Evaluation of VX 445/TEZ/IVA in Cystic Fibrosis Subjects 6 Through 11 Years of Age

• Sponsor: Vertex Pharmaceuticals Incorporated (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03691779
• Collaborator: (none)
• Enrollment: 71
• Locations: 21
• Arms: 2
• Actual Duration (Months): 22.2
• Patients Per Site: 3.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study will evaluate the pharmacokinetics (PK), safety, tolerability, efficacy, and pharmacodynamic effect of VX-445, tezacaftor (TEZ), and ivacaftor (IVA) when dosed in triple combination (TC) in Cystic Fibrosis (CF) subjects 6 through 11 years of age with F/F and F/MF genotypes.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: ELX/TEZ/IVA; Drug: IVA	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 71 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Study Evaluating the Pharmacokinetics, Safety, and Tolerability of VX-445/TEZ/IVA Triple Combination Therapy in Cystic Fibrosis Subjects 6 Through 11 Years of Age
• Actual Study Start Date: Oct 2, 2018
• Actual Primary Completion Date: Aug 7, 2020
• Actual Study Completion Date: Aug 7, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part A: ELX/TEZ/IVA Participants in Part A received ELX 100 milligrams (mg) once daily (qd)/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) in the treatment period for 15 days.	Drug: ELX/TEZ/IVA; Fixed-dose combination tablet orally once daily in the morning.; Other Names: VX-445/VX-661/VX-770 elexacaftor/tezacaftor/ivacaftor ; Drug: IVA; IVA tablet orally once daily in the evening.; Other Names: VX-770 ivacaftor
Experimental: Part B: ELX/TEZ/IVA Participants in Part B weighing less than (<) 30 kilograms (kg) at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing greater than equals to (>=) 30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.	Drug: ELX/TEZ/IVA; Fixed-dose combination tablet orally once daily in the morning.; Other Names: VX-445/VX-661/VX-770 elexacaftor/tezacaftor/ivacaftor ; Drug: IVA; IVA tablet orally once daily in the evening.; Other Names: VX-770 ivacaftor

Outcome Measures

Primary Outcome Measures

1. Part A: Maximum Observed Plasma Concentration (Cmax) of ELX, TEZ, and IVA [Part A: Day 15]

2. Part A: Observed Pre-dose Plasma Concentration (Ctrough) of ELX, TEZ, and IVA [Part A: Day 15]

3. Part A: Area Under the Concentration Versus Time Curve From 0 to 24 Hours (AUC0-24h) of ELX, TEZ, and IVA [Part A: Day 15]

4. Part B: Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [Part B: Day 1 Through Safety Follow-up Visit (up to Week 28)]

Secondary Outcome Measures

1. Part A: Cmax of ELX Metabolite (M23-ELX), TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA) [Part A: Day 15]

2. Part A: Ctrough of ELX Metabolite (M23-ELX), TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA) [Part A: Day 15]

3. Part A: AUC0-24h of ELX Metabolite (M23-ELX) and TEZ Metabolite (M1-TEZ) [Part A: Day 15]

4. Part A: Area Under the Concentration Versus Time Curve From 0 to 6 Hours (AUC0-6h) of IVA Metabolite (M1-IVA) [Part A: Day 15]

   The AUC data was analyzed for up to 6 hours for IVA metabolite (M1-IVA). Therefore, AUC0-6h is reported for M1-IVA metabolite.

5. Part A: Safety and Tolerability as Assessed by Number of Participants With TEAEs and SAEs [Part A: Day 1 Through Safety Follow-up Visit (up to Day 43)]

6. Part B: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) [Part B: From Baseline Through Week 24]

   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

7. Part B: Absolute Change in Sweat Chloride (SwCl) [Part B: From Baseline Through Week 24]

   Sweat samples were collected using an approved collection device.

8. Part B: Absolute Change in Cystic Fibrosis Questionnaire Revised (CFQ-R) Respiratory Domain Score [Part B: 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.

