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19F MRI of Ventilation in Subjects With Cystic Fibrosis Undergoing Treatment for Pulmonary Exacerbation

Primary Purpose

Cystic Fibrosis

Status
Terminated
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Lung Clearance Index
MRI with PFP
Sponsored by
University of North Carolina, Chapel Hill
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Cystic Fibrosis focused on measuring imaging, hyperpolarized, perfluorinated, MRI, lung, multiple breath washout, lung clearance index

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Non-smokers (<10 pack year history and no active smoking in the past year);
  • Diagnosis of cystic fibrosis via standard sweat chloride/phenotypic features/genotyping
  • Able to reproducibly perform lung function testing and have an FEV1 >30% of predicted at screening.
  • No requirement for supplemental oxygen
  • Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the trial.
  • Participants must be willing and able to comply with scheduled visits and other trial procedures.

  • Diagnosis of a pulmonary exacerbation according to Fuchs criteria (4 of the following 12 signs and symptoms) deemed to require antibiotic treatment, and must also include the change in lung function criterion:

    • Change in sputum
    • New or increased hemoptysis
    • Increased cough
    • Increased dyspnea
    • Malaise, fatigue, or lethargy
    • Temperature above 38deg C
    • Anorexia or weight loss
    • Sinus pain or tenderness
    • Change in sinus discharge
    • Change in physical examination of the chest
    • Decrease in pulmonary function by 10% or more from a previously recorded value
    • Radiographic change indicative of pulmonary infection

Exclusion Criteria:

  • Under 18 years of age
  • Active or former smokers with less than 1 years since quitting, or >10 pack-year smoking history
  • Active asthma flare, as perceived by the study physician or unstable asthma characterized by advancement of asthma therapy in the last month or two courses of oral steroids in the past six months.

  • Unable to undergo a 3.0-Tesla MRI of lungs and chest because of contraindications including

    1. Occupation (past or present) of machinist, welder, grinder
    2. Injury to the eye involving a metallic object
    3. Injury to the body by a metallic object (bullet, BB, shrapnel)
    4. Presence of a cardiac pacemaker or defibrillator
    5. Presence of aneurysm clips
    6. Presence of carotid artery vascular clamp
    7. Presence of neurostimulator
    8. Presence of insulin or infusion pump
    9. Presence of implanted drug infusion device that is not known to be MRI compatible (i.e., was placed outside of University of North Carolina Hospitals (UNCH) or is older than 10 years)
    10. Bone growth or fusion simulator
    11. Presence of cochlear, otologic or ear implant
    12. Any type of prosthesis (eye, penile, etc.)
    13. Artificial limb or joint
    14. Non-removable electrodes (on body, head or brain)
    15. Intravascular stents, filters or coils
    16. Shunt (spinal or intraventricular)
    17. Swan-Ganz catheter
    18. Any implant held in place by a magnet
    19. Transdermal delivery system (e.g. Nitro)
    20. Intrauterine device (IUD) or diaphragm
    21. Tattooed makeup (eyeliner, lips, etc.) or tattoos covering >25% of body surface area
    22. Body piercings (MUST BE REMOVED BEFORE MRI)
    23. Any metal fragments
    24. Internal pacing wires
    25. Metal or wire mesh implants
    26. Hearing aid (REMOVE BEFORE MRI) aa. Dentures (REMOVE BEFORE MRI) bb. Claustrophobia
  • Unable to tolerate inhalation of the gas mixture
  • Unable to adequately complete other study measures, including spirometry and multiple breath nitrogen washout
  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or may interfere with the interpretation of trial results and, in the judgment of the PI, would make the participant inappropriate for enrollment.
  • Pregnancy; women of childbearing potential must have a confirmed negative serum pregnancy test at screening, and a negative urine test on the day of the MRI scan, prior to the MRI scan (if serum test not performed the same day).
  • Facial hair preventing a tight fit of the mask used in the study
  • Allergy or intolerance due to side effects to bronchodilators

Sites / Locations

  • University of North Carolina at Chapel Hill

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

CF pulmonary exacerbation group

Arm Description

Patients with cystic fibrosis being treated for a pulmonary exacerbation will undergo Lung Clearance Index (LCI) and an MRI with PFP. LCI testing will take place before the MRI. Each test will take 5-20 minutes and up to three tests will be performed with at least 5-minute rest periods between each test. PFP gas will be administered using a full-face mask during the MRI. Images are acquired during 12-second breath-hold after every 3rd breath. Before and after the MRI is complete, participants will perform spirometry maneuvers in a room outside of the magnet.

