Cystic Fibrosis
Conditions
Brief summary
This is a Phase 3, 2-part (Part A and Part B), open label, multicenter study evaluating the pharmacokinetic (PK), safety, and tolerability of multiple doses of tezacaftor (TEZ) in combination with ivacaftor (IVA) in subjects 6 through 11 years of age with CF who are homozygous or heterozygous for the F508del- CF transmembrane conductance regulator protein (CFTR) mutation.
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
* Subjects who weigh ≥15 kg without shoes at the Screening Visit. * All genotypes as specified by the study protocol are eligible in Part A. * The following genotypes are eligible in Part B: * homozygous for the F508del CFTR mutation * heterozygous for the F508del CFTR mutation and with a second allele with a CFTR mutation predicted to have residual function. * heterozygous for the F508del CFTR mutation and with a second CFTR allele with a gating defect that is clinically demonstrated to be ivacaftor responsive * Subjects with a confirmed diagnosis of CF defined as a sweat chloride value ≥60 mmol/L or chronic sinopulmonary and/or gastrointestinal disease consistent with a diagnosis of CF. Subjects who are homozygous for the F508del-CFTR mutation must have a sweat chloride value ≥60 mmol/L. * Subjects with ppFEV1 of ≥40 percentage points at the Screening Visit * Subjects with stable CF disease as deemed by the investigator at the Screening Visit. * Subjects who are willing to remain on their stable CF medication regimen through Day 14 (Part A) or through Week 24 (Part B) or, if applicable, through the Safety Follow up Visit. * Subjects who are able to swallow tablets. * Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Day 1 Visit before receiving the first dose of study drug. * Subjects of childbearing potential who are sexually active must meet the contraception requirements
Exclusion criteria
* History of any comorbidity reviewed at the Screening Visit 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. * Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject. * An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 28 days before Day 1 * Colonization with organisms associated with a more rapid decline in pulmonary status. * A standard 12 lead ECG demonstrating QTc \>450 msec at the Screening Visit. * History of solid organ or hematological transplantation at the Screening Visit. * Ongoing or prior participation in an investigational drug study or use of commercially available CFTR modulator (except physician-prescribed Kalydeco for approved indications) within 30 days of screening. * Use of restricted medication or food within a specified duration before the Screening Visit or first dose of study drug and/or unwillingness to maintain the restrictions. * History or evidence of cataract, lens opacity, Y-suture, or lamellar rings determined to be clinically significant by the ophthalmologist during the ophthalmologic examination at the Screening Visit. * Pregnant and nursing females.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part A: Maximum Observed Concentration (Cmax) of TEZ and IVA | Day 1 and Day 14 |
| Part A: Area Under the Concentration Versus Time Curve During Dosing Interval (AUCtau) of TEZ and IVA | Day 1 and Day 14 |
| Part B: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Day 1 up to Week 28 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B: Cmax of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA) | Week 16 | — |
| Part B: AUCtau of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA ) | Week 16 | — |
| Part B: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | From Baseline through Week 24 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. |
| Part B: Relative Change in ppFEV1 | From Baseline through Week 24 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. |
| Part B: Absolute Change in Weight | From Baseline at Week 24 | — |
| Part B: Absolute Change in Weight-for-age Z-Score | From Baseline at Week 24 | z-score is a statistical measure to describe whether a mean was above or below the standard. Weight, adjusted for age and sex, was analyzed as weight-for-age z-score. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of higher weight. |
| Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 1 and Day 14 | — |
| Part B: Absolute Change in Height-for-age z-Score | From Baseline at Week 24 | z-score is a statistical measure to describe whether a mean was above or below the standard. Height, adjusted for age and sex, was analyzed as height-for-age z-score. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of higher height. |
| Part B: Absolute Change in Body Mass Index (BMI) | From Baseline at Week 24 | BMI was defined as weight in kg divided by height in square meter (m\^2). |
| Part B: Absolute Change in BMI-for-age z-Score | From Baseline at Week 24 | BMI was defined as weight in kg divided by height in m\^2. z-score is a statistical measure to describe whether a mean was above or below the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age z-score. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of higher BMI. |
| Part B: Absolute Change in Sweat Chloride | From Baseline through Week 4 | Sweat samples were collected using an approved collection device. |
| Part B: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | From Baseline through Week 24 | 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. |
| Part B: Absolute Change in Height | From Baseline at Week 24 | — |
| Part A: AUCtau of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 1 and Day 14 | — |
| Part A: Number of Participants With AEs and SAEs | Day 1 up to Day 28 | — |
Countries
Canada, United States
Participant flow
Pre-assignment details
This study consisted of 2-parts (Part A and B). The planned primary analysis was designed to assess overall treatment arm TEZ/IVA, irrespective of weight-based dosing regimen. The aim of weight based dosing is to achieve similar exposures in children of different weights, thus analysis is presented for the single treatment arm TEZ/IVA.
