Study of Lumacaftor in Combination With Ivacaftor in Subjects 6 Through 11 Years of Age With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation

• Sponsor: Vertex Pharmaceuticals Incorporated (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01897233
• Collaborator: (none)
• Enrollment: 62
• Locations: 20
• Arm: 1
• Duration (Months): 27
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a Phase 3, 2-part (Part A and Part B), open-label, multicenter study to evaluate the pharmacokinetics, safety, and tolerability of lumacaftor in combination with ivacaftor in subjects with cystic fibrosis aged 6 to 11 years who have the F508del-mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: Lumacaftor; Drug: Ivacaftor	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 62 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Open-label Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Lumacaftor in Combination With Ivacaftor in Subjects 6 Through 11 Years of Age With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation
• Study Start Date: Jul 1, 2013
• Actual Primary Completion Date: Oct 1, 2015
• Actual Study Completion Date: Oct 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Lumacaftor/Ivacaftor (LUM/IVA) Part A Cohort 1: Participants aged 6 through 8 years will receive LUM 200 milligram (mg) in fixed-dose combination with IVA 250 mg orally every 12 hours (q12h) for 14 days. Part A Cohort 2: Participants aged 9 through 11 years will receive LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 14 days. Part B: Participants aged 6 through 11 years will receive LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.

Drug: Lumacaftor; Other Names: VX-809 ; Drug: Ivacaftor; Other Names: VX-770

Outcome Measures

Primary Outcome Measures

1. Part A: Observed Plasma Concentration of Lumacaftor (LUM) and Ivacaftor (IVA) at Hour 4 Post-dose (C4h) on Day 1 [4 hours post-morning dose on Day 1]

2. Part A: Observed Plasma Concentration of Lumacaftor (LUM) and Ivacaftor (IVA) at Hour 4 Post-dose (C4h) on Day 14 [4 hours post-morning dose on Day 14]

3. Part A: Area Under the Plasma Concentration-Time Curve From Time 0 to End of Dosing Interval (AUCtau) of Lumacaftor (LUM) and Ivacaftor (IVA) [Day 14 (pre-morning dose, 4, 6, 12, and 24 hours post-morning dose for LUM; pre-morning dose, 2, 4, 6, 12 hours post-morning dose for IVA)]

   The AUCtau is the area under the concentration versus time curve from time 0 to time tau, where tau is the time at the end of dosing interval.

4. Part B: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [Day 1 up to Week 26]

   AE: any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, inpatient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. AEs with start date or increased severity on or after the first study drug dose to Week 26 were considered treatment-emergent.

Secondary Outcome Measures

1. Part A: Observed Plasma Concentration of Lumacaftor Metabolite (M28-LUM) and Ivacaftor Metabolites (M1-IVA and M6-IVA) at Hour 4 Post-dose (C4h) on Day 1 and 14 [Day 1, Day 14]

2. Part A: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [Day 1 up to Day 28]

   AE: any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, inpatient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. AEs with start date or increased severity on or after the first study drug dose through the end of Part A were considered treatment-emergent.

3. Part B: Average Absolute Change From Baseline in Sweat Chloride at Day 15 and at Week 4 [Baseline, Day 15 and Week 4]

   Sweat samples were collected using an approved collection device. Baseline was defined as the average of the measurements at screening and on Day 1 pre-dose. Average of Day 15 and Week 4 measurements was taken and change was calculated as: Average (Day 15 and Week 4 measurement) minus Baseline measurement.

4. Part B: Absolute Change in Sweat Chloride From Week 24 at Week 26 [Week 24, Week 26]

   Sweat samples were collected using an approved collection device. Change = Week 26 minus Week 24.

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

   BMI was defined as weight in kilogram (kg) divided by height*height in square meter (m^2).

6. Part B: Absolute Change From Baseline in BMI-for-age Z-score at Week 24 [Baseline, Week 24]

   BMI was defined as weight in kg divided by height*height in m^2. z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is, with range from -infinity to +infinity; where 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age z-score (BMI z-score). The BMI-for-age z-scores were calculated using National Center for Health Statistics growth charts.

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

8. Part B: Absolute Change From Baseline in Weight-for-age Z-score at Week 24 [Baseline, Week 24]

   Z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is, with range from -infinity to +infinity; where 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. Weight, adjusted for age and sex, was analyzed as weight-for-age z-score (weight z-score). The weight-for-age z-scores were calculated using National Center for Health Statistics growth charts.

