in the past year that would cause the participant to exceed Federal radiation safety guidelines. 2. Pregnant women and children (\< 18 years as this is age of majority in NC) will also be excluded since the risks associated with hypertonic saline inhalation to the fetus or child and the risk of radiation are unknown and cannot be justified. 3. Use of the following medications: 1. Systemic corticosteroids; subjects with systemic corticosteroid-dependent asthma will be excluded. All use of systemic steroids in the last year will be reviewed by a study physician. 2. Use of daily theophylline within the past month 3. Use of any immunosuppressant/immunomodulatory therapy within the preceding 12 months 4. Use of beta blocking medications 5. Receipt of Live Attenuated Influenza Vaccine (LAIV), also known as FluMist®, within the prior 30 days, or any vaccine within the prior 5 days 6. Multivitamins, Vitamin C or E or herbal medications in the 4 days prior to the treatment visit 7. Non-steroidal anti-inflammatory drugs in the 4 days prior to the treatment visit 8. Subjects must be able to withhold morning doses of maintenance inhalers on the treatment days, including long acting bronchodilators and inhaled corticosteroids. 9. Positive COVID-19 test in the prior 90 days. 4. Allergy/sensitivity to study drugs or their formulations: Known Immunoglobulin E (IgE) -mediated hypersensitivity to albuterol, diphenhydramine or corticosteroids. 5. Physical/laboratory indications: 1. Abnormalities on lung auscultation 2. Temperature \> 37.8 3. Systolic BP \>150 mm Hg or \< 90 mm Hg or diastolic BP\> 90 mm Hg or \< 50 4. Oxygen saturation of \< 93% 6. Inability or unwillingness of a participant to give written informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in MCC From Baseline to 7% Post Hypertonic Saline Inhalation | Baseline MCC and at 2-12 weeks later MCC immediately after inhaled 7% HS, within approximately '15' minutes | This outcome was the primary outcome maintained across the entire study (all cohorts). Smaller cohorts also examined the effect of 7% HS on MCC 4 hours after inhalation (Cohort 1), the effect of 3% HS on MCC immediate inhalation (Cohort 2), and the effect of albuterol alone on MCC (Cohort 3). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effects of Hypertonic Saline on MCC by Testing | Baseline MCC, and 1-6 weeks later (MCC scan administered 4 hours after 7% HS inhalation) | The purpose of this outcome during Cohort 1 was to determine if there was a prolonged effect on MCC by 7% HS 4 hours post. Following interim analysis, it was decided that measurement at this timepoint would not be pursued and this outcome was deleted by a protocol amendment. |
| The Proportion of Moderate to Severe Asthmatics Who Are Deemed 'Intolerant' to Hypertonic Saline | 30 minutes post-Hypertonic Saline | A persistent reduction in the forced expiratory volume in one second (FEV1) of greater than or equal to 10% from that day's baseline |
Countries
United States
Participant flow
Pre-assignment details
This exploratory study sought to determine the efficacy of 7% Hypertonic Saline (HS) for accelerating MCC acutely compared to baseline. Multiple cohorts evolved based on preliminary findings. Each cohort consisted of a Baseline MCC scan and albuterol+7% HS nebulization followed by MCC. In addition, differences in each cohort are as follows: cohort 1 late-phase 7% HS was assessed and in cohort 2, acute 3% HS was assessed and in cohort 3 acute albuterol alone was assessed.
Participants by arm
| Arm | Count |
|---|---|
| Early & Late-Phase Hypertonic Saline (HS) 7% (Cohort 1) Following screening, participants returned 1-6 weeks later and received albuterol alone followed by MCC. After another 1-6 weeks washout, participants then received late phase albuterol + 7% HS 4 hours post MCC. After another 1-6 weeks washout, participants then received albuterol + 7% HS followed by MCC. Five to ten days later participants returned for a discontinuation visit.
7% Hypertonic Saline: 4 mL of 7% hypertonic saline Salbutamol: 4 puffs (90 mcg/actuation), Albuterol | 10 |
| Hypertonic Saline (HS) 3% and 7% (Cohort 2) Following screening, participants returned 1-6 weeks later and received albuterol plus 3% HS followed by MCC. After another 1-6 weeks washout, participants then received albuterol + 7% HS followed by MCC. Five to ten days later participants returned for a discontinuation visit.