Participants by arm
| Arm | Count |
|---|---|
| Part A Participants weighing \<25 kg received TEZ 50 mg/IVA 75 mg for 14 days. Participants weighing ≥25 kg received TEZ 50 mg/IVA 150 mg for 14 days. | 13 |
| Part B Participants weighing \<40 kg received TEZ 50 mg/IVA 75 mg as fixed dose combination in the morning and IVA 75 mg in the evening for 24 weeks.
Participants weighing ≥40 kg received TEZ 100 mg/IVA 150 mg as fixed dose combination in the morning and IVA 150 mg in the evening for 24 weeks. | 70 |
| Total | 83 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Withdrawal of consent (not due to AE) | 0 | 2 |
Baseline characteristics
| Characteristic | Part A | Part B | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 13 Participants | 70 Participants | 83 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 67 Participants | 80 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 68 Participants | 80 Participants |
| Sex: Female, Male Female | 7 Participants | 34 Participants | 41 Participants |
| Sex: Female, Male Male | 6 Participants | 36 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 70 |
| other Total, other adverse events | 12 / 13 | 62 / 70 |
| serious Total, serious adverse events | 0 / 13 | 6 / 70 |
Outcome results
Primary
Part A: Area Under the Concentration Versus Time Curve During Dosing Interval (AUCtau) of TEZ and IVA
Time frame: Day 1 and Day 14
Population: PK set. Here Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.Number Analyzed=0 signified no subjects were evaluated for the specified parameter at that time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part A: Area Under the Concentration Versus Time Curve During Dosing Interval (AUCtau) of TEZ and IVA | Day 1: TEZ (<25 Kg) | 54300 hour*nanogram per milliliter (hr*ng/mL) | Geometric Coefficient of Variation 16.2 |
| Part A | Part A: Area Under the Concentration Versus Time Curve During Dosing Interval (AUCtau) of TEZ and IVA | Day 1: TEZ (≥25 Kg) | 41600 hour*nanogram per milliliter (hr*ng/mL) | Geometric Coefficient of Variation 36.2 |
| Part A | Part A: Area Under the Concentration Versus Time Curve During Dosing Interval (AUCtau) of TEZ and IVA | Day 14: TEZ (<25 Kg) | 66500 hour*nanogram per milliliter (hr*ng/mL) | Geometric Coefficient of Variation 30.5 |
| Part A | Part A: Area Under the Concentration Versus Time Curve During Dosing Interval (AUCtau) of TEZ and IVA | Day 14: TEZ (≥25 Kg) | 71600 hour*nanogram per milliliter (hr*ng/mL) | Geometric Coefficient of Variation 61.1 |
| Part A | Part A: Area Under the Concentration Versus Time Curve During Dosing Interval (AUCtau) of TEZ and IVA | Day 14: IVA (<25 Kg) | 5050 hour*nanogram per milliliter (hr*ng/mL) | Geometric Coefficient of Variation 49.1 |
| Part A | Part A: Area Under the Concentration Versus Time Curve During Dosing Interval (AUCtau) of TEZ and IVA | Day 14: IVA (≥25 Kg) | 12400 hour*nanogram per milliliter (hr*ng/mL) | Geometric Coefficient of Variation 118 |
Primary
Part A: Maximum Observed Concentration (Cmax) of TEZ and IVA
Time frame: Day 1 and Day 14
Population: Pharmacokinetic (PK) set included 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 Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part A: Maximum Observed Concentration (Cmax) of TEZ and IVA | Day 1: TEZ (<25 Kg) | 6630 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 10.3 |
| Part A | Part A: Maximum Observed Concentration (Cmax) of TEZ and IVA | Day 1: TEZ (≥25 Kg) | 4310 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 42.6 |
| Part A | Part A: Maximum Observed Concentration (Cmax) of TEZ and IVA | Day 14: TEZ (<25 Kg) | 6300 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 10.3 |
| Part A | Part A: Maximum Observed Concentration (Cmax) of TEZ and IVA | Day 14: TEZ (≥25 Kg) | 5340 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 49 |
