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.

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.

Inclusion Criteria:

• Male or Female age 40-80
• A Clinical diagnosis of COPD as defined by GOLD
• At Least a 10 pack year smoking history
• Exhibit symptoms of chronic bronchitis as defined by the Medical Research Council
• FEV1% predicted ≥ 35% and ≤70% Post Bronchodilator
• Clinically stable in the last 4 weeks with no evidence of COPD exacerbation
• Weight of 40 kg-120 kg
• Willingness to use at least one form of acceptable birth control including abstinence, condom with spermicide, or hormonal contraceptives from time of signing ICF through study follow up visit
• Willing to monitor blood glucose if known history of diabetes mellitus requiring insulin or medical therapy
• Element of CFTR Dysfunction, as defined by Sweat Chloride > 30 mEq/L)

Exclusion Criteria:

• Current Diagnosis of Asthma
• Known Diagnosis of Cystic Fibrosis
• Use of Continuous Oxygen Therapy of greater than 2 liters per minute - patients on 2 liters of Oxygen or less will be excluded if they have been hospitalized for COPD in the prior year or had more than 2 exacerbations requiring steroids and/or antibiotics in the prior year.
• Documented history of drug abuse within the last year
• Subjects should not have a pulmonary exacerbation or changes in therapy for pulmonary disease within 28 days before receiving the first dose of study drug.
• Cirrhosis or elevated liver transaminases > 3X ULN
• GFR < 50 estimated by Cockroft-Gault
• Any illness or abnormal lab finding that, in the opinion of the investigator might confound the results of the study or pose an additional risk in administering study drug to the subject.
• Pregnant or Breastfeeding
• Subjects taking moderate or strong inhibitors or inducers of CYP3A4, including certain herbal medications and grapefruit juice. (Excluded medications and foods including the drugs and foods listed in the IRB HSP application.)
• Uncontrolled Diabetes
• Recent (e.g 1year) arterial thrombotic events (peripheral arterial disease, thrombotic stroke)
• Clinically significant arrhythmias requiring anti-arrhythmic agent(s) or conduction abnormalities that in the opinion of the investigator that affect patient safety such as the abnormalities listed below (patients with stable coronary artery disease are eligible) : (1) Angina symptoms (2) History of MI (3) Revascularization procedure in the last year prior to screening (4) Clinically significant congestive heart failure (known LVEF <= 45%, cor pulmonale, diastolic heart failure, etc)

Screening to Day 98

double-blind