Monitoring Response to Orkambi in Cystic Fibrosis Lung Disease by Inhaled Xenon MRI
| Status: | Recruiting |
|---|---|
| Conditions: | Pulmonary, Pulmonary |
| Therapuetic Areas: | Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 6 - 12 |
| Updated: | 6/7/2018 |
| Start Date: | March 2016 |
| End Date: | May 31, 2021 |
| Contact: | Beth Decker, RN |
| Email: | beth.decker@cchmc.org |
| Phone: | 513-803-4325 |
Validation of MRI as a Sensitive Tool to Longitudinally Monitor CF Lung Disease Progression and Response to CFTR Modulator Therapy in Young Children With CF
This is an observational study for children with Cystic Fibrosis (CF) who are eligible based
on their CF gene type. One group will be called the treatment group because they have the
gene type (homozygous F508del) that makes them clinically eligible through their CF care
provider to begin treatment with the new FDA approved CF drug called orkambi. For the control
group, children will be enrolled who have a similar CF gene type (heterozygous F508del) but
are not eligible to be prescribed orkambi.
The two groups will be followed for four visits over about 3 to 4 years to observe changes in
the lungs. Methods to measure the changes in lung disease will include:
MRI with non-FDA approved inhaled xenon gas to take detailed images of the lungs, Pulmonary
Function Tests (PFT), Lung Clearance Index (LCI), Baseline CT image of the lungs if not
ordered as part of usual clinical care.
The first two visits will be done before starting clinical treatment with orkambi and will be
a minimum of 28 days apart and up to 18 months. The third visit will be scheduled about 3
months after starting orkambi and the fourth visit about 18 months later. For the control
group, the timing of visits will be similar to treatment group and visits may be scheduled
around annual CF care visits.
on their CF gene type. One group will be called the treatment group because they have the
gene type (homozygous F508del) that makes them clinically eligible through their CF care
provider to begin treatment with the new FDA approved CF drug called orkambi. For the control
group, children will be enrolled who have a similar CF gene type (heterozygous F508del) but
are not eligible to be prescribed orkambi.
The two groups will be followed for four visits over about 3 to 4 years to observe changes in
the lungs. Methods to measure the changes in lung disease will include:
MRI with non-FDA approved inhaled xenon gas to take detailed images of the lungs, Pulmonary
Function Tests (PFT), Lung Clearance Index (LCI), Baseline CT image of the lungs if not
ordered as part of usual clinical care.
The first two visits will be done before starting clinical treatment with orkambi and will be
a minimum of 28 days apart and up to 18 months. The third visit will be scheduled about 3
months after starting orkambi and the fourth visit about 18 months later. For the control
group, the timing of visits will be similar to treatment group and visits may be scheduled
around annual CF care visits.
This is a controlled observational longitudinal study designed to capture Cystic Fibrosis
Transmembrane Conductance Regulator (CFTR) modulator therapy naive Cystic Fibrosis (CF)
subjects with F508del(+/+) mutations before they age into the FDA approved treatment window
for the CFTR modulator orkambi (ivacaftor/lumacaftor). These subjects will be compared to
disease controls. The treatment group will be observed twice (at least 28 days apart and up
to 18 months) before clinically starting orkambi and observed twice (at about 3 months and
about 18 months) after clinically starting orkambi .
This study takes advantage of the timely development of Ultrashort Echo Time Magnetic
Resonance Imaging (UTE MRI), Hyperpolarized Xenon (129Xe) MRI, Lung Clearance Index (LCI),
and the approval of F508del CFTR-directed CF therapy in children. The proposal will:
i) validate the emerging biomarker (UTE MRI) within CF children independent of genotype, ii)
define the trajectory of UTE MRI and forced expiratory volume in 1 second (FEV1) changes
before and after initiating orkambi therapy compared with age-matched CF controls, and iii)
determine the relationships between regional structural abnormalities (UTE MRI) and regional
(129Xe MRI) and global (LCI) functional measures of ventilation. Results will establish MRI
as a sensitive lung imaging tool that is translatable to all CF centers and can be applied
throughout the lifespan of CF patients.
CF patients with one or two copies of the F508del CFTR mutation who are 6-12 years old will
undergo UTE MRI soon after a clinical computerized tomography (CT) scan, with disease
quantification using an established scoring system for both modalities. Quantitative imaging
data and LCI will be compared with spirometry (gold standard for CF lung disease) and
clinical predictors of disease progression.
The F508del(+/+) patient cohort will differ genotypically from the control cohort
(F508del[+/-]). All patients in the F508del(+/-) cohort will be pancreatic insufficient and
also have a nonfunctional second allele (Class I or II mutation, not candidates for modulator
therapy). These two cohorts are phenotypically indistinguishable without modulator treatment,
and therefore the untreated cohort will serve as an ideal age and time-matched control group
for the F508del(+/+) subjects who clinically initiate orkambi.
