Primary Ciliary Dyskinesia
Conditions
Keywords
Mucociliary clearance, Radial Spoke Head Component 1 (RSPH1), Dynein Axonemal Heavy Chain 5 (DNAH5), albuterol, short acting beta-adrenergic (SABA), SABA
Brief summary
The purpose of this study is to measure mucociliary clearance (MCC) in groups of subjects with the disease Primary Ciliary Dyskinesia (PCD) caused by mutations in different genes, and compare to healthy subjects. Some of these genes are associated with a milder clinical phenotype. This study seeks to determine if the milder phenotype is a result of mutations in a set of specific genes. The hypothesis is that subjects with PCD caused by mutations in the milder group will maintain a low, but significant rate of mucociliary clearance, while patients with mutations in genes in the more severe group will have a complete absence of mucociliary clearance. These studies will help inform future treatment strategies.
Detailed description
Participants will undergo screening with basic physical exam and lung function testing at the start of the study. Participants will then inhale a radiolabeled substance and undergo medical imaging to measure the clearance of mucus in the airways. Albuterol will be administered after the first imaging is completed. Lung function testing will be repeated. Finally, medical imaging will be repeated two more times to further look at clearance of mucus in the lungs. The study will be completed in one day and will last about 6 hours.
Interventions
DRUGAlbuterol
Albuterol HFA Metered Dose Inhaler (90mcg/puff). Subjects to use 4 puffs one time.
DIAGNOSTIC_TESTTechnetium99m - Sulfur Colloid (Tc99m-SC)
Aerosolized radiolabeled Tc99m-sulfur colloid will be delivered using a modified Pari-LC Star nebulizer. The activity of Tc99m-SC loaded in the nebulizer will be adjusted to provide an estimated 40 microcurie (µCi) deposited in the lung for the MCC/CC scan. Patients between the age 12-18 years old will receive three quarters of the adult dose to account for the smaller lung volume.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of North Carolina, Chapel Hill
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 90 Years
Healthy volunteers
Yes
Inclusion criteria
for PCD Patients * Confirmed PCD diagnosis with identified genetic mutations * Negative pregnancy test for females who are not s/p hysterectomy with oophorectomy * Forced Expiratory Volume (FEV1) of at least 30 percent of predicted Inclusion Criteria for Healthy Controls: * Age ≥ 18 years old * Subjects must have an Forced vital capacity (FVC), Forced Expiratory Volume in one second (FEV1) and FVC/FEV1 of at least 80% of predicted. Subjects who fall out of the normal range will be offered a copy of the test to share with their personal physician. * No pre-existing lung disease (asthma, cystic fibrosis, etc.). * Negative pregnancy test for females who are not s/p hysterectomy with oophorectomy.
Exclusion criteria
* Any chronic medical condition considered by the PI as a contraindication to the exposure study including significant cardiovascular disease, diabetes, chronic renal disease, chronic thyroid disease, immunodeficiency, 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 * History of vaping or current vaping. * Viral upper respiratory tract infection within 4 weeks of challenge. * Radiation exposure history in the past year which would be outside the safe levels * Pregnant or lactating women will also be excluded since the risks associated with radiation are unknown and cannot be justified * Use of the following medications: 1. Use of beta blocking medications 2. Receipt of Live Attenuated Influenza Vaccine (LAIV), also known as FluMist , within the prior 30 days, or any vaccine within the prior 5 days 3. Multivitamins, Vitamin C or E or herbal medications in the 4 days prior to the treatment visit 4. Non-steroidal anti-inflammatory drugs in the 4 days prior to the treatment visit. * Allergy/sensitivity to study drugs or their formulations: * Known Immunoglobulin E (IgE) mediated hypersensitivity to albuterol * Physical/laboratory indications: 1. Temperature \> 37.8 degrees Celsius (C) 2. Subjects \>15 years- Systolic BP \>150 mm hg or \< 90 mm Hg or diastolic BP\> 90 mm Hg or \< 50 and Subjects 12-15 years - Systolic BP \> 130 mmHg or \< 80 mmHg or diastolic BP \> 80 or \<40 3. Oxygen saturation of \< 93 percent * Inability or unwillingness of a participant to give written informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline MCC (Ave60Clr; Average Clearance Over 60 Minutes) | 60 minutes | The average percent clearance in subjects with Primary Ciliary Dyskinesia (PCD) caused by mutations associated with mild and severe clinical phenotypes. Prior to each MCC study, a