Cystic Fibrosis
Conditions
Brief summary
Study VX16-661-114 (Study 114) is a Phase 3b, randomized, double-blind, placebo-controlled, parallel-group, multicenter study in subjects aged 12 years and older with CF who are homozygous for the F508del mutation on the cystic fibrosis transmembrane conductance regulator gene (CFTR) gene and who discontinued treatment with Orkambi due to respiratory symptoms considered related to treatment. This study is designed to evaluate the safety and efficacy of Tezacaftor/Ivacaftor (TEZ/IVA).
Interventions
TEZ 100 mg/IVA 150 mg fixed-dose combination tablet.
DRUGIvacaftor
IVA 150 mg tablet.
DRUGPlacebo
Placebo matched to TEZ/IVA fixed-dose combination tablet.
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
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures. * Prior discontinuation of Orkambi, with at least 1 respiratory sign or symptom considered related to therapy. * Resolution or stabilization of qualifying event(s) \>28 days prior to Screening. * Discontinuation of Orkambi therapy must have occurred within approximately 12 weeks from the first dose of Orkambi. * Homozygous for F508del mutation in the CFTR gene as documented in the subject's medical record. If genotype documentation is not available in the medical record, genotyping will be performed during screening. * FEV1 ≥25% and ≤90% of predicted normal for age, sex, and height. * Stable CF disease as judged by the investigator. * Other protocol defined inclusion criteria could apply.
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. * Recent rapid or progressive deterioration in respiratory status. * Receiving continuous oxygen at \>2L/min or on face-mask ventilation. * Any protocol-defined exclusionary laboratory values at Screening. * Child-Pugh Class B or C hepatic impairment. * An acute upper or lower respiratory infection, pulmonary exacerbation, or change in therapy for pulmonary disease within 28 days before Day 1. * Documentation of colonization with organisms associated with a more rapid decline in pulmonary status. * History of lung transplantation since most recent initiation of Orkambi. * History of alcohol or drug abuse in the past year as deemed by the investigator. * Participation in an investigational drug study or use of a CFTR modulator within 28 days or 5 terminal half-lives of the investigational drug or modulator (whichever is longer). * Use of restricted medications or foods within the specified window before the first dose of study drug, or an anticipated need or use of restricted medication or foods after the first dose of study drug. * Pregnant or nursing females: Females of child-bearing potential must have a negative pregnancy test at Screening and Day 1. * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Respiratory Adverse Events of Special Interest (RAESIs) | Day 1 up to Day 84 | RAESIs included chest discomfort, dyspnea (shortness of breath), respiration abnormal (chest tightness), asthma, bronchial hyperreactivity, bronchospasm, and wheezing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Day 28 and Day 56 Measurements | Baseline, Day 28 and Day 56 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. |
| Relative Change From Baseline in ppFEV1 at Average of Day 28 and Day 56 Measurements | Baseline, Day 28 and Day 56 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. |
| Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Day 28 and Day 56 Measurements | Baseline, Day 28 and Day 56 | The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. |
| Tolerability as Assessed by Number of Participants Who Discontinued Treatment | Day 1 through Day 56 | — |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Day 1 up to Day 84 | — |
Countries
France, Germany, United States
Participant flow
Pre-assignment details
A total of 98 participants were randomized: 47 in placebo group and 51 in tezacaftor (TEZ)/ivacaftor (IVA) group. One participant in TEZ/IVA group did not receive any study drug.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo matched to TEZ/IVA fixed-dose combination tablet orally once daily in the morning followed by placebo matched to IVA tablet orally once daily in the evening for 56 days. | 47 |
| TEZ/IVA Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination tablet orally once daily in the morning and IVA 150 mg tablet orally once daily in the evening for 56 days. | 50 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Other | 1 | 0 |
Baseline characteristics
| Characteristic | TEZ/IVA | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 34.3 years STANDARD_DEVIATION 8.7 | 33.8 years STANDARD_DEVIATION 9.3 | 33.3 years STANDARD_DEVIATION 10 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants | 81 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 12 Participants | 4 Participants |
| 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 | 1 Participants | 1 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 | 8 Participants | 12 Participants | 4 Participants |
| Race (NIH/OMB) White | 42 Participants | 84 Participants | 42 Participants |
| Sex: Female, Male Female | 31 Participants | 61 Participants | 30 Participants |
| Sex: Female, Male Male | 19 Participants | 36 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 47 | 1 / 50 |
| other Total, other adverse events | 28 / 47 | 30 / 50 |
| serious Total, serious adverse events | 9 / 47 | 5 / 50 |
Outcome results
Primary
Incidence of Respiratory Adverse Events of Special Interest (RAESIs)
RAESIs included chest discomfort, dyspnea (shortness of breath), respiration abnormal (chest tightness), asthma, bronchial hyperreactivity, bronchospasm, and wheezing.
Time frame: Day 1 up to Day 84
Population: Safety set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Incidence of Respiratory Adverse Events of Special Interest (RAESIs) | 10 Participants |
| TEZ/IVA | Incidence of Respiratory Adverse Events of Special Interest (RAESIs) | 7 Participants |
Secondary
Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Day 28 and Day 56 Measurements
The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
Time frame: Baseline, Day 28 and Day 56
Population: FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Day 28 and Day 56 Measurements | 4.7 units on a scale | Standard Deviation 15.4 |
| TEZ/IVA | Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Day 28 and Day 56 Measurements | 5.7 units on a scale | Standard Deviation 14.2 |
95% CI: [-4.9, 7]
Secondary
Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Day 28 and Day 56 Measurements
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time frame: Baseline, Day 28 and Day 56
Population: Full analysis set (FAS) included all randomized participants who carried the intended cystic fibrosis transmembrane conductance regulator gene (CFTR) allele mutation and had received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Day 28 and Day 56 Measurements | -0.6 percent predicted of FEV1 | Standard Deviation 3.4 |
| TEZ/IVA | Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Day 28 and Day 56 Measurements | 2.2 percent predicted of FEV1 | Standard Deviation 4.8 |
95% CI: [1, 4.4]
Secondary
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: Day 1 up to Day 84
Population: Safety set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 39 Participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 9 Participants |
| TEZ/IVA | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 37 Participants |
| TEZ/IVA | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 5 Participants |
Secondary
Relative Change From Baseline in ppFEV1 at Average of Day 28 and Day 56 Measurements
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time frame: Baseline, Day 28 and Day 56
Population: FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Relative Change From Baseline in ppFEV1 at Average of Day 28 and Day 56 Measurements | -1.5 percent change | Standard Deviation 8.1 |
| TEZ/IVA | Relative Change From Baseline in ppFEV1 at Average of Day 28 and Day 56 Measurements | 5.2 percent change | Standard Deviation 12 |
95% CI: [2.5, 10.9]
Secondary
Tolerability as Assessed by Number of Participants Who Discontinued Treatment
Time frame: Day 1 through Day 56
Population: Safety set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Tolerability as Assessed by Number of Participants Who Discontinued Treatment | 2 Participants |
| TEZ/IVA | Tolerability as Assessed by Number of Participants Who Discontinued Treatment | 2 Participants |