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The Multicenter Topic Trial

Primary Purpose

Chronic Obstructive Pulmonary Disease

Status

Withdrawn

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

Ivacaftor

About this trial

This is an interventional treatment trial for Chronic Obstructive Pulmonary Disease

Eligibility Criteria

40 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 ≤80% 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 insulin dependent diabetes mellitus
Capable of giving signed informed consent

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 affect patient safety
A standard digital ECG demonstrating QTc >450 msec for men and > QTc 470 msec for women at screening. If QTc exceeds 450 msec for men and > QTc 470 msec for women at the screening ECG, the ECG should be repeated 2 more times during the screening period, and the subject will be excluded if the average of the 3 QTc values is >450 msec for men and > QTc 470 msec for women.
Angina symptoms
History of MI or revascularization procedure within the last three years prior to screening
Clinically significant congestive heart failure (known LVEF <= 45%, cor pulmonale, diastolic heart failure, etc)
Patients with stable coronary artery disease are eligible
History of stroke/CVA or non-skin cancer <5 years prior

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Ivacaftor

Placebo

Arm Description

Ivacaftor, 150 mg PO every 12 hrs for 84 days

Placebo, 150 mg PO every 12 hrs for 84 days

Outcomes

Primary Outcome Measures

CFTR activity

Change in peripheral CFTR activity as detected by sweat chloride testing

FEV1

Change in lung function as measured by FEV1 (Pulmonary Function testing.)

Secondary Outcome Measures

Full Information

NCT ID

NCT04066751

First Posted

August 19, 2019

Last Updated

January 11, 2022

Sponsor

University of Alabama at Birmingham

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Vertex Pharmaceuticals Incorporated

1. Study Identification

Unique Protocol Identification Number

NCT04066751

Brief Title

The Multicenter Topic Trial

Official Title

A Multicenter Randomized, Double-blind, Phase 2, Placebo Controlled Study to Determine the Safety and Efficacy of Ivacaftor (VX-770) for the Treatment of Chronic Obstructive Pulmonary Disease (The Multicenter Topic Trial)

Study Type

Interventional

2. Study Status

Record Verification Date

January 2022

Overall Recruitment Status

Withdrawn

Why Stopped

Study never started due to change in availability of study drug

Study Start Date

December 1, 2021 (Anticipated)

Primary Completion Date

October 31, 2024 (Anticipated)

Study Completion Date

October 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Alabama at Birmingham

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Vertex Pharmaceuticals Incorporated

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this protocol is to test the safety, pharmacokinetics, and pharmacodynamics of the Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, ivacaftor in patients with chronic obstructive pulmonary disease (COPD) and chronic bronchitis. 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 study is a multicenter, randomized, double-blind, placebo-controlled, stratified study of orally-administered ivacaftor.

Detailed Description

Like CF, COPD is characterized by small airway mucus obstruction that is associated with accelerated loss of lung function and mortality. Our 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. Our 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 patient-reported outcomes (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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Obstructive Pulmonary Disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ivacaftor

Arm Type

Active Comparator

Arm Description

Ivacaftor, 150 mg PO every 12 hrs for 84 days

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo, 150 mg PO every 12 hrs for 84 days

Intervention Type

Drug

Intervention Name(s)

Ivacaftor

Other Intervention Name(s)

Kalydeco

Intervention Description

Ivacaftor will be supplied as a tablet for oral administration, film-coated, 150 mg

Primary Outcome Measure Information:

Title

CFTR activity

Description

Change in peripheral CFTR activity as detected by sweat chloride testing

Time Frame

assessed at day1, day 28, day 56, and day 84

Title

FEV1

Description

Change in lung function as measured by FEV1 (Pulmonary Function testing.)

Time Frame

assesed at day 1, day 28, day 56, and day 84

10. Eligibility

Sex

All

Minimum Age & Unit of Time

40 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

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 ≤80% 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 insulin dependent diabetes mellitus Capable of giving signed informed consent 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 affect patient safety A standard digital ECG demonstrating QTc >450 msec for men and > QTc 470 msec for women at screening. If QTc exceeds 450 msec for men and > QTc 470 msec for women at the screening ECG, the ECG should be repeated 2 more times during the screening period, and the subject will be excluded if the average of the 3 QTc values is >450 msec for men and > QTc 470 msec for women. Angina symptoms History of MI or revascularization procedure within the last three years prior to screening Clinically significant congestive heart failure (known LVEF <= 45%, cor pulmonale, diastolic heart failure, etc) Patients with stable coronary artery disease are eligible History of stroke/CVA or non-skin cancer <5 years prior

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Mark Dransfield, MD

Organizational Affiliation

University of Alabama at Birmingham

Official's Role

Principal Investigator

12. IPD Sharing Statement

Plan to Share IPD

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The Multicenter Topic Trial

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