transmission Co57 scan will be performed to define the lung boundaries, to assign regions of interest, and to normalize these regions for lung volume differences. Radiolabeled Tc99m-sulfur colloid will be delivered using a modified Pari-LC Star nebulizer. The subject will then (within a minute of final inhalation maneuver) be seated in front of a large-field-of-view gamma camera to begin acquiring consecutive 2 minute images. The first two-2-minute images will provide initial, time zero activity (i.e. 100% retention) followed by the same imaging at the start of every 10-minute period until 1 hour has passed to assess baseline MCC. Clearance will be determined by measuring the decrease in radiolabeled Tc99m-sulfur colloid in the lungs over time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in MCC (Ave120Clr-Ave60Clr;Average Clearance Between 60 and 120 Minutes) | 120 minutes | The change in average percent clearance after the administration of albuterol in subjects with PCD caused by mutations associated with mild and severe clinical phenotypes PCD patients with mild disease compared to PCD patients with more severe disease. A transmission Cobalt57 scan will be performed to define the lung boundaries. Radiolabeled Tc99m-sulfur colloid (Technetium99m) will be delivered using a modified nebulizer. The subject will be seated in front of a large-field-of-view gamma camera to begin consecutive 2 minute images. The first two-2-minute images will provide initial, time zero activity followed by the same imaging at every 10-minute period until 1 hour. Subjects will then inhale 4 puffs of albuterol from the Metered Dose Inhaler (MDI) and consecutive 2 minute imaging continues for the next hour to assess the effect of albuterol on MCC. Clearance will be determined by measuring the decrease in radiolabeled Tc99m-sulfur colloid in the lungs over time. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Cough Clearance (Ave150Clr-Ave120Clr; Average Clearance Between 120 and 150 Minutes) | 150 minutes | The change in average percent of cough clearance in subjects with PCD caused by mutations associated with mild and severe clinical phenotypes PCD patients with mild disease compared to PCD patients with more severe disease. After completion of baseline MCC measurement and post-Albuterol MCC measurement. Subjects will cough a total of 30 times over a 30-minute period to assess cough clearance by gamma imaging over that period. Clearance will be determined by measuring the decrease in radiolabeled Tc99m-sulfur colloid in the lungs over time. |
Countries
United States
Participant flow
Pre-assignment details
Of the 27 participants who signed informed consent, three participants failed screening and were ineligible to continue participation and did not receive the study intervention.
Participants by arm
| Arm | Count |
|---|---|
| Genotypes Associated With Mild Phenotype Subjects with 2 confirmed mutations in RSPH1, Radial Spoke Head Component 9 (RSPH9), Radial Spoke Head Component 4A (RSPH4a), or Dynein Axonemal Heavy Chain 11 (DNAH11). This group may also include subjects with mutations in newly identified genes that are associated with a milder clinical phenotype.
Albuterol: Albuterol HFA Metered Dose Inhaler (90mcg/puff). Subjects to use 4 puffs one time.
Technetium99m - Sulfur Colloid (Tc99m-SC): Aerosolized radiolabeled Tc99m-sulfur colloid will be delivered using a modified Pari-LC Star nebulizer. The activity of Tc99m-SC loaded in the nebulizer will be adjusted to provide an estimated 40 microcurie (µCi) deposited in the lung for the MCC/CC scan. Patients between the age 12-18 years old will receive ¾ of the adult dose to account for the smaller lung volume. | 8 |
| Genotypes Associated With Severe Phenotype Subjects with 2 confirmed mutations in DNAH5, Dynein Axonemal Intermediate Chain 1 (DNAI1), Coiled-Coil Domain Containing 39 (CCDC39), or Coiled-Coil Domain Containing 40 (CCDC40). This group may also include subjects with mutations in newly identified genes that are associated with a more severe clinical phenotype.
Albuterol: Albuterol HFA Metered Dose Inhaler (90mcg/puff). Subjects to use 4 puffs one time.
Technetium99m - Sulfur Colloid (Tc99m-SC): Aerosolized radiolabeled Tc99m-sulfur colloid will be delivered using a modified Pari-LC Star nebulizer. The activity of Tc99m-SC loaded in the nebulizer will be adjusted to provide an estimated 40 microcurie (µCi) deposited in the lung for the MCC/CC scan. Patients between the age 12-18 years old will receive ¾ of the adult dose to account for the smaller lung volume. | 8 |
| Healthy Control Healthy subjects with no pre-existing lung disease.
Albuterol: Albuterol HFA Metered Dose Inhaler (90mcg/puff). Subjects to use 4 puffs one time.