Outcomes

Primary Outcome Measures

Whole lung ventilation defect volume (VDV)
To obtain ventilation defect volumes (VDVs), investigators will use the final wash-in image to identify all regions of interest having a signal intensity below the pre-defined threshold which indicates poor ventilation. The combined volume of all these 'ventilation defect' regions will be computed to obtain the VDV.

Secondary Outcome Measures

The wash-in kinetics of PFP
For each participant, an exponential model will be fit to obtain a statistical estimate, T, of the rate constant that characterizes the kinetics of gas wash-in. Aggregating across all participants, the frequency distributions of T values will be characterized by tabulating estimates of the mean and standard deviation (SD). Corresponding 95% confidence intervals and the minimum, maximum, and interquartile range of T values will also be tabulated.
Ventilation defect percent (VDP) correlation with LCI
Changes in VDP from pre/post treatment will be correlated with changes in LCI pre- and post-exacerbation.
Ventilation defect percent (VDP) correlation with FEV1
Changes in VDP from pre/post treatment will be correlated with changes in FEV1 pre- and post- exacerbation.

Full Information

First Posted
March 29, 2018
Last Updated
October 7, 2020
Sponsor
University of North Carolina, Chapel Hill
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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1. Study Identification

Unique Protocol Identification Number
NCT03497117
Brief Title
19F MRI of Ventilation in Subjects With Cystic Fibrosis Undergoing Treatment for Pulmonary Exacerbation
Official Title
19F Magnetic Resonance Imaging of Ventilation in Subjects With Cystic Fibrosis Undergoing Treatment for Pulmonary Exacerbation
Study Type
Interventional

2. Study Status

Record Verification Date
October 2020
Overall Recruitment Status
Terminated
Why Stopped
Enrollment barriers made study completion impossible
Study Start Date
August 25, 2015 (Actual)
Primary Completion Date
September 13, 2019 (Actual)
Study Completion Date
September 13, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of North Carolina, Chapel Hill
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to use perfluorinated gas imaging to highlight regions of functional variation within the lungs of participants with cystic fibrosis (CF), and to correlate this with changes in spirometry, lung clearance index, and quality of life of CF subjects undergoing treatment for a pulmonary exacerbation.
Detailed Description
The investigators hypothesize that 19F-enhanced MRI will detect improvements in lung ventilation following the treatment of a CF pulmonary exacerbation, and changes in ventilation as well as global MRI scores will track with both spirometry and quality of life assessments. Therefore, investigators propose this pilot and feasibility study to gain preliminary data on a comparison of the changes in ventilation that occur with treatment of a pulmonary exacerbation, as well as to begin to understand the repeatability of this novel outcome measure. Through this study, the investigators aim to: 1) Compare quantitative and qualitative assessments of lung ventilation using 19F MRI imaging and traditional, global physiologic assessments (spirometry, LCI) and compare these with images obtained in an age-matched healthy control population; 2) Correlate changes in MRI scoring with subjective changes in health related outcomes as measured by the CFQ-R (Cystic Fibrosis Questionnaire - Revised); 3) Determine the ability of 19F MRI to detect changes in ventilation that occur with treatment of a CF pulmonary exacerbation; and 4) Determine the repeatability of 19F MRI assessment of ventilation in a disease population. Participants with CF with baseline forced expiratory volume in 1 second (FEV1) of at least 40%, no contraindications to MRI, and oxygen saturation >90% on room air will be prospectively enrolled. Investigators will recruit a pre-defined cross-section of CF patients with mild, moderate, and severe lung disease, with approximately 4 subjects per group at the onset of a disease exacerbation requiring antibiotic intervention. The research team will obtain a pre-response MRI (within 3 days of initiating oral, inhaled, or IV antibiotic therapy), and a post-treatment MRI (within 3 days of terminating antibiotic treatment) to assess the responsiveness of 19F-MRI to a change in disease status. Each 19F-MRI study will be combined with assessments of spirometry, LCI (multiple breath nitrogen washout), and quality of life (CFQ-R quality of life tool). 19F-MRI will be performed by having each participant inhale a mixture of 79% perfluorinated propane (PFP) and 21% oxygen (pre-mixed) while using MRI to obtain 3D images. Subsequently, participants will be switched to room air, and cycled breathing will be continued while additional MRI images are captured to characterize gas wash-out. Safety measures, including pulse oximetry, will be monitored continuously, and spirometry will be performed before and after each MRI. Participants will also perform multiple breath washout maneuvers to obtain a lung clearance index, so this may be correlated to wash-out kinetics of the PFP.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cystic Fibrosis
Keywords
imaging, hyperpolarized, perfluorinated, MRI, lung, multiple breath washout, lung clearance index

