(Study: Vertex IIS) Does Ivacaftor Alter Wild Type CFTR-Open Probability In The Sweat Gland Secretory Coil?

(Study: Vertex IIS) Does Ivacaftor Alter Wild Type CFTR-Open Probability In The Sweat Gland Secretory Coil?

(Study: Vertex IIS) A Study To Access the Effects of Ivacaftor on Wild Type CFTR-Open Probability (PO) In The Sweat Gland Secretory Coil

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.

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.

Participants will receive ivacaftor orally for 3 days, followed by 35 days off drug. Participants will repeat this cycle then receive ivacaftor for 3 additional days. For sweat testing, participants will receive β-adrenergic cocktail to stimulated sweating, at both 1% stimulation strength and full stimulation strength. Each participant will also receive pilocarpine nitrate 5% administered by Macroduct sweat stimulator device. Sweat stimulation testing will be done on- and off-ivacaftor.

Administered subcutaneously to induce sweating. Cocktail composed of atropine (280µM), isoproterenol (160µM), and aminophylline (20 mM).

CFTR-dependent sweat rate (C-sweat) was analyzed using a linear mixed model, combining on- and off-ivacaftor data.

Sweat chloride concentration was measured via the traditional sweat collection methods using the pilocarpine stimulation with the Macroduct device.

Inclusion Criteria: Healthy adults without a Cystic Fibrosis (CF) mutation Carriers with a known CF mutation Exclusion Criteria: Documented liver disease 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.