Cystic Fibrosis
Conditions
Brief summary
This study evaluates the long-term safety and tolerability of tezacaftor in combination with ivacaftor (TEZ/IVA) in participants with cystic fibrosis (CF) aged 6 years and older, homozygous or heterozygous for the F508del mutation.
Interventions
DRUGTEZ/IVA
Fixed-dose combination tablet for oral administration.
DRUGIVA
Tablet for oral administration.
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Completed the Week 24 Visit in Study 113 Part B or the Week 8 Visit in Study 115 * Eligible CFTR Mutation
Exclusion criteria
* Pregnant and nursing females * History of poor compliance with study drug and/or procedures in a previous study as deemed by the investigator * Ongoing participation in another study with investigational drug Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part A: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Day 1 up to Week 100 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Absolute Change in LCI2.5 for 113B/116 LCI FAS | From Parent Study 113B Baseline at Week 96 (Study 116) | The LCI2.5 index is the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting values and is calculated by dividing the sum of exhaled tidal breaths (cumulative exhaled volume (CEV)) by simultaneously measured functional residual capacity (FRC). An LCI of 7.5 and below is normal; values greater than 7.5 are abnormal. LCI is able to detect abnormalities in lung function earlier than more traditional modalities such as spirometry. |
| Part A: Absolute Change in Sweat Chloride (SwCl) for 115/116 FAS (TEZ/IVA Group) | From Parent Study 115 Baseline at Week 96 (Study 116) | Sweat samples were collected using an approved collection device. |
| Part A: Absolute Change in SwCl for 113B/116 FAS | From Parent Study 113B Baseline at Week 96 (Study 116) | Sweat samples were collected using an approved collection device. |
| Part A: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for 115/116 FAS (TEZ/IVA Group) | From Parent Study 115 Baseline at Week 96 (Study 116) | The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with CF. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. |
| Part A: Absolute Change in Lung Clearance Index2.5 (LCI2.5) for 115/116 FAS (TEZ/IVA Group) | From Parent Study 115 Baseline at Week 96 (Study 116) | The LCI2.5 index is the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting values and is calculated by dividing the sum of exhaled tidal breaths (cumulative exhaled volume (CEV)) by simultaneously measured functional residual capacity (FRC). An LCI of 7.5 and below is normal; values greater than 7.5 are abnormal. LCI is able to detect abnormalities in lung function earlier than more traditional modalities such as spirometry. |
| Part A: Absolute Change in Body Mass Index (BMI) for 115/116 FAS (TEZ/IVA Group) | From Parent Study 115 Baseline at Week 96 (Study 116) | BMI was defined as weight in kilograms (kg) divided by squared height in meters (m\^2). |
| Part A: Absolute Change in BMI for 113B/116 FAS | From Parent Study 113B Baseline at Week 96 (Study 116) | BMI was defined as weight in kg divided by m\^2. |
| Part B: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Day 1 up to Week 192 | — |
| Part A: Absolute Change in CFQ-R Respiratory Domain Score for 113B/116 FAS | From Parent Study 113B Baseline at Week 96 (Study 116) | The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with CF. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. |
Countries
Australia, Belgium, Canada, Denmark, France, Germany, Ireland, Poland, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted in 2 parts, Part A and Part B. Participants from Part A also participated in Part B. The Participant flow was planned to be presented for the overall treatment arm.
Pre-assignment details
This study was conducted in cystic fibrosis (CF) participants aged 6 years or older who participated in parent studies VX15-661-113 Part B (Study 113B; NCT02953314) or VX16-661-115 (Study 115; NCT03559062). Eligible participants from parent studies were enrolled in Study 116.
Participants by arm
| Arm | Count |
|---|---|
| TEZ/IVA Part A: Participants weighing \<40 kg at Day 1 received TEZ 50 mg qd/ IVA 75 mg q12h and the participants weighing \>= 40 kg at Day 1 received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 96 weeks. Doses were adjusted upward for changes in body weight and/or age.