9. Part B: Absolute Change in Body Mass Index (BMI) [Part B: From Baseline at Week 24]

   BMI was defined as weight in kg divided by squared height in meters (m^2).

10. Part B: Absolute Change in BMI For-Age Z-Score [Part B: From Baseline at Week 24]

    BMI was defined as weight in kg divided by squared height in meters (m^2). The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.

11. Part B: Absolute Change in Weight [Part B: From Baseline at Week 24]

12. Part B: Absolute Change in Weight-for-age Z-Score [Part B: From Baseline at Week 24]

    The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.

13. Part B: Absolute Change in Height [Part B: From Baseline at Week 24]

14. Part B: Absolute Change in Height-for-Age Z-Score [Part B: From Baseline at Week 24]

    The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.

15. Part B: Drug Acceptability Assessment Using Modified Facial Hedonic Scale [Part B: At Week 24]

    The study drug acceptability (participant reaction) was assessed by a visual analog scale that incorporates a 5 point facial hedonic scale (Liked it Very Much, Liked it a Little, Not sure, Disliked it a Little, Disliked it Very Much). Number of participants with the indicated categorical response in the drug acceptability assessment were reported.

16. Part B: Number of Pulmonary Exacerbations Events [Part B: From Baseline Through Week 24]

    Pulmonary exacerbation was defined as new or changed treatment with oral, inhaled, or intravenous antibiotics and fulfillment of pre-specified protocol defined criteria. The total number of pulmonary exacerbations events across all participants were reported.

17. Part B: Number of CF Related Hospitalizations [Part B: From Baseline Through Week 24]

    The total number of CF related hospitalization events across all participants were reported.

18. Part B: Ctrough of ELX, ELX Metabolite (M23-ELX), TEZ, TEZ Metabolite (M1-TEZ), IVA and IVA Metabolite (M1-IVA) [Part B: At Week 4]

19. Part B: Absolute Change in Lung Clearance Index 2.5 (LCI2.5) [Part B: From Baseline Through Week 24]

    LCI 2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 11 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Homozygous or heterozygous for F508del mutation (F/F or F/MF genotypes)

• Forced expiratory volume in 1 second (FEV1) value ≥40% of predicted mean for age, sex, and height.

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/Exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Orange County	Orange	California	United States	92868
2	Children's Hospital Colorado	Aurora	Colorado	United States	80045
3	Ann & Robert Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
4	Boston Children's Hospital	Boston	Massachusetts	United States	02115
5	Children's Respiratory and Critical Care Specialists, P.A., Children's Hospitals and Clinics of Minnesota	Minneapolis	Minnesota	United States	55404
6	The Children's Mercy Hospital	Kansas City	Missouri	United States	64108
7	Northwell Health- Long Island Jewish Medical Center	New Hyde Park	New York	United States	11040
8	Clinical Research of Charlotte	Charlotte	North Carolina	United States	28277
9	Rainbow Babies and Children's Hospital/University Hospitals Cleveland Medical Center	Cleveland	Ohio	United States	44106
10	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
11	Oregon Health & Science University	Portland	Oregon	United States	97239
12	Texas Children's Hospital	Houston	Texas	United States	77030
13	Seattle Children's Hospital	Seattle	Washington	United States	98105
14	Queensland Children's Hospital	South Brisbane		Australia
15	The Children's Hospital at Westmead	Westmead		Australia
16	The Hospital for Sick Children	Toronto		Canada
17	British Columbia's Children's Hospital	Vancouver		Canada
18	Children's Health Ireland at Crumlin	Dublin		Ireland
19	Children's Health Ireland at Temple Street	Dublin		Ireland
20	Birmingham Children's Hospital	Birmingham		United Kingdom
21	Royal Brompton & Harefield NHS Foundation Trust, Royal Brompton Hospital	London		United Kingdom

Sponsors and Collaborators

• Vertex Pharmaceuticals Incorporated

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Dec 18, 2019
• Statistical Analysis Plan - Aug 11, 2020

