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

Primary Purpose

Primary Ciliary Dyskinesia

Status
Recruiting
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Albuterol
Technetium99m - Sulfur Colloid (Tc99m-SC)
Sponsored by
University of North Carolina, Chapel Hill
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Primary Ciliary Dyskinesia focused on measuring Mucociliary clearance, Radial Spoke Head Component 1 (RSPH1), Dynein Axonemal Heavy Chain 5 (DNAH5), albuterol, short acting beta-adrenergic (SABA), SABA

Eligibility Criteria

12 Years - 90 Years (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • University of North Carolina Chapel HillRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Active Comparator

Arm Label

Genotypes associated mild phenotype

Genotypes associated with severe phenotype

Healthy Control

Arm Description

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.

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 subjects with no pre-existing lung disease.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Full Information

First Posted
May 19, 2021
Last Updated
May 4, 2023
Sponsor
University of North Carolina, Chapel Hill
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT04901715
Brief Title
Functional Studies of Novel Genes Mutated in Primary Ciliary Dyskinesia II: Genotype to Phenotype
Official Title
Functional Studies of Novel Genes Mutated in Primary Ciliary Dyskinesia II: Genotype to Phenotype
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 10, 2021 (Actual)
Primary Completion Date
April 30, 2024 (Anticipated)
Study Completion Date
April 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of North Carolina, Chapel Hill
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Basic Science
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Genotypes associated mild phenotype
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Genotypes associated with severe phenotype
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Healthy Control
Arm Type
Active Comparator
Arm Description
Healthy subjects with no pre-existing lung disease.
Intervention Type
Drug
Intervention Name(s)
Albuterol
Other Intervention Name(s)
ProAir HFA (hydrofluoroalkane) Inhaler, Ventolin HFA (hydrofluoroalkane) Inhaler
Intervention Description
Albuterol HFA Metered Dose Inhaler (90mcg/puff). Subjects to use 4 puffs one time.
Intervention Type
Diagnostic Test
Intervention Name(s)
Technetium99m - Sulfur Colloid (Tc99m-SC)
Intervention Description
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.
Primary Outcome Measure Information:
Title
Baseline MCC (Ave60Clr; average clearance over 60 minutes)
Description
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.
Time Frame
60 minutes
Secondary Outcome Measure Information:
Title
Change in MCC (Ave120Clr-Ave60Clr;average clearance between 60 and 120 minutes)
Description
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
Other Pre-specified Outcome Measures:
Title
Change in cough clearance (Ave150Clr-Ave120Clr; average clearance between 120 and 150 minutes)
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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: Use of beta blocking medications Receipt of LAIV (Live Attenuated Influenza Vaccine), 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: Known Immunoglobulin E (IgE) mediated hypersensitivity to albuterol Physical/laboratory indications: Temperature > 37.8 degrees Celsius (C) 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 Oxygen saturation of < 93 percent Inability or unwillingness of a participant to give written informed consent.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Corinne N Lawler, MR
Phone
919-962-9841
Email
corinne.lawler@unc.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lawrence Ostrowski, PhD
Organizational Affiliation
University of North Carolina at Chapel Hil
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of North Carolina Chapel Hill
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27514
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sara Abu-Nasser, DO
Phone
984-987-1072
Email
sabunass@email.unc.edu
First Name & Middle Initial & Last Name & Degree
Corinne N Lawler
Phone
919-962-9841
Email
corinne.lawler@unc.edu

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.

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

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