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

NCT ID: NCT04901715

Last Updated: 2025-09-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 27 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-06-10
• Study Completion Date: 2024-07-22

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.

Conditions

Primary Ciliary Dyskinesia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Genotypes associated 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.

Group Type: ACTIVE_COMPARATOR

Albuterol

Intervention Type: DRUG

Albuterol HFA Metered Dose Inhaler (90mcg/puff). Subjects to use 4 puffs one time.

Technetium99m - Sulfur Colloid (Tc99m-SC)

Intervention Type: DIAGNOSTIC_TEST

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.

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.

Group Type: ACTIVE_COMPARATOR

Albuterol

Intervention Type: DRUG

Albuterol HFA Metered Dose Inhaler (90mcg/puff). Subjects to use 4 puffs one time.

Technetium99m - Sulfur Colloid (Tc99m-SC)

Intervention Type: DIAGNOSTIC_TEST

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.

Healthy Control

Healthy subjects with no pre-existing lung disease.

Group Type: ACTIVE_COMPARATOR

Albuterol

Intervention Type: DRUG

Albuterol HFA Metered Dose Inhaler (90mcg/puff). Subjects to use 4 puffs one time.

Technetium99m - Sulfur Colloid (Tc99m-SC)

Intervention Type: DIAGNOSTIC_TEST

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.

Interventions

Albuterol

Albuterol HFA Metered Dose Inhaler (90mcg/puff). Subjects to use 4 puffs one time.

Intervention Type: DRUG

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 three quarters of the adult dose to account for the smaller lung volume.

Intervention Type: DIAGNOSTIC_TEST

Other Intervention Names

ProAir HFA hydrofluoroalkane (HFA) Inhaler; Ventolin HFA (hydrofluoroalkane) Inhaler

Eligibility Criteria

Inclusion Criteria

• 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

• 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.

• Minimum Eligible Age: 12 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of North Carolina, Chapel Hill

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Lawrence Ostrowski, PhD

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina at Chapel Hil

Locations

University of North Carolina Chapel Hill

Chapel Hill, North Carolina, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

R01HL117836

Identifier Type: NIH

Identifier Source: secondary_id

View Link

20-3465

Identifier Type: -

Identifier Source: org_study_id