More Information

Publications

None provided.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT03691779
• Other Study ID Numbers: VX18-445-106; 2018-001695-38
• First Posted: Oct 2, 2018
• Last Update Posted: Oct 22, 2021
• Last Verified: Aug 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Ivacaftor; Elexacaftor

Study Results

Participant Flow

Recruitment Details	The study was conducted in 2 parts, Part A and Part B. All results were planned to be analyzed and reported separately for Part A and Part B of the study.
Pre-assignment Detail	This study was conducted in cystic fibrosis (CF) participants 6 through 11 years of age who were homozygous for F508del (F/F) genotype or heterozygous for F508del and a CF transmembrane conductance regulator gene (CFTR) minimal function mutation (F/MF) genotypes.

Arm/Group Title	Part A: ELX/TEZ/IVA	Part B: ELX/TEZ/IVA
Arm/Group Description	Participants in Part A received elexacaftor (ELX) 100 milligrams (mg) once daily (qd)/tezacaftor (TEZ) 50 mg qd/ivacaftor (IVA) 75 mg every 12 hours (q12h) in the treatment period for 15 days.	Participants in Part B weighing less than (<) 30 kilograms (kg) at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing greater than equals to (>=) 30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Period Title: Part A (15 Days)
STARTED	16	0
COMPLETED	16	0
NOT COMPLETED	0	0
Period Title: Part A (15 Days)
STARTED	0	66
COMPLETED	0	64
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	ELX/TEZ/IVA
Arm/Group Description	Part A: Participants in Part A received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h in the treatment period for 15 days. Part B: Participants in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Overall Participants	71
Age (Count of Participants)
<=18 years	16 22.5%
Between 18 and 65 years	0 0%
>=65 years	0 0%
<=18 years	66 93%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	11 15.5%
Male	5 7%
Female	39 54.9%
Male	27 38%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	16 22.5%
Unknown or Not Reported	0 0%
Hispanic or Latino	0 0%
Not Hispanic or Latino	58 81.7%
Unknown or Not Reported	8 11.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	16 22.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	57 80.3%
More than one race	1 1.4%
Unknown or Not Reported	8 11.3%

Outcome Measures

1. Primary Outcome

Title	Part A: Maximum Observed Plasma Concentration (Cmax) of ELX, TEZ, and IVA
Time Frame	Part A: Day 15

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set for Part A included all participants who have received at least 1 dose of study drug in Part A. Here, the "number analyzed" signifies participants who were evaluable at the specified time point. This outcome measure was planned only for Part A arm.

Arm/Group Title	Part A: ELX/TEZ/IVA
Arm/Group Description	Participants in Part A received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h in the treatment period for 15 days.
Measure Participants	16
ELX	6.13 (1.52)
TEZ	6.93 (1.96)
IVA	1.01 (0.281)

2. Primary Outcome

Title	Part A: Observed Pre-dose Plasma Concentration (Ctrough) of ELX, TEZ, and IVA
Time Frame	Part A: Day 15

Outcome Measure Data

Analysis Population Description

PK set (Part A). Here, the "number analyzed" signifies participants who were evaluable at the specified time point. This outcome measure was planned only for Part A arm.

Arm/Group Title	Part A: ELX/TEZ/IVA
Arm/Group Description	Participants in Part A received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h in the treatment period for 15 days.
Measure Participants	16
ELX	2.86 (1.37)
TEZ	1.06 (0.366)
IVA	0.297 (0.173)

3. Primary Outcome

Title	Part A: Area Under the Concentration Versus Time Curve From 0 to 24 Hours (AUC0-24h) of ELX, TEZ, and IVA
Time Frame	Part A: Day 15

Outcome Measure Data

Analysis Population Description

PK set (Part A). This outcome measure was planned only for Part A arm.

Arm/Group Title	Part A: ELX/TEZ/IVA
Arm/Group Description	Participants in Part A received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h in the treatment period for 15 days.
Measure Participants	16
ELX	107 (28.7)
TEZ	58.4 (13.5)
IVA	8.12 (2.93)

4. Primary Outcome

Title	Part B: Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time Frame	Part B: Day 1 Through Safety Follow-up Visit (up to Week 28)

Outcome Measure Data

Analysis Population Description

Safety set for Part B included all participants who received at least 1 dose of study drug in Part B. The safety and tolerability analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.

