The Topic Trial - Study to Determine the Safety and Efficacy of Ivacaftor
Condition: Chronic Obstructive Pulmonary Disease; Chronic Bronchitis
MeSH terms: Bronchitis; Bronchitis, Chronic; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Study type: Interventional
Phase: Phase 2

Summary: 
      The study is a Phase 2 Study to establish the safety and efficacy of a drug called Ivacaftor
      (VX-770) in patients with chronic obstructive pulmonary disease (COPD), chronic bronchitis,
      and acquired CFTR dysfunction as detected by sweat chloride analysis. The design is a pilot,
      randomized (3:1, active:placebo), double-blind, placebo-controlled study. Approximately 40
      subjects with COPD will be randomized.
    

Detailed description: 
      Like CF, COPD is characterized by small airway mucus obstruction that is associated with
      accelerated loss of lung function and mortality. Preliminary data indicate that cigarette
      smoke exerts deleterious effects on airway epithelial function including the reduction of
      CFTR activity, enhanced mucus expression, and a pronounced reduction in mucociliary transport
      (MCT). Preliminary data also indicate that approximately 50% of patients with COPD have
      reduced CFTR activity, as detected in the upper airways, lower airways and sweat glands.
      Furthermore, CFTR dysfunction is independently associated with chronic bronchitis, can
      persist despite smoking cessation, and can be reversed by the CFTR potentiator ivacaftor
      (VX-770) in vitro by activating wild-type CFTR, resulting in a robust increase in MCT.
      Combined with unprecedented clinical improvement via augmented mucociliary clearance in CF
      patients with a responsive CFTR mutation treated with ivacaftor, these data indicate that
      CFTR represents a viable therapeutic target to address mucus stasis in a large subset of COPD
      patients (potentially representing over 4 million patients in the U.S. alone). This project
      will investigate the hypothesis that ivacaftor can augment CFTR activity in individuals with
      COPD who exhibit chronic bronchitis, resulting in meaningful improvements in epithelial
      function and respiratory health. The investigators' initial pilot study in patients with COPD
      and chronic bronchitis demonstrated that ivacaftor was safe, demonstrated stable
      pharmacokinetics, and exhibited a trend towards efficacy in measures of PROs and sweat
      chloride. The current trial will test the safety, pharmacokinetics, and pharmacodynamics of
      ivacaftor in a larger number of COPD patients with chronic bronchitis and for a longer
      treatment period, evaluating the potential of CFTR potentiator therapy to address acquired
      CFTR dysfunction in this population and set the stage for larger and longer-term trials in
      the future. Based on an IND already in place in the Rowe laboratory, an IRB familiar with the
      proposed study, an experienced clinical investigation team with expertise in all of the
      endpoints proposed, and a well characterized COPD population prioritized for the presence
      chronic bronchitis, CFTR dysfunction, and the absence of congenital CFTR mutations, the
      investigators are poised to deliver the trial.

      Enrollment is planned at a single center, The University of Alabama at Birmingham. Patients
      will be randomized 3:1 to active drug (n=30) and placebo (10) to achieve the enrollment goal.

      A sufficient number of subjects will be screened to randomize up to 50 subjects to achieve 40
      completed subjects to receive either ivacaftor 150 mg BID (n=30) or placebo (n=10) for 84
      days.

      Ivacaftor and matching placebo will be orally administered as capsules according to the
      following guidelines:

      Between study visit Day 1 and study visit Day 84, subjects will take 1 dose of study drug
      each day in the morning, beginning any time between 08:00 h (8:00 AM) and 12:00 h (12:00 PM).
      Whenever possible, subjects should take the study drug at the same time each day.

      On the study visit days when PK samples are collected (study visit Days 1, 28, 56, and 84),
      the study drug is to be taken by the subject while he/she is at the study site

      For visits after the Day 1 visit, subjects will be instructed to bring all remaining study
      drug materials to the site; study drug will be dispensed at each visit.

      Ivacaftor will be prepared and dispensed by an unblinded pharmacist.

      Subjects will be instructed to continue their standard COPD medication regimen.
    

Intervention name(s): Ivacaftor 150 MG; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Ivacaftor is a CFTR potentiator; placebo pills
Other intervention name(s): KALYDECO
Intervention MeSH terms: Ivacaftor
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: The design is a pilot, randomized (3:1, active:placebo), double-blind, placebo-controlled study
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: COPD; CFTR; ivacaftor; topic trial