Disease trajectories in the two groups, as quantified by changes in pulmonary UTE MRI, will
be compared with FEV1. MRI analysis will include quantitative and reader-based "Brody"
scoring for the whole lung, lung lobes, and for subcategories of the Brody scoring system (in
particular bronchiectasis, bronchial wall thickening, and mucus plugging).
The longitudinal study will capture both cohorts at their scheduled annual CF visits when
possible over about 4 years with modifications to the timeline for the treatment group based
on when they are clinically scheduled to begin orkambi treatment.
As FDA approved indications for orkambi change, subjects in the F508del(+/+) cohort will
become candidates for modulators prior to their 12th birthday. The FDA is currently reviewing
for approval in Fall 2016 to lower the prescribing age to 6 years and the investigators will
be enrolling to meet the changes at that time.
Transmembrane Conductance Regulator (CFTR) modulator therapy naive Cystic Fibrosis (CF)
subjects with F508del(+/+) mutations before they age into the FDA approved treatment window
for the CFTR modulator orkambi (ivacaftor/lumacaftor). These subjects will be compared to
disease controls. The treatment group will be observed twice (at least 28 days apart and up
to 18 months) before clinically starting orkambi and observed twice (at about 3 months and
about 18 months) after clinically starting orkambi .
This study takes advantage of the timely development of Ultrashort Echo Time Magnetic
Resonance Imaging (UTE MRI), Hyperpolarized Xenon (129Xe) MRI, Lung Clearance Index (LCI),
and the approval of F508del CFTR-directed CF therapy in children. The proposal will:
i) validate the emerging biomarker (UTE MRI) within CF children independent of genotype, ii)
define the trajectory of UTE MRI and forced expiratory volume in 1 second (FEV1) changes
before and after initiating orkambi therapy compared with age-matched CF controls, and iii)
determine the relationships between regional structural abnormalities (UTE MRI) and regional
(129Xe MRI) and global (LCI) functional measures of ventilation. Results will establish MRI
as a sensitive lung imaging tool that is translatable to all CF centers and can be applied
throughout the lifespan of CF patients.
CF patients with one or two copies of the F508del CFTR mutation who are 6-12 years old will
undergo UTE MRI soon after a clinical computerized tomography (CT) scan, with disease
quantification using an established scoring system for both modalities. Quantitative imaging
data and LCI will be compared with spirometry (gold standard for CF lung disease) and
clinical predictors of disease progression.
The F508del(+/+) patient cohort will differ genotypically from the control cohort
(F508del[+/-]). All patients in the F508del(+/-) cohort will be pancreatic insufficient and
also have a nonfunctional second allele (Class I or II mutation, not candidates for modulator
therapy). These two cohorts are phenotypically indistinguishable without modulator treatment,
and therefore the untreated cohort will serve as an ideal age and time-matched control group
for the F508del(+/+) subjects who clinically initiate orkambi.
Disease trajectories in the two groups, as quantified by changes in pulmonary UTE MRI, will
be compared with FEV1. MRI analysis will include quantitative and reader-based "Brody"
scoring for the whole lung, lung lobes, and for subcategories of the Brody scoring system (in
particular bronchiectasis, bronchial wall thickening, and mucus plugging).
The longitudinal study will capture both cohorts at their scheduled annual CF visits when
possible over about 4 years with modifications to the timeline for the treatment group based
on when they are clinically scheduled to begin orkambi treatment.
As FDA approved indications for orkambi change, subjects in the F508del(+/+) cohort will
become candidates for modulators prior to their 12th birthday. The FDA is currently reviewing
for approval in Fall 2016 to lower the prescribing age to 6 years and the investigators will
be enrolling to meet the changes at that time.
Inclusion Criteria:
Treatment group:
- male or female between the ages of 6 through 12 years at enrollment
- two copies of the F508del CFTR mutation
- anticipated to be a candidate for treatment with orkambi
Control group:
- male or female between the ages of 6 through 12 years at enrollment
- two non-functional CFTR mutations with one of them being F508del CFTR mutation
- not eligible for CFTR modulation therapy
Exclusion Criteria:
- FEV1 percent predicted of <60%
- standard MRI exclusions (metal implants, claustrophobia)
- pregnancy
We found this trial at
1
site
3333 Burnet Avenue # Mlc3008
Cincinnati, Ohio 45229
Cincinnati, Ohio 45229
1-513-636-4200
Principal Investigator: Jason Woods, PhD
Phone: 513-803-4325
Cincinnati Children's Hospital Medical Center Patients and families from across the region and around the...
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