Arm/Group Title	Part B: ELX/TEZ/IVA
Arm/Group Description	Participants in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	66
Participants With TEAEs	65 91.5%
Participants With SAEs	1 1.4%

5. Secondary Outcome

Title	Part A: Cmax of ELX Metabolite (M23-ELX), TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)
Time Frame	Part A: Day 15

Outcome Measure Data

Analysis Population Description

PK set (Part A). Here, the "number analyzed" signifies participants who were evaluable at the specified time point. This outcome measure was planned only for Part A arm.

Arm/Group Title	Part A: ELX/TEZ/IVA
Arm/Group Description	Participants in Part A received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h in the treatment period for 15 days.
Measure Participants	16
M23-ELX	1.60 (0.657)
M1-TEZ	6.26 (1.54)
M1-IVA	2.36 (0.694)

6. Secondary Outcome

Title	Part A: Ctrough of ELX Metabolite (M23-ELX), TEZ Metabolite (M1-TEZ), and IVA Metabolite (M1-IVA)
Time Frame	Part A: Day 15

Outcome Measure Data

Analysis Population Description

PK set (Part A). Here, the "number analyzed" signifies participants who were evaluable at the specified time point. This outcome measure was planned only for Part A arm.

Arm/Group Title	Part A: ELX/TEZ/IVA
Arm/Group Description	Participants in Part A received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h in the treatment period for 15 days.
Measure Participants	16
M23-ELX	1.30 (0.585)
M1-TEZ	4.64 (1.36)
M1-IVA	0.890 (0.460)

7. Secondary Outcome

Title	Part A: AUC0-24h of ELX Metabolite (M23-ELX) and TEZ Metabolite (M1-TEZ)
Time Frame	Part A: Day 15

Outcome Measure Data

Analysis Population Description

PK set (Part A). This outcome measure was planned only for Part A arm.

Arm/Group Title	Part A: ELX/TEZ/IVA
Arm/Group Description	Participants in Part A received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h in the treatment period for 15 days.
Measure Participants	16
M23-ELX	35.6 (13.2)
M1-TEZ	133 (30.4)

8. Secondary Outcome

Title	Part A: Area Under the Concentration Versus Time Curve From 0 to 6 Hours (AUC0-6h) of IVA Metabolite (M1-IVA)
Description	The AUC data was analyzed for up to 6 hours for IVA metabolite (M1-IVA). Therefore, AUC0-6h is reported for M1-IVA metabolite.
Time Frame	Part A: Day 15

Outcome Measure Data

Analysis Population Description

PK set (Part A). Here "overall number of participants analyzed" signifies participants who were evaluable at the specified time points. This outcome measure was planned only for Part A arm.

Arm/Group Title	Part A: ELX/TEZ/IVA
Arm/Group Description	Participants in Part A received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h in the treatment period for 15 days.
Measure Participants	15
Mean (Standard Deviation) [h*mcg/mL]	9.41 (3.06)

9. Secondary Outcome

Title	Part A: Safety and Tolerability as Assessed by Number of Participants With TEAEs and SAEs
Time Frame	Part A: Day 1 Through Safety Follow-up Visit (up to Day 43)

Outcome Measure Data

Analysis Population Description

Safety set for Part A included all participants who received at least 1 dose of study drug in Part A. This outcome measure was planned only for Part A arm.

Arm/Group Title	Part A: ELX/TEZ/IVA
Arm/Group Description	Participants in part A received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h in the treatment period for 15 days.
Measure Participants	16
Participants With TEAEs	12 16.9%
Participants With SAEs	0 0%

10. Secondary Outcome

Title	Part B: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time Frame	Part B: From Baseline Through Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) for Part B included all enrolled participants who carry the intended CFTR allele mutation and received at least 1 dose of study drug in Part B. The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.