Part B: Participants weighing \<30 kg at Day 1 received TEZ 50 mg qd/IVA 75 mg q12h and the participants weighing \>=30 kg at Day 1 received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period up to 192 weeks. Doses were adjusted upward for changes in body weight and/or age. | 130 |
| Total | 130 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Part A (Up to 96 Weeks) | Adverse Event | 2 |
| Part A (Up to 96 Weeks) | Commercial Drug is Available for Participant | 56 |
| Part A (Up to 96 Weeks) | Other | 1 |
| Part A (Up to 96 Weeks) | Withdrawal of Consent (not due to AE) | 2 |
| Part B (Up to 192 Weeks) | Adverse Event | 1 |
| Part B (Up to 192 Weeks) | Commercial Drug is available for Participant | 56 |
| Part B (Up to 192 Weeks) | Other | 1 |
| Part B (Up to 192 Weeks) | Withdrawal of Consent (not due to AE) | 1 |
Baseline characteristics
| Characteristic | TEZ/IVA |
|---|---|
| Age, Continuous Part A | 8.3 years STANDARD_DEVIATION 1.7 |
| Age, Continuous Part B | 8.3 years STANDARD_DEVIATION 1.7 |
| Race/Ethnicity, Customized Part A Asian | 1 Participants |
| Race/Ethnicity, Customized Part A Black or African American | 1 Participants |
| Race/Ethnicity, Customized Part A Hispanic or Latino | 4 Participants |
| Race/Ethnicity, Customized Part A Not collected per local regulations | 7 Participants |
| Race/Ethnicity, Customized Part A Not Hispanic or Latino | 119 Participants |
| Race/Ethnicity, Customized Part A Other | 1 Participants |
| Race/Ethnicity, Customized Part A White | 125 Participants |
| Race/Ethnicity, Customized Part B Asian | 0 Participants |
| Race/Ethnicity, Customized Part B Black or African American | 1 Participants |
| Race/Ethnicity, Customized Part B Hispanic or Latino | 3 Participants |
| Race/Ethnicity, Customized Part B Not collected per local regulations | 2 Participants |
| Race/Ethnicity, Customized Part B Not Hispanic or Latino | 52 Participants |
| Race/Ethnicity, Customized Part B Other | 0 Participants |
| Race/Ethnicity, Customized Part B White | 59 Participants |
| Sex: Female, Male Part A Female | 67 Participants |
| Sex: Female, Male Part A Male | 63 Participants |
| Sex: Female, Male Part B Female | 35 Participants |
| Sex: Female, Male Part B Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 130 | 0 / 62 |
| other Total, other adverse events | 128 / 130 | 49 / 62 |
| serious Total, serious adverse events | 31 / 130 | 8 / 62 |
Outcome results
Primary
Part A: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time frame: Day 1 up to Week 100
Population: Safety Set included all participants who were enrolled and received at least 1 dose of TEZ/IVA in Part A of Study 116.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: TEZ/IVA | Part A: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants With TEAEs | 129 Participants |
| Part A: TEZ/IVA | Part A: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants With SAEs | 31 Participants |
Secondary
Part A: Absolute Change in BMI for 113B/116 FAS
BMI was defined as weight in kg divided by m\^2.
Time frame: From Parent Study 113B Baseline at Week 96 (Study 116)
Population: 113B/116 FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: TEZ/IVA | Part A: Absolute Change in BMI for 113B/116 FAS | 1.19 kg/m^2 |
Secondary
Part A: Absolute Change in Body Mass Index (BMI) for 115/116 FAS (TEZ/IVA Group)
BMI was defined as weight in kilograms (kg) divided by squared height in meters (m\^2).