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

10. Part B: Absolute Change From Baseline in Height-for-age Z-score at Week 24 [Baseline, Week 24]

    Z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is, with range from -infinity to +infinity; where 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. Height, adjusted for age and sex, was analyzed as height-for-age z-score (height z-score). The height-for-age z-scores were calculated using National Center for Health Statistics growth charts.

11. Part B: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Week 24 [Baseline, Week 24]

    The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.

12. Part B: Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domains at Week 24 [Baseline, Week 24]

    The TSQM is a 14-item self-administered questionnaire which measures participants' experiences with their medication on four dimensions: effectiveness, side effects, convenience and global satisfaction. For each dimension, responses are added and transformed to a scale from 0 to 100, where higher scores indicate greater satisfaction.

13. Part B: Pre-dose Concentration (Ctrough) and 3 to 6 Hours Post-dose Concentration (C3-6hr) of Lumacaftor, Lumacaftor Metabolite (M28-LUM), Ivacaftor and Ivacaftor Metabolites (M1-IVA and M6-IVA) [For Ctrough: pre-morning dose on Week 4, Week 6 and Week 24; For C3-6hr: 3 to 6 hours post-morning dose on Day 1, 15 and Week 4]

    Ctrough and C3-6hr for lumacaftor, M28 lumacaftor (lumacaftor metabolite), ivacaftor, M1 ivacaftor (ivacaftor metabolite), and M6 ivacaftor (ivacaftor metabolite) were calculated. Ctrough was observed pre-dose concentration. C3-6hr was observed concentration at 3 to 6 hours post- dose.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Confirmed diagnosis of CF defined as: with 2 CF-causing mutations, chronic sinopulmonary disease or gastrointestinal/nutritional abnormalities

• Subjects who weigh ≥15 kg without shoes at Screening Visit

• Subjects who are homozygous for the F508del-CFTR mutation

• Subjects with percent predicted forced expiratory volume in 1 second (FEV1) of 70% to 105% (inclusive) (Part A) or ≥40% (Part B) at Screening Visit where the predicted values are adjusted for age, sex, and height using the Wang equation

• Subjects with stable CF disease and who are willing to remain on stable CF medication regimen

• Able to swallow tablets

Exclusion Criteria:

• History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject

• Acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 28 days before Day 1 of the study

• Abnormal liver function as defined in the protocol at Screening Visit

• Abnormal renal function as defined in the protocol at Screening Visit

• History of solid organ or hematological transplantation

• Ongoing participation in an investigational drug study or prior participation in an investigational drug study within 30 days prior of Screening Visit

• History or evidence of lens opacity or cataract at Screening Visit

• Colonization with organisms associated with a more rapid decline in pulmonary status at Screening Visit (Part A only)

• A standard 12-lead ECG demonstrating QTcF >450 msec at Screening Visit

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Tucson	Arizona	United States
3		Long Beach	California	United States
4		Palo Alto	California	United States
5		Aurora	Colorado	United States
6		Atlanta	Georgia	United States
7		Indianapolis	Indiana	United States
8		Boston	Massachusetts	United States
9		Kansas City	Missouri	United States
10		Saint Louis	Missouri	United States
11		Buffalo	New York	United States
12		Rochester	New York	United States
13		Syracuse	New York	United States
14		Charleston	South Carolina	United States
15		Austin	Texas	United States
16		Salt Lake City	Utah	United States
17		Norfolk	Virginia	United States
18		Seattle	Washington	United States
19		Milwaukee	Wisconsin	United States
20		Toronto	Ontario	Canada

Sponsors and Collaborators

• Vertex Pharmaceuticals Incorporated

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Wang X, Dockery DW, Wypij D, Fay ME, Ferris BG Jr. Pulmonary function between 6 and 18 years of age. Pediatr Pulmonol. 1993 Feb;15(2):75-88.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT01897233
• Other Study ID Numbers: VX13-809-011
• First Posted: Jul 11, 2013
• Last Update Posted: Jun 20, 2017
• Last Verified: May 1, 2017

• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Ivacaftor

Study Results

Participant Flow

Pre-assignment Detail	The study was conducted in 2 parts - Part A and Part B. Part A consisted of 2 cohorts, in which participants aged 6 to 8 years were enrolled in Cohort 1 and participants aged 9 to 11 years were enrolled in Cohort 2. Part B consisted of a single cohort. Participants from Part A may have also participated in Part B of the study.

