Cystic Fibrosis
Conditions
Brief summary
To evaluate the clinical mechanisms of action in lung and extrapulmonary systems of VX-661 (tezacaftor; TEZ) in combination with ivacaftor (IVA) (TEZ/IVA) in participants with cystic fibrosis (CF) who are homozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene.
Interventions
Tezacaftor/Ivacaftor FDC
DRUGIvacaftor
DRUGTezacaftor/Ivacaftor matching placebo
DRUGIvacaftor matching placebo
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
* Male and female participants, homozygous for the F508del CFTR mutation * Confirmed diagnosis of CF by sweat chloride testing * Forced Expiratory Volume in 1 Second (FEV1) ≥40% and ≤90% of predicted normal for age, sex, and height at Screening Visit * Stable CF disease as judged by the investigator.
Exclusion criteria
* History of any comorbidity 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. * An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 28 days before Day 1 * History or evidence of clinically significant findings on ophthalmologic examination during the Screening Period. * History of solid organ or hematological transplantation * Pregnant or nursing females * Participants who have had radiation exposure within 1 year before the first mucociliary clearance (MCC) procedure that would cause them to exceed federal regulations by participating in this study * In the opinion of the investigator, unable to adequately perform inhalation maneuvers during the MCC procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Mucociliary Clearance (MCC) at Day 28 | Baseline, Day 28 | MCC was assessed using an imaging technique that enables the tracking of mucus within the airways. MCC was expressed as the percentage of whole-lung clearance through 60 minutes at Baseline and Day 28. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28 | Baseline, Day 28 | Percent predicted FEV1 is the ratio of FEV1 to the predicted FEV1, expressed as a percentage. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. |
| Absolute Change From Baseline in Small-bowel Area Under the Curve (AUC) Over 1-minute Mean pH Increments at Day 29 | Baseline, Day 29 | Absolute change from Baseline in small bowel AUC over 1-minute mean pH increments through 30 minutes at Day 29 was assessed. |
| Absolute Change From Baseline in Sweat Chloride at Day 29 | Baseline, Day 29 | — |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline up to Day 57 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo matched to TEZ/IVA FDC tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 29 days. | 7 |
| TEZ/IVA Participants received 100 mg TEZ/150 mg IVA FDC tablet orally once daily in the morning followed by 150 mg IVA tablet orally once daily in the evening for 29 days. | 27 |
| Total | 34 |
Baseline characteristics
| Characteristic | Placebo | TEZ/IVA | Total |
|---|---|---|---|
| Age, Continuous | 38 years STANDARD_DEVIATION 11.8 | 32.1 years STANDARD_DEVIATION 8.6 | 33.4 years STANDARD_DEVIATION 9.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 27 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Mucociliary Clearance (MCC): Percentage of Whole-lung Clearance | 15.3 percentage of whole-lung clearance STANDARD_DEVIATION 15.1 | 18.4 percentage of whole-lung clearance STANDARD_DEVIATION 11.3 | 17.8 percentage of whole-lung clearance STANDARD_DEVIATION 12 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 27 Participants | 34 Participants |
| Sex: Female, Male Female | 4 Participants | 15 Participants | 19 Participants |
| Sex: Female, Male Male | 3 Participants | 12 Participants | 15 Participants |
| Small-bowel Area Under the Curve (AUC) Over 1-minute Mean pH Increments | 5.8 pH minutes STANDARD_DEVIATION 0.4 | 5.7 pH minutes STANDARD_DEVIATION 0.6 | 5.8 pH minutes STANDARD_DEVIATION 0.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 27 |
| other Total, other adverse events | 2 / 7 | 18 / 27 |
| serious Total, serious adverse events | 0 / 7 | 0 / 27 |
Outcome results
Primary
Absolute Change From Baseline in Mucociliary Clearance (MCC) at Day 28
MCC was assessed using an imaging technique that enables the tracking of mucus within the airways. MCC was expressed as the percentage of whole-lung clearance through 60 minutes at Baseline and Day 28.
Time frame: Baseline, Day 28
Population: The Full Analysis Set (FAS) included all randomized participants who carry the relevant cystic fibrosis transmembrane conductance regulator (CFTR) allele and received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Mucociliary Clearance (MCC) at Day 28 | -0.5 percentage of whole-lung clearance | Standard Deviation 11.2 |
| TEZ/IVA | Absolute Change From Baseline in Mucociliary Clearance (MCC) at Day 28 | -0.9 percentage of whole-lung clearance | Standard Deviation 12.1 |
p-value: 0.7151t-test, 2 sided
Secondary
Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28
Percent predicted FEV1 is the ratio of FEV1 to the predicted FEV1, expressed as a percentage. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time frame: Baseline, Day 28
Population: The FAS was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28 | -0.4 percentage of predicted FEV1 | Standard Deviation 5.9 |
| TEZ/IVA | Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28 | 2.4 percentage of predicted FEV1 | Standard Deviation 3.1 |
p-value: 0.0004t-test, 2 sided
Secondary
Absolute Change From Baseline in Small-bowel Area Under the Curve (AUC) Over 1-minute Mean pH Increments at Day 29
Absolute change from Baseline in small bowel AUC over 1-minute mean pH increments through 30 minutes at Day 29 was assessed.
Time frame: Baseline, Day 29
Population: The FAS was used. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Small-bowel Area Under the Curve (AUC) Over 1-minute Mean pH Increments at Day 29 | 0.3 pH minutes | Standard Deviation 0.5 |
| TEZ/IVA | Absolute Change From Baseline in Small-bowel Area Under the Curve (AUC) Over 1-minute Mean pH Increments at Day 29 | -0.2 pH minutes | Standard Deviation 0.8 |
p-value: 0.3345t-test, 2 sided
Secondary
Absolute Change From Baseline in Sweat Chloride at Day 29
Time frame: Baseline, Day 29
Population: The FAS was used. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Sweat Chloride at Day 29 | -0.2 millimoles per liter | Standard Deviation 6 |
| TEZ/IVA | Absolute Change From Baseline in Sweat Chloride at Day 29 | -8.4 millimoles per liter | Standard Deviation 9.2 |
p-value: 0.0002t-test, 2 sided
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: Baseline up to Day 57
Population: The Safety Set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 0 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 2 Participants |
| TEZ/IVA | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 0 Participants |
| TEZ/IVA | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 24 Participants |