Arm/Group Title	Part B: ELX/TEZ/IVA
Arm/Group Description	Participants in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	66
Least Squares Mean (95% Confidence Interval) [percentage points]	10.2

11. Secondary Outcome

Title	Part B: Absolute Change in Sweat Chloride (SwCl)
Description	Sweat samples were collected using an approved collection device.
Time Frame	Part B: From Baseline Through Week 24

Outcome Measure Data

Analysis Population Description

FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.

Arm/Group Title	Part B: ELX/TEZ/IVA
Arm/Group Description	Participants in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	66
Least Squares Mean (95% Confidence Interval) [millimole per liter (mmol/L)]	-60.9

12. Secondary Outcome

Title	Part B: Absolute Change in Cystic Fibrosis Questionnaire Revised (CFQ-R) Respiratory Domain Score
Description	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	Part B: From Baseline Through Week 24

Outcome Measure Data

Analysis Population Description

FAS (Part B). The efficacy analysis for Part B was planned for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.

Arm/Group Title	Part B: ELX/TEZ/IVA
Arm/Group Description	Participants in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	66
Least Squares Mean (95% Confidence Interval) [units on a scale]	7.0

13. Secondary Outcome

Title	Part B: Absolute Change in Body Mass Index (BMI)
Description	BMI was defined as weight in kg divided by squared height in meters (m^2).
Time Frame	Part B: From Baseline at Week 24

Outcome Measure Data

Analysis Population Description

FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.

Arm/Group Title	Part B: ELX/TEZ/IVA
Arm/Group Description	Participants in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	66
Least Squares Mean (95% Confidence Interval) [kg/m^2]	1.02

14. Secondary Outcome

Title	Part B: Absolute Change in BMI For-Age Z-Score
Description	BMI was defined as weight in kg divided by squared height in meters (m^2). The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.
Time Frame	Part B: From Baseline at Week 24

Outcome Measure Data

Analysis Population Description

FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.

Arm/Group Title	Part B: ELX/TEZ/IVA
Arm/Group Description	Participants in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	66
Least Squares Mean (95% Confidence Interval) [z-score]	0.37

15. Secondary Outcome

Title	Part B: Absolute Change in Weight
Time Frame	Part B: From Baseline at Week 24

Outcome Measure Data

Analysis Population Description

FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.

Arm/Group Title	Part B: ELX/TEZ/IVA
Arm/Group Description	Participants in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	66
Least Squares Mean (95% Confidence Interval) [kg]	3.0

16. Secondary Outcome

Title	Part B: Absolute Change in Weight-for-age Z-Score
Description	The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.
Time Frame	Part B: From Baseline at Week 24

Outcome Measure Data

Analysis Population Description

FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.

Arm/Group Title	Part B: ELX/TEZ/IVA
Arm/Group Description	Participants in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	66
Least Squares Mean (95% Confidence Interval) [z-score]	0.25

17. Secondary Outcome

Title	Part B: Absolute Change in Height
Time Frame	Part B: From Baseline at Week 24

Outcome Measure Data

Analysis Population Description

FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.

Arm/Group Title	Part B: ELX/TEZ/IVA
Arm/Group Description	Participants in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	66
Least Squares Mean (95% Confidence Interval) [centimeters (cm)]	2.3

18. Secondary Outcome

Title	Part B: Absolute Change in Height-for-Age Z-Score
Description	The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.
Time Frame	Part B: From Baseline at Week 24

Outcome Measure Data

Analysis Population Description

FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.

Arm/Group Title	Part B: ELX/TEZ/IVA
Arm/Group Description	Participants in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	66
Least Squares Mean (95% Confidence Interval) [z-score]	-0.05

19. Secondary Outcome

Title	Part B: Drug Acceptability Assessment Using Modified Facial Hedonic Scale
Description	The study drug acceptability (participant reaction) was assessed by a visual analog scale that incorporates a 5 point facial hedonic scale (Liked it Very Much, Liked it a Little, Not sure, Disliked it a Little, Disliked it Very Much). Number of participants with the indicated categorical response in the drug acceptability assessment were reported.
Time Frame	Part B: At Week 24

Outcome Measure Data

Analysis Population Description

FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm. Here "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome.

