(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.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Ivacaftor; Drug: β-Adrenergic cocktail; Drug: Pilocarpine Nitrate 5%; Device: Macroduct sweat stimulator

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Ivacaftor; 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.

Drug: Ivacaftor; 150mg administered orally twice daily.; Other Names: Kalydeco; Drug: β-Adrenergic cocktail; Administered subcutaneously to induce sweating. Cocktail composed of atropine (280µM), isoproterenol (160µM), and aminophylline (20 mM).; Drug: Pilocarpine Nitrate 5%; Administered subcutaneously using Macroduct sweat stimulator device.; Device: Macroduct sweat stimulator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 79 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change Sweat Chloride Production	Sweat chloride concentration was measured via the traditional sweat collection methods using the pilocarpine stimulation with the Macroduct device.	Up to 79 days

Collaborators and Investigators

• Sponsor: Richard Barry Moss
• Investigators: Principal Investigator: Jeffrey Wine, PhD, Stanford University

Publications and helpful links

Helpful Links

• Sweat rate analysis of ivacaftor potentiation of CFTR in non-CF adults

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2015
• Primary Completion (Actual): August 2, 2016
• Study Completion (Actual): August 23, 2017

Study Registration Dates

• First Submitted: September 3, 2014
• First Submitted That Met QC Criteria: December 5, 2014
• First Posted (Estimate): December 8, 2014

Study Record Updates

• Last Update Posted (Actual): January 9, 2019
• Last Update Submitted That Met QC Criteria: December 21, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Cystic Fibrosis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Membrane Transport Modulators; Cholinergic Agonists; Chloride Channel Agonists; Miotics; Muscarinic Agonists; Ivacaftor; Pilocarpine; Adrenergic Agents
• Other Study ID Numbers: 31238