Cystic Fibrosis
Conditions
Brief summary
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.
Interventions
DRUGVX-770
Tablet.
DRUGPlacebo
Tablet.
Sponsors
Cystic Fibrosis Foundation
Vertex Pharmaceuticals Incorporated
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Change From Baseline in Total Ventilation Defect Defined by Hyperpolarized Helium 3 Magnetic Resonance Imaging (3He-MRI) at Day 43 | Part A: Baseline (pre-dose Day 15), 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 B: Change From Baseline in Total Ventilation Defect Defined by Hyperpolarized Helium 3 Magnetic Resonance Imaging (3He-MRI) at Week 48 | Part B: Baseline (Day -1), 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Absolute Change From Baseline in Sweat Chloride at Day 43 | Part A: Baseline (pre-dose Day 15), 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: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score At Day 43 | Baseline (pre-dose Day 15), 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). |
| Part B: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Related AEs | Part B: Day 1 up to Week 48 | 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: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Related AEs | Part A: Day 1 up to Day 57 | 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: Absolute Change From Baseline in Sweat Chloride at Week 48 | Part B: Baseline (Day -1), 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: Absolute Change From Baseline in in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score At Week 48 | Part B: Baseline (Day -1), 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: Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 48 | Part B: Baseline (Day -1), 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 A: Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Day 43 | Part A: Baseline (pre-dose Day 15), 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). |
Countries
United States
Participant flow
Recruitment details
Study was initiated on October 10, 2010 after first eligible subject signed informed consent form and enrolled in study.
Pre-assignment details
All results were planned to be reported separately for Part A and Part B of the study.
Participants by arm
| Arm | Count |
|---|---|
| VX-770 Part A: Subjects received placebo tablets matched to VX-770 150 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. | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Part B | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | VX-770 |
|---|---|
| Age, Continuous Part A (n = 8) | 18.9 years STANDARD_DEVIATION 4.64 |
| Age, Continuous Part B (n = 9) | 24.4 years STANDARD_DEVIATION 10.3 |
| Body Mass Index (BMI) Part A (n = 8) | 23.44 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.57 |
| Body Mass Index (BMI) Part B (n = 9) | 22.96 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 4.066 |
| Body Weight Part A (n = 8) | 66.31 kilogram (kg) STANDARD_DEVIATION 14.393 |
| Body Weight Part B (n = 9) | 66.53 kilogram (kg) STANDARD_DEVIATION 13.693 |
| Height Part A (n = 8) | 167.5 centimeter (cm) STANDARD_DEVIATION 9.66 |
| Height Part B (n = 9) | 169.9 centimeter (cm) STANDARD_DEVIATION 11.82 |
| Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Part A: >=70%-<90% (n = 8) | 1 participants |
| Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Part A: <70% (n = 8) | 2 participants |
| Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Part A: >=90% (n = 8) | 5 participants |
| Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Part B: >=70%-<90% (n = 9) | 1 participants |
| Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Part B: <70% (n = 9) | 6 participants |
| Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Part B: >=90% (n = 9) | 2 participants |
| Race/Ethnicity, Customized Part A, Ethnicity: Not Hispanic or Latino (n = 8) | 8 participants |
| Race/Ethnicity, Customized Part A, Race: Black or African American (n = 8) | 1 participants |
| Race/Ethnicity, Customized Part A, Race: White (n = 8) | 7 participants |
| Race/Ethnicity, Customized Part B, Ethnicity: Not Hispanic or Latino (n = 9) | 9 participants |
| Race/Ethnicity, Customized Part B, Race: White (n = 9) | 9 participants |
| Sex/Gender, Customized Part A: Female (n = 8) | 4 participants |
| Sex/Gender, Customized Part A: Male (n = 8) | 4 participants |
| Sex/Gender, Customized Part B: Female (n = 9) | 3 participants |
| Sex/Gender, Customized Part B: Male (n = 9) | 6 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 8 | 3 / 8 | 6 / 9 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 1 / 9 |
Outcome results
Primary
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).
