Study of the Effect of VX-770 on Hyperpolarized Helium-3 Magnetic Resonance Imaging in Subjects With Cystic Fibrosis and the G551D Mutation

A Phase 2, Single-Blind, Placebo-Controlled Study to Evaluate the Effect of VX-770 on Hyperpolarized Helium-3 Magnetic Resonance Imaging in Subjects With Cystic Fibrosis, the G551D Mutation, and FEV1 ≥40% Predicted

Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The encoded protein, CFTR, is an epithelial chloride ion channel responsible for aiding in the regulation of salt and water absorption and secretion in various tissues. Although the disease affects multiple organs, the leading cause of mortality is the progressive loss of lung function. Obstruction of airways with thick mucus, chronic bacterial infection of the airways, and inflammatory response are all thought to play a role in causing lung damage. Through its function as a chloride channel, CFTR is believed to be integral in epithelial ion and water transport and hence, maintaining the normal hydration of lung secretions.

VX-770 (ivacaftor) is a potent and selective potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR. Based on in vitro studies and pharmacologic, pharmacokinetic (PK), and safety profiles, VX-770 has been selected for clinical development as a possible treatment for patients with CF.

Hyperpolarized noble gas magnetic resonance imaging (HG-MRI) is a promising new means of assessing lung function by direct imaging of certain non-radioactive isotopes of an inert noble gas, such as helium or xenon. Through this technique, high-resolution 3-dimensional images of lung ventilation can be obtained in both pediatric and adult patients during a single short breath-hold following inhalation of the gas.

This is a 2-part study to evaluate the effect of VX-770 on hyperpolarized helium-3 magnetic resonance imaging (3He-MRI), and to evaluate the safety and efficacy of VX-770 in subjects aged 12 years and older with CF who have the G551D-CFTR mutation. Part A is a single-blind, placebo-controlled study that includes 4 weeks of VX-770 treatment and 4 weeks of placebo treatment. Part B is an open-label, 48 week study of long-term effect of VX 770 on hyperpolarized 3He-MRI.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: VX-770; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female with Cystic Fibrosis
• Must have the G551D-CFTR mutation on at least 1 allele
• FEV1 ≥40% of predicted normal for age, gender, and height at Screening
• 12 years of age or older
• Must be able to swallow tablets

Exclusion Criteria:

• History of solid organ or hematological transplantation
• Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening
• Use of inhaled hypertonic saline treatment within 14 days prior to the Screening Visit
• Extensive body tattoos or other physical features that will confound MRI

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: SINGLE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: VX-770; Part A: Subjects received placebo tablets matched to VX-770 150 milligram (mg) orally twice daily from Day 1 to 14 (Placebo run-in period), followed by VX-770 150 mg tablets orally twice daily from Day 15 to 42 (VX-770 treatment period), and then placebo tablets matched to VX-770 150 mg orally twice daily from Day 43 to 57 (Placebo washout period) during Part A of the study. Part B: Subjects received VX-770 150 mg tablets orally twice daily for 48 weeks during Part B of the study. Part B included subjects from Part A and newly enrolled subjects.

Drug: VX-770; Tablet.; Other Names: Ivacaftor; Drug: Placebo; Tablet.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Change From Baseline in Total Ventilation Defect Defined by Hyperpolarized Helium 3 Magnetic Resonance Imaging (3He-MRI) at Day 43	Subjects inhaled hyperpolarized helium-3 (3He) gas mixed with nitrogen to make a total volume of approximately one-third forced vital capacity (FVC) to a maximum of 1 liter and hold their breath for 20 seconds or less. Rapid magnetic resonance imaging (MRI) was performed during inhalation/exhalation and/or breath-hold. Areas of decreased ventilation were observed as ventilation defects that are visualized as decreased (and/or absent) 3He intensity in 3He-MRI. The total ventilation defect was defined as the ratio of total ventilation defect volume (L) to total lung volume (L), expressed as a percentage. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in VX-770 treatment phase (Day 15 to 42).	Part A: Baseline (pre-dose Day 15), Day 43
Part B: Change From Baseline in Total Ventilation Defect Defined by Hyperpolarized Helium 3 Magnetic Resonance Imaging (3He-MRI) at Week 48	Subjects were asked to inhale hyperpolarized 3 He gas mixed with nitrogen to make a total volume of approximately one-third forced vital capacity (FVC) to a maximum of 1 liter and hold their breath for 20 seconds or less. Rapid MRI was performed during inhalation/exhalation and/or breath-hold. Areas of decreased ventilation were observed as ventilation defects that are visualized as decreased (and/or absent) 3He intensity in 3He MRI. The total ventilation defect was defined as the ratio of total ventilation defect volume (L) to total lung volume (L), expressed as a percentage. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in Part B (48 weeks).	Part B: Baseline (Day -1), Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Related AEs	AE: any adverse change from subject's baseline (pre-treatment) condition, including any adverse experience, abnormal recording/clinical laboratory assessment which occurs during course of study, whether it is considered related to study drug or not. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event. Related AEs includes all AEs for which the causality was either related to study drug or possibly related to study drug.	Part A: Day 1 up to Day 57
Part A: Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Day 43	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Predicted FEV1 (for age, gender, and height) was calculated using the Knudson method. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in VX-770 treatment phase (Day 15 to 42).	Part A: Baseline (pre-dose Day 15), Day 43
Part A: Absolute Change From Baseline in Sweat Chloride at Day 43	Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in VX-770 treatment phase (Day 15 to 42).	Part A: Baseline (pre-dose Day 15), Day 43
Part A: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score At Day 43	The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in VX-770 treatment phase (Day 15 to 42).	Baseline (pre-dose Day 15), Day 43
Part B: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Related AEs	AE: any adverse change from subject's baseline (pre-treatment) condition, including any adverse experience, abnormal recording/clinical laboratory assessment which occurs during course of study, whether it is considered related to study drug or not. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event. Related AEs includes all AEs for which the causality was either related to study drug or possibly related to study drug.	Part B: Day 1 up to Week 48
Part B: Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 48	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Predicted FEV1 (for age, gender, and height) was calculated using the Knudson method. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in Part B (48 weeks).	Part B: Baseline (Day -1), Week 48
Part B: Absolute Change From Baseline in Sweat Chloride at Week 48	Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in Part B (48 weeks).	Part B: Baseline (Day -1), Week 48
Part B: Absolute Change From Baseline in in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score At Week 48	The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in Part B (48 weeks).	Part B: Baseline (Day -1), Week 48

Collaborators and Investigators

• Sponsor: Vertex Pharmaceuticals Incorporated
• Collaborators: Cystic Fibrosis Foundation
• Investigators: Principal Investigator: Talissa Altes, MD, University of Virginia

Publications and helpful links

General Publications

• Altes TA, Johnson M, Fidler M, Botfield M, Tustison NJ, Leiva-Salinas C, de Lange EE, Froh D, Mugler JP 3rd. Use of hyperpolarized helium-3 MRI to assess response to ivacaftor treatment in patients with cystic fibrosis. J Cyst Fibros. 2017 Mar;16(2):267-274. doi: 10.1016/j.jcf.2016.12.004. Epub 2017 Jan 26.

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (ACTUAL): February 1, 2013
• Study Completion (ACTUAL): February 1, 2013

Study Registration Dates

• First Submitted: July 9, 2010
• First Submitted That Met QC Criteria: July 9, 2010
• First Posted (ESTIMATE): July 13, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): July 31, 2014
• Last Update Submitted That Met QC Criteria: July 1, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Chloride Channel Agonists; Ivacaftor
• Other Study ID Numbers: VX10-770-107