Cystic Fibrosis
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy, safety, pharmacodynamic (PD) and pharmacokinetic (PK) effect of VX-561.
Interventions
DRUGVX-561
VX-561 tablets for oral administration.
DRUGIVA
150-mg film-coated tablet for oral administration.
DRUGPlacebo
Placebo matched to IVA.
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Must have 1 of the following 9 CFTR mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D * On ivacaftor therapy * FEV1 value ≥40% and ≤100% of predicted mean for age, sex, and height Key
Exclusion criteria
* History of clinically significant cirrhosis with or without portal hypertension * History of solid organ or hematological transplantation * Lung infection with organisms associated with a more rapid decline in pulmonary status Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | From Baseline at Week 12 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Sweat Chloride (SwCl) | From Baseline at Week 12 | Sweat samples were collected using an approved collection device. |
| Observed Pre-Dose Concentration (Ctrough) of VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) and IVA and Its Metabolites (M1-IVA and M6-IVA) | At Week 4 | — |
| Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline up to Week 16 | — |
Countries
Australia, Belgium, Germany, Ireland, Netherlands, United Kingdom, United States
Participant flow
Pre-assignment details
This study was conducted in cystic fibrosis (CF) participants aged 18 years or older who have a gating mutation and were previously taking stable dose of ivacaftor (IVA).
Participants by arm
| Arm | Count |
|---|---|
| Ivacaftor Participants received IVA 150 mg orally q12h in the treatment period for 12 weeks. | 11 |
| VX-561: 25 mg Participants received VX-561 25 mg orally qd in the treatment period for 12 weeks. | 6 |
| VX-561: 50 mg Participants received VX-561 50 mg orally qd in the treatment period for 12 weeks. | 11 |
| VX-561: 150 mg Participants received VX-561 150 mg orally qd in the treatment period for 12 weeks. | 23 |
| VX-561: 250 mg Participants received VX-561 250 mg orally qd in the treatment period for 12 weeks. | 24 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 2 | 0 | 0 | 0 |
| Overall Study | Other | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Randomized, Never Dosed | 1 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Ivacaftor | VX-561: 25 mg | VX-561: 50 mg | VX-561: 150 mg | VX-561: 250 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 33.3 years STANDARD_DEVIATION 11.7 | 33.0 years STANDARD_DEVIATION 10.6 | 27.8 years STANDARD_DEVIATION 9 | 32.5 years STANDARD_DEVIATION 8.5 | 37.4 years STANDARD_DEVIATION 11.4 | 33.5 years STANDARD_DEVIATION 10.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 6 Participants | 10 Participants | 22 Participants | 24 Participants | 73 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | 74.0 percentage points STANDARD_DEVIATION 21.2 | 63.6 percentage points STANDARD_DEVIATION 22.4 | 66.8 percentage points STANDARD_DEVIATION 17.4 | 72.6 percentage points STANDARD_DEVIATION 17.3 | 73.9 percentage points STANDARD_DEVIATION 17 | 71.6 percentage points STANDARD_DEVIATION 18 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 6 Participants | 11 Participants | 23 Participants | 24 Participants | 74 Participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 3 Participants | 8 Participants | 9 Participants | 26 Participants |
| Sex: Female, Male Male | 7 Participants | 4 Participants | 8 Participants | 15 Participants | 15 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 6 | 0 / 11 | 0 / 23 | 0 / 24 |
| other Total, other adverse events | 8 / 11 | 4 / 6 | 8 / 11 | 17 / 23 | 20 / 24 |
| serious Total, serious adverse events | 1 / 11 | 2 / 6 | 2 / 11 | 2 / 23 | 1 / 24 |
Outcome results
Primary
Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time frame: From Baseline at Week 12
Population: Full analysis set (FAS) included all randomized participants who have intended CF transmembrane conductance regulator gene (CFTR) genotype and received at least 1 dose of study drug in treatment period. VX-561:25 mg and VX-561:50 mg arms were discontinued at sponsor's discretion and it was specified in statistical plan that data will be reported for only IVA, VX-561:150 mg and VX-561:250 mg arms for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ivacaftor | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | -0.8 percentage points |
| VX-561: 150 mg | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | 3.1 percentage points |
| VX-561: 250 mg | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | 2.7 percentage points |
Secondary
Absolute Change in Sweat Chloride (SwCl)
Sweat samples were collected using an approved collection device.
