Cystic Fibrosis
Conditions
Brief summary
Clinical studies of lumacaftor + ivacaftor (combo therapy) produced better FEV1 (forced expiratory volume in 1 second) improvements than ivacaftor alone, without further improvement in sweat chloride results. To help understand why sweat chloride was unresponsive, the investigators will use a newly developed sweat secretion test that provides accurate, in vivo readout of CFTR (cystic fibrosis transmembrane conductance regulator) function in the sweat gland secretory coil. The investigators devised a protocol to determine if short courses of ivacaftor (3.5 days) will produce significant increases in WT (Wild-Type, i.e. normal) CFTR open probability by measuring CFTR-dependent sweating (C-sweat) in subjects with WT CFTR.
Detailed description
Cystic fibrosis (CF) is a genetic disease caused by malfunctioning of a protein called CFTR. CF affects various organs including the sweat glands and the lungs. An FDA approved drug called ivacaftor helps some people with CF, and laboratory tests show that it produces further improvement when combined with an investigational drug called lumacaftor. However, results from clinical tests of the two drugs used together gave mixed results: lung function improved but sweat gland function did not improve. This study will measure CFTR-dependent sweat rate to test the hypothesis that CFTR in the normal sweat glands might be functioning at peak efficiency, and so can't be improved further with ivacaftor, thus accounting for the apparent discrepancy between lung function and sweat gland results. CFTR-dependent sweat rate is important to understanding CF because it is a very accurate measure of CFTR function.
Interventions
DRUGIvacaftor
150mg administered orally twice daily.
DRUGβ-Adrenergic cocktail
Administered subcutaneously to induce sweating. Cocktail composed of atropine (280µM), isoproterenol (160µM), and aminophylline (20 mM).
DRUGPilocarpine Nitrate 5%
Administered subcutaneously using Macroduct sweat stimulator device.
DEVICEMacroduct sweat stimulator
Sponsors
Richard Barry Moss
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Healthy adults without a Cystic Fibrosis (CF) mutation * Carriers with a known CF mutation
Exclusion criteria
1. Documented liver disease 2. Participants should not be taking: * medicines that are strong CYP3A (Cytochrome P450, family 3, subfamily A) inducers, such as: * the antibiotics rifampin and rifabutin; * seizure medications (phenobarbital, carbamazepine, or phenytoin); and * the herbal supplement St. John's Wort, substantially decreases exposure of ivacaftor and may diminish effectiveness.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Dependent Sweat Rate | Up to 79 days | CFTR-dependent sweat rate (C-sweat) was analyzed using a linear mixed model, combining on- and off-ivacaftor data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change Sweat Chloride Production | Up to 79 days | Sweat chloride concentration was measured via the traditional sweat collection methods using the pilocarpine stimulation with the Macroduct device. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ivacaftor Participants received ivacaftor orally for 3 days, followed by 35 days off drug. Participants repeated this cycle then received ivacaftor for 3 additional days. For sweat testing, participants received β-adrenergic cocktail to stimulated sweating, at both 1% stimulation strength and full stimulation strength. Each participant also received pilocarpine nitrate 5% administered by Macroduct sweat stimulator device. Sweat stimulation testing was done on- and off-ivacaftor. | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Ivacaftor |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Age, Continuous | 46.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Healthy Volunteers | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment United States | 8 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 8 |
| other Total, other adverse events | 1 / 8 |
| serious Total, serious adverse events | 0 / 8 |
Outcome results
Primary
Change in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Dependent Sweat Rate
CFTR-dependent sweat rate (C-sweat) was analyzed using a linear mixed model, combining on- and off-ivacaftor data.
Time frame: Up to 79 days
Population: Participants with available data were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ivacaftor | Change in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Dependent Sweat Rate | 1% β-adrenergic stimulation | 16.45 percent change | Standard Deviation 2.25 |
| Ivacaftor | Change in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Dependent Sweat Rate | Full β-adrenergic stimulation | 6.60 percent change | Standard Deviation 2.97 |
Secondary
Change Sweat Chloride Production
Sweat chloride concentration was measured via the traditional sweat collection methods using the pilocarpine stimulation with the Macroduct device.
Time frame: Up to 79 days
Population: Participants with available data were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ivacaftor | Change Sweat Chloride Production | On ivacaftor | 25.1 percent change | Standard Deviation 11.4 |
| Ivacaftor | Change Sweat Chloride Production | Off Ivacaftor | 24.9 percent change | Standard Deviation 6.1 |