| Part A | Part A: Maximum Observed Concentration (Cmax) of TEZ and IVA | Day 1: IVA (<25 Kg) | 656 nanogram per milliliter (ng/mL) | — |
| Part A | Part A: Maximum Observed Concentration (Cmax) of TEZ and IVA | Day 1: IVA (≥25 Kg) | 1010 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 64.3 |
| Part A | Part A: Maximum Observed Concentration (Cmax) of TEZ and IVA | Day 14: IVA (<25 Kg) | 578 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 60.4 |
| Part A | Part A: Maximum Observed Concentration (Cmax) of TEZ and IVA | Day 14: IVA (≥25 Kg) | 1490 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 105 |
Primary
Part B: Number of Participants With Treatment-Emergent Adverse Events (AEs) 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. The planned analysis was designed to assess overall treatment arm, irrespective of weight-based dosing regimen. The aim of weight based dosing is to achieve similar exposures in children of different weights, thus analysis is presented for the single treatment arm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A | Part B: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 65 participants |
| Part A | Part B: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 6 participants |
Secondary
Part A: AUCtau of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA)
Time frame: Day 1 and Day 14
Population: PK set. Here Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points. Number Analyzed=0 signified no subjects were evaluated for the specified parameter at that time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part A: AUCtau of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 14: M6-IVA (<25 kg) | 10200 hr*ng/mL | Geometric Coefficient of Variation 58.5 |
| Part A | Part A: AUCtau of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 14: M6-IVA (≥25 kg) | 26000 hr*ng/mL | Geometric Coefficient of Variation 70.6 |
| Part A | Part A: AUCtau of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 1: M1-TEZ (<25 kg) | 36500 hr*ng/mL | Geometric Coefficient of Variation 5.8 |
| Part A | Part A: AUCtau of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 1: M1-TEZ (≥25 kg) | 27400 hr*ng/mL | Geometric Coefficient of Variation 26.3 |
| Part A | Part A: AUCtau of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 14: M1-TEZ (<25 kg) | 160000 hr*ng/mL | Geometric Coefficient of Variation 15.5 |
| Part A | Part A: AUCtau of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 14: M1-TEZ (≥25 kg) | 121000 hr*ng/mL | Geometric Coefficient of Variation 17.1 |
| Part A | Part A: AUCtau of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 1: M2-TEZ (<25 kg) | 14200 hr*ng/mL | Geometric Coefficient of Variation 12.3 |
| Part A | Part A: AUCtau of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 1: M2-TEZ (≥25 kg) | 11100 hr*ng/mL | Geometric Coefficient of Variation 25.9 |
| Part A | Part A: AUCtau of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 14: M2-TEZ (<25 kg) | 137000 hr*ng/mL | Geometric Coefficient of Variation 32.7 |
| Part A | Part A: AUCtau of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 14: M2-TEZ (≥25 kg) | 119000 hr*ng/mL | Geometric Coefficient of Variation 27.7 |
| Part A | Part A: AUCtau of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 14: M1-IVA (<25 kg) | 13700 hr*ng/mL | Geometric Coefficient of Variation 52.1 |
| Part A | Part A: AUCtau of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 14: M1-IVA (≥25 kg) | 30300 hr*ng/mL | Geometric Coefficient of Variation 81.1 |
Secondary
Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA)
Time frame: Day 1 and Day 14