Technetium99m - Sulfur Colloid (Tc99m-SC): Aerosolized radiolabeled Tc99m-sulfur colloid will be delivered using a modified Pari-LC Star nebulizer. The activity of Tc99m-SC loaded in the nebulizer will be adjusted to provide an estimated 40 microcurie (µCi) deposited in the lung for the MCC/CC scan. Patients between the age 12-18 years old will receive ¾ of the adult dose to account for the smaller lung volume. | 8 |
| Total | 24 |
Baseline characteristics
| Characteristic | Genotypes Associated With Mild Phenotype | Genotypes Associated With Severe Phenotype | Healthy Control | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 3 Participants | 0 Participants | 6 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 5 Participants | 8 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 8 Participants | 6 Participants | 21 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 | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 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 | 6 Participants | 8 Participants | 8 Participants | 22 Participants |
| Region of Enrollment United States | 8 Participants | 8 Participants | 8 Participants | 24 Participants |
| Sex: Female, Male Female | 5 Participants | 1 Participants | 3 Participants | 9 Participants |
| Sex: Female, Male Male | 3 Participants | 7 Participants | 5 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Baseline MCC (Ave60Clr; Average Clearance Over 60 Minutes)
The average percent clearance in subjects with Primary Ciliary Dyskinesia (PCD) caused by mutations associated with mild and severe clinical phenotypes. Prior to each MCC study, a transmission Co57 scan will be performed to define the lung boundaries, to assign regions of interest, and to normalize these regions for lung volume differences. Radiolabeled Tc99m-sulfur colloid will be delivered using a modified Pari-LC Star nebulizer. The subject will then (within a minute of final inhalation maneuver) be seated in front of a large-field-of-view gamma camera to begin acquiring consecutive 2 minute images. The first two-2-minute images will provide initial, time zero activity (i.e. 100% retention) followed by the same imaging at the start of every 10-minute period until 1 hour has passed to assess baseline MCC. Clearance will be determined by measuring the decrease in radiolabeled Tc99m-sulfur colloid in the lungs over time.
Time frame: 60 minutes
Population: One participant was originally included in the Genotypes Associated with Mild Phenotype Arm based on available knowledge. Upon further study of the genotype, it was concluded that this participant did not meet the criteria for a mild phenotype and was therefore excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Genotypes Associated With Mild Phenotype | Baseline MCC (Ave60Clr; Average Clearance Over 60 Minutes) | 1.4 percent clearance |
| Genotypes Associated With Severe Phenotype | Baseline MCC (Ave60Clr; Average Clearance Over 60 Minutes) | -1.1 percent clearance |
| Healthy Control | Baseline MCC (Ave60Clr; Average Clearance Over 60 Minutes) | 7.3 percent clearance |
p-value: 0.002ANOVA
p-value: 0.054ANOVA
p-value: 0.27ANOVA
Secondary
Change in MCC (Ave120Clr-Ave60Clr;Average Clearance Between 60 and 120 Minutes)
The change in average percent clearance after the administration of albuterol in subjects with PCD caused by mutations associated with mild and severe clinical phenotypes PCD patients with mild disease compared to PCD patients with more severe disease. A transmission Cobalt57 scan will be performed to define the lung boundaries. Radiolabeled Tc99m-sulfur colloid (Technetium99m) will be delivered using a modified nebulizer. The subject will be seated in front of a large-field-of-view gamma camera to begin consecutive 2 minute images. The first two-2-minute images will provide initial, time zero activity followed by the same imaging at every 10-minute period until 1 hour. Subjects will then inhale 4 puffs of albuterol from the Metered Dose Inhaler (MDI) and consecutive 2 minute imaging continues for the next hour to assess the effect of albuterol on MCC. Clearance will be determined by measuring the decrease in radiolabeled Tc99m-sulfur colloid in the lungs over time.
Time frame: 120 minutes
Population: One participant was originally included in the Genotypes Associated with Mild Phenotype Arm based on available knowledge. Upon further study of the genotype, it was concluded that this participant did not meet the criteria for a mild phenotype and was therefore excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Genotypes Associated With Mild Phenotype | Change in MCC (Ave120Clr-Ave60Clr;Average Clearance Between 60 and 120 Minutes) | 0.82 percent clearance |
| Genotypes Associated With Severe Phenotype | Change in MCC (Ave120Clr-Ave60Clr;Average Clearance Between 60 and 120 Minutes) | -0.42 percent clearance |
| Healthy Control | Change in MCC (Ave120Clr-Ave60Clr;Average Clearance Between 60 and 120 Minutes) | 9.7 percent clearance |
p-value: 0.014ANOVA
p-value: 0.066ANOVA
p-value: 0.58ANOVA
Other Pre-specified
Change in Cough Clearance (Ave150Clr-Ave120Clr; Average Clearance Between 120 and 150 Minutes)
The change in average percent of cough clearance in subjects with PCD caused by mutations associated with mild and severe clinical phenotypes PCD patients with mild disease compared to PCD patients with more severe disease. After completion of baseline MCC measurement and post-Albuterol MCC measurement. Subjects will cough a total of 30 times over a 30-minute period to assess cough clearance by gamma imaging over that period. Clearance will be determined by measuring the decrease in radiolabeled Tc99m-sulfur colloid in the lungs over time.
Time frame: 150 minutes