Time frame: From Parent Study 115 Baseline at Week 96 (Study 116)
Population: 115/116 FAS (TEZ/IVA group). As pre-specified in the SAP, model-based efficacy analysis for participants from parent Study 115 was planned only for the TEZ/IVA treatment group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: TEZ/IVA | Part A: Absolute Change in Body Mass Index (BMI) for 115/116 FAS (TEZ/IVA Group) | 1.25 kilogram per meter square (kg/m^2) |
Secondary
Part A: Absolute Change in CFQ-R Respiratory Domain Score for 113B/116 FAS
The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with CF. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
Time frame: From Parent Study 113B Baseline at Week 96 (Study 116)
Population: 113B/116 FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: TEZ/IVA | Part A: Absolute Change in CFQ-R Respiratory Domain Score for 113B/116 FAS | 6.0 units on a scale |
Secondary
Part A: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for 115/116 FAS (TEZ/IVA Group)
The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with CF. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
Time frame: From Parent Study 115 Baseline at Week 96 (Study 116)
Population: 115/116 FAS (TEZ/IVA group). As pre-specified in the SAP, model-based efficacy analysis for participants from parent Study 115 was planned only for the TEZ/IVA treatment group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: TEZ/IVA | Part A: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for 115/116 FAS (TEZ/IVA Group) | 6.4 units on a scale |
Secondary
Part A: Absolute Change in LCI2.5 for 113B/116 LCI FAS
The LCI2.5 index is the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting values and is calculated by dividing the sum of exhaled tidal breaths (cumulative exhaled volume (CEV)) by simultaneously measured functional residual capacity (FRC). An LCI of 7.5 and below is normal; values greater than 7.5 are abnormal. LCI is able to detect abnormalities in lung function earlier than more traditional modalities such as spirometry.
Time frame: From Parent Study 113B Baseline at Week 96 (Study 116)
Population: 113B/116 LCI FAS included all enrolled participants who participated in the LCI sub study in parent Study 113B and received at least 1 dose of TEZ/IVA in Study 116 and had an eligible genotype. As pre-specified in the SAP, only descriptive summary statistics were planned to be reported for the 113B/116 LCI FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: TEZ/IVA | Part A: Absolute Change in LCI2.5 for 113B/116 LCI FAS | -2.04 Index | Standard Deviation 1.73 |
Secondary
Part A: Absolute Change in Lung Clearance Index2.5 (LCI2.5) for 115/116 FAS (TEZ/IVA Group)
The LCI2.5 index is the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting values and is calculated by dividing the sum of exhaled tidal breaths (cumulative exhaled volume (CEV)) by simultaneously measured functional residual capacity (FRC). An LCI of 7.5 and below is normal; values greater than 7.5 are abnormal. LCI is able to detect abnormalities in lung function earlier than more traditional modalities such as spirometry.
Time frame: From Parent Study 115 Baseline at Week 96 (Study 116)
Population: 115/116 Full analysis set (FAS) (TEZ/IVA group) included all enrolled participants who were randomized to the TEZ/IVA treatment group in parent Study 115 and received at least 1 dose of TEZ/IVA in Study 116 and had an eligible genotype. As pre-specified in the SAP, model-based efficacy analysis for participants from parent Study 115 was planned only for the TEZ/IVA treatment group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: TEZ/IVA | Part A: Absolute Change in Lung Clearance Index2.5 (LCI2.5) for 115/116 FAS (TEZ/IVA Group) | -0.95 Index |
Secondary
Part A: Absolute Change in SwCl for 113B/116 FAS
Sweat samples were collected using an approved collection device.
Time frame: From Parent Study 113B Baseline at Week 96 (Study 116)
Population: 113B/116 FAS included all enrolled participants from parent Study 113B who received at least 1 dose of TEZ/IVA in Study 116 and had an eligible genotype.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: TEZ/IVA | Part A: Absolute Change in SwCl for 113B/116 FAS | -16.2 mmol/L |
Secondary
Part A: Absolute Change in Sweat Chloride (SwCl) for 115/116 FAS (TEZ/IVA Group)
Sweat samples were collected using an approved collection device.
Time frame: From Parent Study 115 Baseline at Week 96 (Study 116)
Population: 115/116 FAS (TEZ/IVA group). As pre-specified in the SAP, model-based efficacy analysis for participants from parent Study 115 was planned only for the TEZ/IVA treatment group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: TEZ/IVA | Part A: Absolute Change in Sweat Chloride (SwCl) for 115/116 FAS (TEZ/IVA Group) | -13.8 millimole per liter (mmol/L) |
Secondary
Part B: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: Day 1 up to Week 192
Population: Safety Set included all participants who were enrolled and received at least 1 dose of TEZ/IVA in Part B of Study 116.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: TEZ/IVA | Part B: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 8 Participants |
| Part A: TEZ/IVA | Part B: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with TEAEs | 53 Participants |