Population: PK set. Here Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 1: M2-TEZ (<25 kg) | 1130 ng/mL | Geometric Coefficient of Variation 4.36 |
| Part A | Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 1: M2-TEZ (≥25 kg) | 922 ng/mL | Geometric Coefficient of Variation 25.8 |
| Part A | Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 14: M2-TEZ (<25 kg) | 6180 ng/mL | Geometric Coefficient of Variation 27.2 |
| Part A | Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 14: M1-IVA (<25 kg) | 1460 ng/mL | Geometric Coefficient of Variation 34.6 |
| Part A | Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 14: M1-IVA (≥25 kg) | 3420 ng/mL | Geometric Coefficient of Variation 72.7 |
| Part A | Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 1: M6-IVA (<25 kg) | 849 ng/mL | — |
| Part A | Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 1: M6-IVA (≥25 kg) | 1070 ng/mL | Geometric Coefficient of Variation 55.7 |
| Part A | Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 1: M1-TEZ (<25 kg) | 1720 ng/mL | Geometric Coefficient of Variation 3.29 |
| Part A | Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 1: M1-TEZ (≥25 kg) | 1530 ng/mL | Geometric Coefficient of Variation 22 |
| Part A | Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 14: M1-TEZ (<25 kg) | 8360 ng/mL | Geometric Coefficient of Variation 22 |
| Part A | Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 14: M1-TEZ (≥25 kg) | 5930 ng/mL | Geometric Coefficient of Variation 19.9 |
| Part A | Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 14: M2-TEZ (≥25 kg) | 5350 ng/mL | Geometric Coefficient of Variation 27.2 |
| Part A | Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 1: M1-IVA (<25 kg) | 2320 ng/mL | — |
| Part A | Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 1: M1-IVA (≥25 kg) | 2430 ng/mL | Geometric Coefficient of Variation 57.1 |
| Part A | Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 14: M6-IVA (<25 kg) | 1090 ng/mL | Geometric Coefficient of Variation 31.4 |
| Part A | Part A: Cmax of TEZ Metabolites (M1-TEZ, M2-TEZ) and IVA Metabolites (M1-IVA, M6-IVA) | Day 14: M6-IVA (≥25 kg) | 2720 ng/mL | Geometric Coefficient of Variation 59.2 |
Secondary
Part A: Number of Participants With AEs and SAEs
Time frame: Day 1 up to Day 28
Population: Safety set: included all participants who received at least 1 dose of study drug. The planned analysis was designed to assess overall treatment arm, irrespective of weight-based dosing regimen. The aim of weight based dosing is to achieve similar exposures in children of different weights, thus analysis is presented for the single treatment arm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A | Part A: Number of Participants With AEs and SAEs | Participants with AEs | 12 participants |
| Part A | Part A: Number of Participants With AEs and SAEs | Participants with SAEs | 0 participants |
Secondary
Part B: Absolute Change in BMI-for-age z-Score
BMI was defined as weight in kg divided by height in m\^2. z-score is a statistical measure to describe whether a mean was above or below the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age z-score. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of higher BMI.
Time frame: From Baseline at Week 24
Population: FAS: participants who carry the intended CFTR mutations and received at least 1 dose of study drug. The aim of weight based dosing is to achieve similar exposures in children of different weights, thus the planned analysis is presented for the single treatment arm irrespective of weight-based dosing regimen.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A | Part B: Absolute Change in BMI-for-age z-Score | -0.03 z-score |
Secondary
Part B: Absolute Change in Body Mass Index (BMI)
BMI was defined as weight in kg divided by height in square meter (m\^2).