Time frame: Part A: Baseline (pre-dose Day 15), Day 43
Population: FAS for Part A = all enrolled subjects who received at least 1 dose of study drug (VX-770 or placebo) in Part A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VX-770 | Part A: Change From Baseline in Total Ventilation Defect Defined by Hyperpolarized Helium 3 Magnetic Resonance Imaging (3He-MRI) at Day 43 | -8.20 percentage of total lung volume | Standard Deviation 9.013 |
Primary
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).
Time frame: Part B: Baseline (Day -1), Week 48
Population: FAS for Part B = all enrolled subjects who received at least 1 dose of study drug (VX-770) in Part B.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VX-770 | Part B: Change From Baseline in Total Ventilation Defect Defined by Hyperpolarized Helium 3 Magnetic Resonance Imaging (3He-MRI) at Week 48 | -6.33 percentage of total lung volume | Standard Deviation 11.859 |
Secondary
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).
Time frame: Baseline (pre-dose Day 15), Day 43
Population: FAS for Part A = all enrolled subjects who received at least 1 dose of study drug (VX-770 or placebo) in Part A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VX-770 | Part A: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score At Day 43 | -7.64 units on a scale | Standard Deviation 27.529 |
Secondary
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).
Time frame: Part A: Baseline (pre-dose Day 15), Day 43
Population: FAS for Part A = all enrolled subjects who received at least 1 dose of study drug (VX-770 or placebo) in Part A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VX-770 | Part A: Absolute Change From Baseline in Sweat Chloride at Day 43 | -42.31 millimole per liter (mmol/L) | Standard Deviation 13.475 |
Secondary
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).
Time frame: Part A: Baseline (pre-dose Day 15), Day 43
Population: FAS for Part A = all enrolled subjects who received at least 1 dose of study drug (VX-770 or placebo) in Part A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VX-770 | Part A: Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Day 43 | 12.78 percent predicted of FEV1 | Standard Deviation 9.203 |
Secondary
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.
Time frame: Part A: Day 1 up to Day 57
Population: Safety Set for Part A = all enrolled subjects who received at least 1 dose of study drug (VX-770 or placebo) in Part A. Data was reported as per the intervention received (Placebo \[Placebo Run in/Washout\] or VX-770 \[VX-770 Treatment\]).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| VX-770 | Part A: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Related AEs | AEs | 2 participants |
| VX-770 | Part A: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Related AEs | SAEs | 0 participants |
| VX-770 | Part A: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Related AEs | Related AEs | 0 participants |
| Part A VX-770 Treatment | Part A: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Related AEs | AEs | 3 participants |
| Part A VX-770 Treatment | Part A: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Related AEs | SAEs | 0 participants |
| Part A VX-770 Treatment | Part A: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Related AEs | Related AEs | 0 participants |
Secondary
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).
Time frame: Part B: Baseline (Day -1), Week 48
Population: FAS for Part B = all enrolled subjects who received at least 1 dose of study drug (VX-770) in Part B. Here, Number of participants analyzed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VX-770 | Part B: Absolute Change From Baseline in in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score At Week 48 | 15.08 units on a scale | Standard Deviation 7.667 |
Secondary
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).
Time frame: Part B: Baseline (Day -1), Week 48
Population: FAS for Part B = all enrolled subjects who received at least 1 dose of study drug (VX-770) in Part B. Here, Number of participants analyzed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VX-770 | Part B: Absolute Change From Baseline in Sweat Chloride at Week 48 | -48.88 mmol/L | Standard Deviation 22.271 |
Secondary
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).
Time frame: Part B: Baseline (Day -1), Week 48
Population: FAS for Part B = all enrolled subjects who received at least 1 dose of study drug (VX-770) in Part B. Here, Number of participants analyzed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VX-770 | Part B: Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 48 | 5.17 percent predicted of FEV1 | Standard Deviation 9.422 |
Secondary
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.
Time frame: Part B: Day 1 up to Week 48
Population: Safety Set for Part B = all enrolled subjects who received at least 1 dose of study drug (VX-770 or placebo) in Part B.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| VX-770 | Part B: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Related AEs | AEs | 6 participants |
| VX-770 | Part B: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Related AEs | SAEs | 1 participants |
| VX-770 | Part B: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Related AEs | Related AEs | 4 participants |