Arm/Group Title	Part B: ELX/TEZ/IVA
Arm/Group Description	Participants in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	33
Liked it Very Much	16 22.5%
Liked it a Little	6 8.5%
Not sure	10 14.1%
Disliked it a Little	1 1.4%
Disliked it Very Much	0 0%

20. Secondary Outcome

Title	Part B: Number of Pulmonary Exacerbations Events
Description	Pulmonary exacerbation was defined as new or changed treatment with oral, inhaled, or intravenous antibiotics and fulfillment of pre-specified protocol defined criteria. The total number of pulmonary exacerbations events across all participants were reported.
Time Frame	Part B: From Baseline Through Week 24

Outcome Measure Data

Analysis Population Description

FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.

Arm/Group Title	Part B: ELX/TEZ/IVA
Arm/Group Description	Participants in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	66
Number [pulmonary exacerbations events]	4

21. Secondary Outcome

Title	Part B: Number of CF Related Hospitalizations
Description	The total number of CF related hospitalization events across all participants were reported.
Time Frame	Part B: From Baseline Through Week 24

Outcome Measure Data

Analysis Population Description

FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.

Arm/Group Title	Part B: ELX/TEZ/IVA
Arm/Group Description	Participants in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	66
Number [hospitalizations]	0

22. Secondary Outcome

Title	Part B: Ctrough of ELX, ELX Metabolite (M23-ELX), TEZ, TEZ Metabolite (M1-TEZ), IVA and IVA Metabolite (M1-IVA)
Time Frame	Part B: At Week 4

Outcome Measure Data

Analysis Population Description

The PK set for Part B included all participants who have received at least 1 dose of study drug in Part B. Here "number analyzed" signifies those participants who were evaluable at specified time points.

Arm/Group Title	Part B: ELX/TEZ/IVA
Arm/Group Description	Participants in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	65
ELX: Week 4 (<30 kg)	2.71 (1.77)
ELX: Week 4 (>=30 kg)	5.69 (3.00)
M23-ELX: Week 4 (<30 kg)	1.59 (1.24)
M23-ELX: Week 4 (>=30 kg)	4.41 (2.97)
TEZ: Week 4 (<30 kg)	1.43 (1.19)
TEZ: Week 4 (>=30 kg)	2.37 (1.07)
M1-TEZ: Week 4 (<30 kg)	5.57 (1.78)
M1-TEZ: Week 4 (>=30 kg)	8.12 (1.88)
IVA: Week 4 (<30 kg)	0.455 (0.681)
IVA: Week 4 (>=30 kg)	0.851 (0.489)
M1-IVA: Week 4 (<30 kg)	1.00 (0.630)
M1-IVA: Week 4 (>=30 kg)	2.18 (1.04)

23. Secondary Outcome

Title	Part B: Absolute Change in Lung Clearance Index 2.5 (LCI2.5)
Description	LCI 2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value.
Time Frame	Part B: From Baseline Through Week 24

Outcome Measure Data

Analysis Population Description

FAS (Part B). The efficacy analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm.

Arm/Group Title	Part B: ELX/TEZ/IVA
Arm/Group Description	Participants in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
Measure Participants	66
Least Squares Mean (95% Confidence Interval) [lung clearance index]	-1.71