Time frame: From Baseline at Week 24
Population: FAS: participants who carry the intended CFTR mutations and received at least 1 dose of study drug. The aim of weight based dosing is to achieve similar exposures in children of different weights, thus the planned analysis is presented for the single treatment arm irrespective of weight-based dosing regimen.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A | Part B: Absolute Change in Body Mass Index (BMI) | 0.23 kg/m^2 |
Secondary
Part B: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score
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: From Baseline through Week 24
Population: FAS: participants who carry the intended CFTR mutations and received at least 1 dose of study drug. The aim of weight based dosing is to achieve similar exposures in children of different weights, thus the planned analysis is presented for the single treatment arm irrespective of weight-based dosing regimen.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A | Part B: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | 3.4 units on a scale |
Secondary
Part B: Absolute Change in Height
Time frame: From Baseline at Week 24
Population: FAS: participants who carry the intended CFTR mutations and received at least 1 dose of study drug. The aim of weight based dosing is to achieve similar exposures in children of different weights, thus the planned analysis is presented for the single treatment arm irrespective of weight-based dosing regimen.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A | Part B: Absolute Change in Height | 2.7 centimeter (cm) |
Secondary
Part B: Absolute Change in Height-for-age z-Score
z-score is a statistical measure to describe whether a mean was above or below the standard. Height, adjusted for age and sex, was analyzed as height-for-age z-score. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of higher height.
Time frame: From Baseline at Week 24
Population: FAS: participants who carry the intended CFTR mutations and received at least 1 dose of study drug. The aim of weight based dosing is to achieve similar exposures in children of different weights, thus the planned analysis is presented for the single treatment arm irrespective of weight-based dosing regimen.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A | Part B: Absolute Change in Height-for-age z-Score | 0.00 z-score |
Secondary
Part B: 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 through Week 24
Population: FAS: participants who carry the intended CFTR mutations and received at least 1 dose of study drug. The aim of weight based dosing is to achieve similar exposures in children of different weights, thus the planned analysis is presented for the single treatment arm irrespective of weight-based dosing regimen.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A | Part B: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | 0.9 percentage points |
Secondary
Part B: Absolute Change in Sweat Chloride
Sweat samples were collected using an approved collection device.
Time frame: From Baseline through Week 4
Population: FAS: participants who carry the intended CFTR mutations and received at least 1 dose of study drug. The aim of weight based dosing is to achieve similar exposures in children of different weights, thus the planned analysis is presented for the single treatment arm irrespective of weight-based dosing regimen.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A | Part B: Absolute Change in Sweat Chloride | -13.0 millimole per liter (mmol/L) |
Secondary
Part B: Absolute Change in Sweat Chloride
Sweat samples were collected using an approved collection device.
Time frame: From Baseline through Week 24
Population: FAS: participants who carry the intended CFTR mutations and received at least 1 dose of study drug. The aim of weight based dosing is to achieve similar exposures in children of different weights, thus the planned analysis is presented for the single treatment arm irrespective of weight-based dosing regimen.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A | Part B: Absolute Change in Sweat Chloride | -14.5 mmol/L |
Secondary
Part B: Absolute Change in Weight
Time frame: From Baseline at Week 24
Population: FAS: participants who carry the intended CFTR mutations and received at least 1 dose of study drug. The aim of weight based dosing is to achieve similar exposures in children of different weights, thus the planned analysis is presented for the single treatment arm irrespective of weight-based dosing regimen.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A | Part B: Absolute Change in Weight | 1.7 kg |
Secondary
Part B: Absolute Change in Weight-for-age Z-Score
z-score is a statistical measure to describe whether a mean was above or below the standard. Weight, adjusted for age and sex, was analyzed as weight-for-age z-score. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of higher weight.