7% Hypertonic Saline: 4 mL of 7% hypertonic saline 3% Hypertonic Saline: 4 mL of 3% hypertonic saline Salbutamol: 4 puffs (90 mcg/actuation), Albuterol | 8 |
| Acute Hypertonic Saline (HS) 7% (Cohort 3) Following screening, participants returned 1-6 weeks later and received albuterol alone followed by MCC. After another 1-6 weeks washout, participants then received albuterol + 7% HS followed by MCC. Five to ten days later participants returned for a discontinuation visit.
7% Hypertonic Saline: 4 mL of 7% hypertonic saline Salbutamol: 4 puffs (90 mcg/actuation), Albuterol | 6 |
| Total | 24 |
Baseline characteristics
| Characteristic | Early & Late-Phase Hypertonic Saline (HS) 7% (Cohort 1) | Hypertonic Saline (HS) 3% and 7% (Cohort 2) | Acute Hypertonic Saline (HS) 7% (Cohort 3) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 8 Participants | 6 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 8 Participants | 6 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 7 Participants | 4 Participants | 19 Participants |
| Region of Enrollment United States | 10 Participants | 8 Participants | 6 Participants | 24 Participants |
| Sex: Female, Male Female | 9 Participants | 5 Participants | 4 Participants | 18 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 8 | 0 / 6 |
| other Total, other adverse events | 2 / 10 | 1 / 8 | 0 / 6 |
| serious Total, serious adverse events | 0 / 10 | 0 / 8 | 0 / 6 |
Outcome results
Primary
Change in MCC From Baseline to 7% Post Hypertonic Saline Inhalation
This outcome was the primary outcome maintained across the entire study (all cohorts). Smaller cohorts also examined the effect of 7% HS on MCC 4 hours after inhalation (Cohort 1), the effect of 3% HS on MCC immediate inhalation (Cohort 2), and the effect of albuterol alone on MCC (Cohort 3).
Time frame: Baseline MCC and at 2-12 weeks later MCC immediately after inhaled 7% HS, within approximately '15' minutes
Population: This outcome was the only outcome assessed across all cohorts of the study evaluating both the effect and tolerability of 7% HS immediately after inhalation. This is the most effective clinically relevant timepoint for effect and tolerability. For this endpoint, considering the entire sample size together was considered the most statistically sound way to report this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hypertonic Saline | Change in MCC From Baseline to 7% Post Hypertonic Saline Inhalation | 29.9 percent clearance | Standard Deviation 7.9 |
Comparison: Effect immediately following hypertonic saline treatment.p-value: <0.001Mixed Models Analysis
Secondary
Effects of Hypertonic Saline on MCC by Testing
The purpose of this outcome during Cohort 1 was to determine if there was a prolonged effect on MCC by 7% HS 4 hours post. Following interim analysis, it was decided that measurement at this timepoint would not be pursued and this outcome was deleted by a protocol amendment.
Time frame: Baseline MCC, and 1-6 weeks later (MCC scan administered 4 hours after 7% HS inhalation)
Population: Only 9 participants underwent study for 4-hour effect of Hypertonic Saline which was only studied in Cohort 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hypertonic Saline | Effects of Hypertonic Saline on MCC by Testing | 11.8 Percent clearance | Standard Deviation 8.3 |
Comparison: Effect of hypertonic saline 4 hours after treatment.p-value: 0.99Mixed Models Analysis
Secondary
The Proportion of Moderate to Severe Asthmatics Who Are Deemed 'Intolerant' to Hypertonic Saline
A persistent reduction in the forced expiratory volume in one second (FEV1) of greater than or equal to 10% from that day's baseline
Time frame: 30 minutes post-Hypertonic Saline
Population: This procedure was only done for Cohort 1. Data are reported for the 9 participants who completed the procedure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hypertonic Saline | The Proportion of Moderate to Severe Asthmatics Who Are Deemed 'Intolerant' to Hypertonic Saline | 0 proportion participants |