Cystic Fibrosis
Conditions
Brief summary
This study will evaluate the efficacy and safety of elexacaftor (ELX) / tezacaftor (TEZ) / ivacaftor (IVA) triple combination (TC) in subjects 6 through 11 years of age with cystic fibrosis (CF) who are heterozygous for F508del and a minimal function (MF) mutation (F/MF genotypes).
Interventions
DRUGELX/TEZ/IVA
Fixed-dose combination tablet for oral administration qd in the morning.
DRUGIVA
Tablet for oral administration qd in the evening.
Placebo matched to ELX/TEZ/IVA for oral administration once daily (qd) in the morning.
Placebo matched to IVA for oral administration qd in the evening.
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
6 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Heterozygous for the F508del mutation (F/MF) * Forced expiratory volume in 1 second (FEV1) value greater than equal to(≥) 70% Key
Exclusion criteria
* Clinically significant cirrhosis with or without portal hypertension * Lung infection with organisms associated with a more rapid decline in pulmonary status * Solid organ or hematological transplantation Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Lung Clearance Index 2.5 (LCI2.5) | From Baseline Through Week 24 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Sweat Chloride (SwCl) | From Baseline Through Week 24 | Sweat samples were collected using an approved collection device. |
| 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 28 | — |
Countries
Australia, Canada, Denmark, France, Germany, Israel, Netherlands, Spain, Switzerland, United Kingdom
Participant flow
Pre-assignment details
This study was conducted in cystic fibrosis (CF) participants aged 6 through 11 years of age.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo matched to ELX/TEZ/IVA and placebo matched to IVA in the treatment period for 24 weeks. | 61 |
| ELX/TEZ/IVA Participants weighing \<30 kg at screening received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing \>=30 kg at screening received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. | 60 |
| Total | 121 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Placebo | ELX/TEZ/IVA |
|---|---|---|---|
| Age, Continuous | 9.2 years STANDARD_DEVIATION 1.7 | 9.2 years STANDARD_DEVIATION 1.7 | 9.1 years STANDARD_DEVIATION 1.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 90 Participants | 42 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 30 Participants | 19 Participants | 11 Participants |
| Lung Clearance Index2.5 (LCI2.5) | 10.01 index STANDARD_DEVIATION 2.09 | 9.75 index STANDARD_DEVIATION 1.95 | 10.26 index STANDARD_DEVIATION 2.22 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 30 Participants | 19 Participants | 11 Participants |
| Race (NIH/OMB) White | 87 Participants | 42 Participants | 45 Participants |
| Sex: Female, Male Female | 70 Participants | 35 Participants | 35 Participants |
| Sex: Female, Male Male | 51 Participants | 26 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 61 | 0 / 60 |
| other Total, other adverse events | 53 / 61 | 46 / 60 |
| serious Total, serious adverse events | 9 / 61 | 4 / 60 |
Outcome results
Primary
Absolute Change in Lung Clearance Index 2.5 (LCI2.5)
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 Baseline Through Week 24
Population: Full analysis set (FAS) included all randomized participants who carry the intended CFTR allele mutation and receive at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change in Lung Clearance Index 2.5 (LCI2.5) | -0.02 index | Standard Error 0.16 |
| ELX/TEZ/IVA | Absolute Change in Lung Clearance Index 2.5 (LCI2.5) | -2.29 index | Standard Error 0.16 |
p-value: <0.000195% CI: [-2.71, -1.81]Mixed-effects Model for Repeated Measure
Secondary
Absolute Change in Sweat Chloride (SwCl)
Sweat samples were collected using an approved collection device.
Time frame: From Baseline Through Week 24
Population: FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change in Sweat Chloride (SwCl) | -0.9 millimole per liter (mmol/L) | Standard Error 1.5 |
| ELX/TEZ/IVA | Absolute Change in Sweat Chloride (SwCl) | -52.1 millimole per liter (mmol/L) | Standard Error 1.5 |
p-value: <0.000195% CI: [-55.3, -47.1]Mixed-effects Model for Repeated Measure
Secondary
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 28
Population: Safety set included all participants who received at least 1 dose of study drug in the treatment period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants With TEAEs | 57 participants |
| Placebo | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants With SAEs | 9 participants |
| ELX/TEZ/IVA | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants With TEAEs | 48 participants |
| ELX/TEZ/IVA | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants With SAEs | 4 participants |