7. Study Design

Primary Purpose
Other
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Model Description
Participants undergoing treatment for a pulmonary exacerbation will perform multiple breath washout and undergo an MRI with inhalation of a gas contrast agent (79% perfluoropropane (PFP) mixed with 21% oxygen) at the beginning and end of treatment.
Masking
None (Open Label)
Allocation
N/A
Enrollment
5 (Actual)

8. Arms, Groups, and Interventions

Arm Title
CF pulmonary exacerbation group
Arm Type
Other
Arm Description
Patients with cystic fibrosis being treated for a pulmonary exacerbation will undergo Lung Clearance Index (LCI) and an MRI with PFP. LCI testing will take place before the MRI. Each test will take 5-20 minutes and up to three tests will be performed with at least 5-minute rest periods between each test. PFP gas will be administered using a full-face mask during the MRI. Images are acquired during 12-second breath-hold after every 3rd breath. Before and after the MRI is complete, participants will perform spirometry maneuvers in a room outside of the magnet.
Intervention Type
Device
Intervention Name(s)
Lung Clearance Index
Other Intervention Name(s)
LCI
Intervention Description
To assess the efficiency of ventilation distribution and gas mixing by measuring the rate of clearance of an inert gas (nitrogen) from the lungs.
Intervention Type
Drug
Intervention Name(s)
MRI with PFP
Other Intervention Name(s)
Perfluoropropane gas (C3F8); 19F
Intervention Description
Description: inhaled PFP, a gaseous contrast agent (79% PFP, 21% O2, pre-mixed, medical grade gas) Administration: Full-face disposable ventilation mask and a standard Douglas Bag system. Dosage: Two controlled breaths of contrast gas followed by a full breath and a 12-second breath-hold and scan for image acquisition. Frequency: Repeated 5 times followed by an identical five cycles with room air to ensure PFP gas wash-out has occurred.
Primary Outcome Measure Information:
Title
Whole lung ventilation defect volume (VDV)
Description
To obtain ventilation defect volumes (VDVs), investigators will use the final wash-in image to identify all regions of interest having a signal intensity below the pre-defined threshold which indicates poor ventilation. The combined volume of all these 'ventilation defect' regions will be computed to obtain the VDV.
Time Frame
1 day
Secondary Outcome Measure Information:
Title
The wash-in kinetics of PFP
Description
For each participant, an exponential model will be fit to obtain a statistical estimate, T, of the rate constant that characterizes the kinetics of gas wash-in. Aggregating across all participants, the frequency distributions of T values will be characterized by tabulating estimates of the mean and standard deviation (SD). Corresponding 95% confidence intervals and the minimum, maximum, and interquartile range of T values will also be tabulated.
Time Frame
1 day
Title
Ventilation defect percent (VDP) correlation with LCI
Description
Changes in VDP from pre/post treatment will be correlated with changes in LCI pre- and post-exacerbation.
Time Frame
1 day
Title
Ventilation defect percent (VDP) correlation with FEV1
Description
Changes in VDP from pre/post treatment will be correlated with changes in FEV1 pre- and post- exacerbation.
Time Frame
1 day