Adverse Events

Time Frame	Day 1 Through Safety Follow-up Visit (up to Day 43 for Part A, up to Week 28 for Part B)
Adverse Event Reporting Description	The safety analysis for Part B was assessed for the overall treatment arm, irrespective of weight based dose regimen. Therefore, the analysis is reported for the single triple combination (Part B: ELX/TEZ/IVA) arm. MedDRA version 21.1 applied for Part A, MedDRA version 23.0 applied for Part B.
Arm/Group Title	Part A: ELX/TEZ/IVA		Part B: ELX/TEZ/IVA
Arm/Group Description	Participants in Part A received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h in the treatment period for 15 days.		Participants in Part B weighing <30 kg at Day 1 received ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h and participants weighing >=30 kg at Day 1 received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks.
All Cause Mortality
	Part A: ELX/TEZ/IVA		Part B: ELX/TEZ/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/66 (0%)
Serious Adverse Events
	Part A: ELX/TEZ/IVA		Part B: ELX/TEZ/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		1/66 (1.5%)
Infections and infestations
Metapneumovirus infection	0/16 (0%)		1/66 (1.5%)
Pneumonia	0/16 (0%)		1/66 (1.5%)
Rhinovirus infection	0/16 (0%)		1/66 (1.5%)
Other (Not Including Serious) Adverse Events
	Part A: ELX/TEZ/IVA		Part B: ELX/TEZ/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/16 (75%)		62/66 (93.9%)
Gastrointestinal disorders
Abdominal pain	1/16 (6.3%)		8/66 (12.1%)
Abdominal pain upper	1/16 (6.3%)		5/66 (7.6%)
Constipation	0/16 (0%)		4/66 (6.1%)
Diarrhoea	0/16 (0%)		7/66 (10.6%)
Nausea	1/16 (6.3%)		2/66 (3%)
Vomiting	1/16 (6.3%)		7/66 (10.6%)
General disorders
Asthenia	1/16 (6.3%)		0/66 (0%)
Chest pain	1/16 (6.3%)		0/66 (0%)
Fatigue	0/16 (0%)		5/66 (7.6%)
Pyrexia	1/16 (6.3%)		14/66 (21.2%)
Vessel puncture site pain	1/16 (6.3%)		0/66 (0%)
Infections and infestations
Croup infectious	1/16 (6.3%)		0/66 (0%)
Ear infection	0/16 (0%)		4/66 (6.1%)
Influenza	0/16 (0%)		7/66 (10.6%)
Parainfluenzae virus infection	1/16 (6.3%)		0/66 (0%)
Pneumonia	1/16 (6.3%)		0/66 (0%)
Respiratory tract infection viral	1/16 (6.3%)		0/66 (0%)
Upper respiratory tract infection	0/16 (0%)		11/66 (16.7%)
Viral upper respiratory tract infection	0/16 (0%)		8/66 (12.1%)
Vulvovaginal mycotic infection	1/16 (6.3%)		0/66 (0%)
Injury, poisoning and procedural complications
Contusion	1/16 (6.3%)		1/66 (1.5%)
Craniocerebral injury	1/16 (6.3%)		0/66 (0%)
Investigations
Alanine aminotransferase increased	0/16 (0%)		7/66 (10.6%)
Blood alkaline phosphatase increased	1/16 (6.3%)		0/66 (0%)
Human rhinovirus test positive	1/16 (6.3%)		0/66 (0%)
Pulmonary function test decreased	1/16 (6.3%)		0/66 (0%)
Transaminases increased	1/16 (6.3%)		0/66 (0%)
Nervous system disorders
Headache	0/16 (0%)		16/66 (24.2%)
Lethargy	1/16 (6.3%)		0/66 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	5/16 (31.3%)		28/66 (42.4%)
Nasal congestion	2/16 (12.5%)		10/66 (15.2%)
Oropharyngeal pain	1/16 (6.3%)		12/66 (18.2%)
Productive cough	2/16 (12.5%)		5/66 (7.6%)
Respiration abnormal	1/16 (6.3%)		1/66 (1.5%)
Rhinorrhoea	1/16 (6.3%)		8/66 (12.1%)
Sinus congestion	1/16 (6.3%)		0/66 (0%)
Sputum increased	3/16 (18.8%)		3/66 (4.5%)
Skin and subcutaneous tissue disorders
Pruritus generalised	1/16 (6.3%)		0/66 (0%)
Rash	3/16 (18.8%)		8/66 (12.1%)
Rash erythematous	1/16 (6.3%)		3/66 (4.5%)
Rash maculo-papular	1/16 (6.3%)		2/66 (3%)
Rash papular	1/16 (6.3%)		2/66 (3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.