Time frame: From Baseline at Week 24
Population: FAS: participants who carry the intended CFTR mutations and received at least 1 dose of study drug. The aim of weight based dosing is to achieve similar exposures in children of different weights, thus the planned analysis is presented for the single treatment arm irrespective of weight-based dosing regimen.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A | Part B: Absolute Change in Weight-for-age Z-Score | 0.00 z-score |
Secondary
Part B: AUCtau of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA )
Time frame: Week 16
Population: PK set. Here Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part B: AUCtau of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA ) | TEZ (≥40 kg) | 60900 hr*ng/mL | Geometric Coefficient of Variation 50.6 |
| Part A | Part B: AUCtau of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA ) | TEZ (<40 kg) | 50300 hr*ng/mL | Geometric Coefficient of Variation 36.3 |
| Part A | Part B: AUCtau of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA ) | M1-TEZ (<40 kg) | 104000 hr*ng/mL | Geometric Coefficient of Variation 44.2 |
| Part A | Part B: AUCtau of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA ) | M1-TEZ (≥40 kg) | 100000 hr*ng/mL | Geometric Coefficient of Variation 87.2 |
| Part A | Part B: AUCtau of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA ) | M2-TEZ (<40 kg) | 88400 hr*ng/mL | Geometric Coefficient of Variation 57 |
| Part A | Part B: AUCtau of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA ) | M2-TEZ (≥40 kg) | 93600 hr*ng/mL | Geometric Coefficient of Variation 46.5 |
| Part A | Part B: AUCtau of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA ) | IVA (<40 kg) | 5330 hr*ng/mL | Geometric Coefficient of Variation 62.2 |
| Part A | Part B: AUCtau of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA ) | IVA (≥40 kg) | 7410 hr*ng/mL | Geometric Coefficient of Variation 53.8 |
| Part A | Part B: AUCtau of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA ) | M1-IVA (<40 kg) | 12700 hr*ng/mL | Geometric Coefficient of Variation 55.9 |
| Part A | Part B: AUCtau of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA ) | M1-IVA (≥40 kg) | 17200 hr*ng/mL | Geometric Coefficient of Variation 40.4 |
| Part A | Part B: AUCtau of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA ) | M6-IVA (<40 kg) | 8140 hr*ng/mL | Geometric Coefficient of Variation 70.2 |
| Part A | Part B: AUCtau of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA ) | M6-IVA (≥40 kg) | 11100 hr*ng/mL | Geometric Coefficient of Variation 39.4 |
Secondary
Part B: Cmax of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA)
Time frame: Week 16
Population: PK set. Here Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part B: Cmax of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA) | TEZ (<40 kg) | 4800 ng/mL | Geometric Coefficient of Variation 33.7 |
| Part A | Part B: Cmax of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA) | TEZ (≥40 kg) | 5870 ng/mL | Geometric Coefficient of Variation 46.5 |
| Part A | Part B: Cmax of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA) | M1-TEZ (<40 kg) | 5310 ng/mL | Geometric Coefficient of Variation 36 |
| Part A | Part B: Cmax of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA) | M1-TEZ (≥40 kg) | 5440 ng/mL | Geometric Coefficient of Variation 61.5 |
| Part A | Part B: Cmax of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA) | M2-TEZ (<40 kg) | 4170 ng/mL | Geometric Coefficient of Variation 47.4 |
| Part A | Part B: Cmax of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA) | M2-TEZ (≥40 kg) | 5210 ng/mL | Geometric Coefficient of Variation 55 |
| Part A | Part B: Cmax of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA) | IVA (<40 kg) | 725 ng/mL | Geometric Coefficient of Variation 56.9 |
| Part A | Part B: Cmax of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA) | IVA (≥40 kg) | 886 ng/mL | Geometric Coefficient of Variation 58.7 |
| Part A | Part B: Cmax of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA) | M1-IVA (<40 kg) | 1560 ng/mL | Geometric Coefficient of Variation 54.8 |
| Part A | Part B: Cmax of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA) | M1-IVA (≥40 kg) | 1870 ng/mL | Geometric Coefficient of Variation 50.2 |
| Part A | Part B: Cmax of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA) | M6-IVA (<40 kg) | 870 ng/mL | Geometric Coefficient of Variation 69.2 |
| Part A | Part B: Cmax of TEZ, TEZ Metabolites (M1-TEZ, M2-TEZ), IVA, and IVA Metabolites (M1-IVA, M6-IVA) | M6-IVA (≥40 kg) | 1120 ng/mL | Geometric Coefficient of Variation 29.5 |
Secondary
Part B: Relative Change in ppFEV1
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time frame: From Baseline through Week 24
Population: FAS: participants who carry the intended CFTR mutations and received at least 1 dose of study drug. The aim of weight based dosing is to achieve similar exposures in children of different weights, thus the planned analysis is presented for the single treatment arm irrespective of weight-based dosing regimen.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A | Part B: Relative Change in ppFEV1 | 1.4 percent change |