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

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.

Study Overview

• Status: Recruiting
• Conditions: Primary Ciliary Dyskinesia
• Intervention / Treatment: Drug: Albuterol; Diagnostic test: Technetium99m - Sulfur Colloid (Tc99m-SC)

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 Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Corinne N Lawler, MR; Phone Number: 919-962-9841; Email: corinne.lawler@unc.edu

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • Recruiting
      • University of North Carolina Chapel Hill
      • Contact: Sara Abu-Nasser, DO; Phone Number: 984-987-1072; Email: sabunass@email.unc.edu
      • Contact: Corinne N Lawler; Phone Number: 919-962-9841; Email: corinne.lawler@unc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 90 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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 FVC, 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 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: Albuterol; Albuterol HFA Metered Dose Inhaler (90mcg/puff). Subjects to use 4 puffs one time.; Other Names: ProAir HFA (hydrofluoroalkane) Inhaler; Ventolin HFA (hydrofluoroalkane) Inhaler; Diagnostic test: 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 uCi 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.
Active Comparator: 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.	Drug: Albuterol; Albuterol HFA Metered Dose Inhaler (90mcg/puff). Subjects to use 4 puffs one time.; Other Names: ProAir HFA (hydrofluoroalkane) Inhaler; Ventolin HFA (hydrofluoroalkane) Inhaler; Diagnostic test: 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 uCi 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.
Active Comparator: Healthy Control; Healthy subjects with no pre-existing lung disease.	Drug: Albuterol; Albuterol HFA Metered Dose Inhaler (90mcg/puff). Subjects to use 4 puffs one time.; Other Names: ProAir HFA (hydrofluoroalkane) Inhaler; Ventolin HFA (hydrofluoroalkane) Inhaler; Diagnostic test: 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 uCi 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline MCC (Ave60Clr; average clearance over 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.	60 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	120 minutes

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	150 minutes

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2021
• Primary Completion (Anticipated): April 30, 2024
• Study Completion (Anticipated): April 30, 2024

Study Registration Dates

• First Submitted: May 19, 2021
• First Submitted That Met QC Criteria: May 24, 2021
• First Posted (Actual): May 25, 2021

Study Record Updates

• Last Update Posted (Estimate): May 8, 2023
• Last Update Submitted That Met QC Criteria: May 4, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: albuterol; SABA; Mucociliary clearance; Radial Spoke Head Component 1 (RSPH1); Dynein Axonemal Heavy Chain 5 (DNAH5); short acting beta-adrenergic (SABA)
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Respiratory Tract Diseases; Neurologic Manifestations; Congenital Abnormalities; Genetic Diseases, Inborn; Otorhinolaryngologic Diseases; Movement Disorders; Abnormalities, Multiple; Ciliopathies; Dyskinesias; Ciliary Motility Disorders; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Albuterol
• Other Study ID Numbers: 20-3465; R01HL117836 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified individual data that supports the results will be shared beginning 12 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.
• IPD Sharing Time Frame: 12-36 months following publication
• IPD Sharing Access Criteria: Investigators with IRB, IEC, or REB approval and an executed data use/sharing agreement with UNC.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No