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Non-smokers (<10 pack year history and no active smoking in the past year); Diagnosis of cystic fibrosis via standard sweat chloride/phenotypic features/genotyping Able to reproducibly perform lung function testing and have an FEV1 >30% of predicted at screening. No requirement for supplemental oxygen Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the trial. Participants must be willing and able to comply with scheduled visits and other trial procedures. Diagnosis of a pulmonary exacerbation according to Fuchs criteria (4 of the following 12 signs and symptoms) deemed to require antibiotic treatment, and must also include the change in lung function criterion: Change in sputum New or increased hemoptysis Increased cough Increased dyspnea Malaise, fatigue, or lethargy Temperature above 38deg C Anorexia or weight loss Sinus pain or tenderness Change in sinus discharge Change in physical examination of the chest Decrease in pulmonary function by 10% or more from a previously recorded value Radiographic change indicative of pulmonary infection Exclusion Criteria: Under 18 years of age Active or former smokers with less than 1 years since quitting, or >10 pack-year smoking history Active asthma flare, as perceived by the study physician or unstable asthma characterized by advancement of asthma therapy in the last month or two courses of oral steroids in the past six months. Unable to undergo a 3.0-Tesla MRI of lungs and chest because of contraindications including Occupation (past or present) of machinist, welder, grinder Injury to the eye involving a metallic object Injury to the body by a metallic object (bullet, BB, shrapnel) Presence of a cardiac pacemaker or defibrillator Presence of aneurysm clips Presence of carotid artery vascular clamp Presence of neurostimulator Presence of insulin or infusion pump Presence of implanted drug infusion device that is not known to be MRI compatible (i.e., was placed outside of University of North Carolina Hospitals (UNCH) or is older than 10 years) Bone growth or fusion simulator Presence of cochlear, otologic or ear implant Any type of prosthesis (eye, penile, etc.) Artificial limb or joint Non-removable electrodes (on body, head or brain) Intravascular stents, filters or coils Shunt (spinal or intraventricular) Swan-Ganz catheter Any implant held in place by a magnet Transdermal delivery system (e.g. Nitro) Intrauterine device (IUD) or diaphragm Tattooed makeup (eyeliner, lips, etc.) or tattoos covering >25% of body surface area Body piercings (MUST BE REMOVED BEFORE MRI) Any metal fragments Internal pacing wires Metal or wire mesh implants Hearing aid (REMOVE BEFORE MRI) aa. Dentures (REMOVE BEFORE MRI) bb. Claustrophobia Unable to tolerate inhalation of the gas mixture Unable to adequately complete other study measures, including spirometry and multiple breath nitrogen washout Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or may interfere with the interpretation of trial results and, in the judgment of the PI, would make the participant inappropriate for enrollment. Pregnancy; women of childbearing potential must have a confirmed negative serum pregnancy test at screening, and a negative urine test on the day of the MRI scan, prior to the MRI scan (if serum test not performed the same day). Facial hair preventing a tight fit of the mask used in the study Allergy or intolerance due to side effects to bronchodilators
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jennifer Goralski, MD
Organizational Affiliation
University of North Carolina, Chapel Hill
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of North Carolina at Chapel Hill
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
23722696
Citation
Halaweish AF, Moon RE, Foster WM, Soher BJ, McAdams HP, MacFall JR, Ainslie MD, MacIntyre NR, Charles HC. Perfluoropropane gas as a magnetic resonance lung imaging contrast agent in humans. Chest. 2013 Oct;144(4):1300-1310. doi: 10.1378/chest.12-2597.
Results Reference
background
PubMed Identifier
23985278
Citation
Couch MJ, Ball IK, Li T, Fox MS, Littlefield SL, Biman B, Albert MS. Pulmonary ultrashort echo time 19F MR imaging with inhaled fluorinated gas mixtures in healthy volunteers: feasibility. Radiology. 2013 Dec;269(3):903-9. doi: 10.1148/radiol.13130609. Epub 2013 Oct 28.
Results Reference
background

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19F MRI of Ventilation in Subjects With Cystic Fibrosis Undergoing Treatment for Pulmonary Exacerbation

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