Functional Studies of Novel Genes Mutated in Primary Ciliary Dyskinesia II: Genotype to Phenotype

Early Phase 1

Recruiting

• Conditions: Primary Ciliary Dyskinesia
• Interventions: Drug: Albuterol; Diagnostic Test: Technetium99m - Sulfur Colloid (Tc99m-SC)

• Registration Number: NCT04901715
• Lead Sponsor: University of North Carolina, Chapel Hill

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.

Study Timeline

• Study First Submitted: 2021-05-19
• Study First Submitted QC: 2021-05-24
• Study First Posted: 2021-05-25
• Study Start: 2021-06-10
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-22
• Last Update Posted: 2024-08-26
• Primary Completion: 2025-04-30
• Study Completion: 2025-04-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

Not provided

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 LAIV (Live Attenuated Influenza Vaccine), 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Genotypes associated with severe phenotype	Albuterol	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.
Healthy Control	Technetium99m - Sulfur Colloid (Tc99m-SC)	Healthy subjects with no pre-existing lung disease.
Genotypes associated with severe phenotype	Technetium99m - Sulfur Colloid (Tc99m-SC)	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.
Genotypes associated mild phenotype	Technetium99m - Sulfur Colloid (Tc99m-SC)	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.
Genotypes associated mild phenotype	Albuterol	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.
Healthy Control	Albuterol	Healthy subjects with no pre-existing lung disease.

Primary Outcome Measures

Name	Time	Method
Baseline MCC (Ave60Clr; average clearance over 60 minutes)	60 minutes	The average percent clearance in subjects with 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 Outcome Measures

Name	Time	Method
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.

Trial Locations

Locations (1)

University of North Carolina Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States