Time frame: From Baseline at Week 12
Population: FAS. VX-561:25 mg and VX-561:50 mg arms were discontinued at sponsor's discretion and it was specified in statistical plan that data will be reported for only IVA, VX-561:150 mg and VX-561:250 mg arms for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ivacaftor | Absolute Change in Sweat Chloride (SwCl) | 0.9 millimole per liter (mmol/L) |
| VX-561: 150 mg | Absolute Change in Sweat Chloride (SwCl) | 3.3 millimole per liter (mmol/L) |
| VX-561: 250 mg | Absolute Change in Sweat Chloride (SwCl) | -6.5 millimole per liter (mmol/L) |
Secondary
Observed Pre-Dose Concentration (Ctrough) of VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) and IVA and Its Metabolites (M1-IVA and M6-IVA)
Time frame: At Week 4
Population: Pharmacokinetic (PK) set included all participants who received at least 1 dose of study drug and for whom the primary PK data were considered to be sufficient and interpretable. Here Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure and Number Analyzed signifies those who were evaluable for the specific category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ivacaftor | Observed Pre-Dose Concentration (Ctrough) of VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) and IVA and Its Metabolites (M1-IVA and M6-IVA) | IVA: Week 4 | 952 nanogram per milliliter (ng/mL) | Standard Deviation 766 |
| Ivacaftor | Observed Pre-Dose Concentration (Ctrough) of VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) and IVA and Its Metabolites (M1-IVA and M6-IVA) | M6-IVA: Week 4 | 662 nanogram per milliliter (ng/mL) | Standard Deviation 398 |
| Ivacaftor | Observed Pre-Dose Concentration (Ctrough) of VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) and IVA and Its Metabolites (M1-IVA and M6-IVA) | M1-IVA: Week 4 | 1330 nanogram per milliliter (ng/mL) | Standard Deviation 774 |
| VX-561: 150 mg | Observed Pre-Dose Concentration (Ctrough) of VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) and IVA and Its Metabolites (M1-IVA and M6-IVA) | VX-561: Week 4 | 26.1 nanogram per milliliter (ng/mL) | Standard Deviation 24.7 |
| VX-561: 150 mg | Observed Pre-Dose Concentration (Ctrough) of VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) and IVA and Its Metabolites (M1-IVA and M6-IVA) | M1-VX-561: Week 4 | 18.1 nanogram per milliliter (ng/mL) | Standard Deviation 17.7 |
| VX-561: 150 mg | Observed Pre-Dose Concentration (Ctrough) of VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) and IVA and Its Metabolites (M1-IVA and M6-IVA) | M6-VX-561: Week 4 | NA nanogram per milliliter (ng/mL) | — |
| VX-561: 250 mg | Observed Pre-Dose Concentration (Ctrough) of VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) and IVA and Its Metabolites (M1-IVA and M6-IVA) | M6-VX-561: Week 4 | 59.8 nanogram per milliliter (ng/mL) | Standard Deviation 34 |
| VX-561: 250 mg | Observed Pre-Dose Concentration (Ctrough) of VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) and IVA and Its Metabolites (M1-IVA and M6-IVA) | M1-VX-561: Week 4 | 108 nanogram per milliliter (ng/mL) | Standard Deviation 58.6 |
| VX-561: 250 mg | Observed Pre-Dose Concentration (Ctrough) of VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) and IVA and Its Metabolites (M1-IVA and M6-IVA) | VX-561: Week 4 | 123 nanogram per milliliter (ng/mL) | Standard Deviation 61.6 |
| VX-561: 150 mg | Observed Pre-Dose Concentration (Ctrough) of VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) and IVA and Its Metabolites (M1-IVA and M6-IVA) | M6-VX-561: Week 4 | 211 nanogram per milliliter (ng/mL) | Standard Deviation 189 |
| VX-561: 150 mg | Observed Pre-Dose Concentration (Ctrough) of VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) and IVA and Its Metabolites (M1-IVA and M6-IVA) | M1-VX-561: Week 4 | 378 nanogram per milliliter (ng/mL) | Standard Deviation 213 |
| VX-561: 150 mg | Observed Pre-Dose Concentration (Ctrough) of VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) and IVA and Its Metabolites (M1-IVA and M6-IVA) | VX-561: Week 4 | 458 nanogram per milliliter (ng/mL) | Standard Deviation 273 |
| VX-561: 250 mg | Observed Pre-Dose Concentration (Ctrough) of VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) and IVA and Its Metabolites (M1-IVA and M6-IVA) | VX-561: Week 4 | 1100 nanogram per milliliter (ng/mL) | Standard Deviation 856 |
| VX-561: 250 mg | Observed Pre-Dose Concentration (Ctrough) of VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) and IVA and Its Metabolites (M1-IVA and M6-IVA) | M1-VX-561: Week 4 | 739 nanogram per milliliter (ng/mL) | Standard Deviation 407 |
| VX-561: 250 mg | Observed Pre-Dose Concentration (Ctrough) of VX-561 and Its Metabolites (M1-VX-561 and M6-VX-561) and IVA and Its Metabolites (M1-IVA and M6-IVA) | M6-VX-561: Week 4 | 370 nanogram per milliliter (ng/mL) | Standard Deviation 233 |
Secondary
Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: Baseline up to Week 16
Population: Safety Set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ivacaftor | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 8 participants |
| Ivacaftor | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 1 participants |
| VX-561: 150 mg | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 4 participants |
| VX-561: 150 mg | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 2 participants |
| VX-561: 250 mg | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 8 participants |
| VX-561: 250 mg | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 2 participants |
| VX-561: 150 mg | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 2 participants |
| VX-561: 150 mg | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 21 participants |
| VX-561: 250 mg | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 23 participants |
| VX-561: 250 mg | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 1 participants |