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

NCT04901715 | Completed Early Phase 1 Results DMC FDA Drug

• 2 other identifiers: 20-3465R01HL117836
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

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.

Conditions

Primary Ciliary Dyskinesia

Keywords

Mucociliary clearance; Radial Spoke Head Component 1 (RSPH1); Dynein Axonemal Heavy Chain 5 (DNAH5); albuterol; short acting beta-adrenergic (SABA); SABA

Outcome Measures

Primary Outcomes (1)

• 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.

  60 minutes

Secondary Outcomes (1)

• Change in MCC (Ave120Clr-Ave60Clr;Average Clearance Between 60 and 120 Minutes)

  120 minutes

Other Outcomes (1)

• Change in Cough Clearance (Ave150Clr-Ave120Clr; Average Clearance Between 120 and 150 Minutes)

  150 minutes

Study Arms (3)

Genotypes associated mild phenotype

ACTIVE COMPARATOR

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.

Drug: Albuterol; Diagnostic Test: Technetium99m - Sulfur Colloid (Tc99m-SC)

Genotypes associated with severe phenotype

ACTIVE COMPARATOR

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.

Drug: Albuterol; Diagnostic Test: Technetium99m - Sulfur Colloid (Tc99m-SC)

Healthy Control

ACTIVE COMPARATOR

Healthy subjects with no pre-existing lung disease.

Drug: Albuterol; Diagnostic Test: Technetium99m - Sulfur Colloid (Tc99m-SC)

Interventions

Albuterol DRUG

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

Also known as: ProAir HFA hydrofluoroalkane (HFA) Inhaler, Ventolin HFA (hydrofluoroalkane) Inhaler

Genotypes associated mild phenotype; Genotypes associated with severe phenotype; Healthy Control

Technetium99m - Sulfur Colloid (Tc99m-SC) 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 mild phenotype; Genotypes associated with severe phenotype; Healthy Control

Eligibility Criteria

• Age: 12 Years - 90 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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:
• Use of beta blocking medications
• Receipt of Live Attenuated Influenza Vaccine (LAIV), also known as FluMist , within the prior 30 days, or any vaccine within the prior 5 days
• Multivitamins, Vitamin C or E or herbal medications in the 4 days prior to the treatment visit
• Non-steroidal anti-inflammatory drugs in the 4 days prior to the treatment visit.
• Allergy/sensitivity to study drugs or their formulations:

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

University of North Carolina Chapel Hill

Chapel Hill, North Carolina, 27514, United States

Location

MeSH Terms

Conditions

Ciliary Motility Disorders

Interventions

Albuterol; Nebulizers and Vaporizers; apaflurane

Condition Hierarchy (Ancestors)

Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Ciliopathies; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Phenethylamines; Ethylamines; Equipment and Supplies

Results Point of Contact

• Title: Kelli Sullivan, MPH
• Organization: University of North Carolina at Chapel Hill

kelli_sullivan@med.unc.edu

919-962-9786

Study Officials

• Lawrence Ostrowski, PhD

  University of North Carolina at Chapel Hil

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 19, 2021
• First Posted: May 25, 2021
• Study Start: June 10, 2021
• Primary Completion: July 22, 2024
• Study Completion: July 22, 2024
• Last Updated: September 5, 2025
• Results First Posted: September 5, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: 12-36 months following publication
• Access Criteria: Investigators with IRB, IEC, or REB approval and an executed data use/sharing agreement with UNC.

Locations

US (1)