Arm/Group Title	Lumacaftor/Ivacaftor (LUM/IVA)
Arm/Group Description	Part A Cohort 1: Participants aged 6 through 8 years received LUM 200 milligram (mg) in fixed-dose combination with IVA 250 mg orally every 12 hours (q12h) for 14 days. Part A Cohort 2: Participants aged 9 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 14 days. Part B: Participants aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.
Period Title: Part A (14 Days)
STARTED	10
Part A Cohort 1 (6 to 8 Years)	5
Part A Cohort 2 (9 to 11 Years)	5
COMPLETED	10
NOT COMPLETED	0
Period Title: Part A (14 Days)
STARTED	58
COMPLETED	54
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Lumacaftor/Ivacaftor (LUM/IVA)
Arm/Group Description	Part A Cohort 1: Participants aged 6 through 8 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 14 days. Part A Cohort 2: Participants aged 9 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 14 days. Part B: Participants aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.
Overall Participants	62
Age (years) [Mean (Standard Deviation) ]
Part A Cohort 1 (n=5)	6.6 (0.89)
Part A Cohort 2 (n=5)	9.6 (0.89)
Part B (n=58)	9.1 (1.53)
Sex/Gender, Customized (participants) [Number]
Part A Cohort 1 (n=5): Female	1 1.6%
Part A Cohort 1 (n=5): Male	4 6.5%
Part A Cohort 2 (n=5): Female	1 1.6%
Part A Cohort 2 (n=5): Male	4 6.5%
Part B (n=58): Female	31 50%
Part B (n=58): Male	27 43.5%

Outcome Measures

1. Primary Outcome

Title	Part A: Observed Plasma Concentration of Lumacaftor (LUM) and Ivacaftor (IVA) at Hour 4 Post-dose (C4h) on Day 1
Time Frame	4 hours post-morning dose on Day 1

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) Set included all enrolled participants who received the study drug and for whom the primary PK data were considered to be sufficient and interpretable.

Arm/Group Title	Part A Overall Arm: LUM/IVA
Arm/Group Description	All participants aged 6 through 11 years who received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 14 days.
Measure Participants	10
LUM	15200 (6740)
IVA	1920 (727)

2. Primary Outcome

Title	Part A: Observed Plasma Concentration of Lumacaftor (LUM) and Ivacaftor (IVA) at Hour 4 Post-dose (C4h) on Day 14
Time Frame	4 hours post-morning dose on Day 14

Outcome Measure Data

Analysis Population Description

The PK Set included all enrolled participants who received the study drug and for whom the primary PK data were considered to be sufficient and interpretable.

Arm/Group Title	Part A Overall Arm: LUM/IVA
Arm/Group Description	All participants aged 6 through 11 years who received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 14 days.
Measure Participants	10
LUM	24500 (10400)
IVA	622 (322)

3. Primary Outcome

Title	Part A: Area Under the Plasma Concentration-Time Curve From Time 0 to End of Dosing Interval (AUCtau) of Lumacaftor (LUM) and Ivacaftor (IVA)
Description	The AUCtau is the area under the concentration versus time curve from time 0 to time tau, where tau is the time at the end of dosing interval.
Time Frame	Day 14 (pre-morning dose, 4, 6, 12, and 24 hours post-morning dose for LUM; pre-morning dose, 2, 4, 6, 12 hours post-morning dose for IVA)

Outcome Measure Data

Analysis Population Description

The PK Set included all enrolled participants who received the study drug and for whom the primary PK data were considered to be sufficient and interpretable.

Arm/Group Title	Part A Overall Arm: LUM/IVA
Arm/Group Description	All participants aged 6 through 11 years who received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 14 days.
Measure Participants	10
LUM	387600
IVA	6838

4. Primary Outcome

Title	Part B: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	AE: any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, inpatient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. AEs with start date or increased severity on or after the first study drug dose to Week 26 were considered treatment-emergent.
Time Frame	Day 1 up to Week 26

Outcome Measure Data

Analysis Population Description

The Safety Set included all participants who received any amount of Part B study drug

Arm/Group Title	Part B: LUM/IVA
Arm/Group Description	Participants aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.
Measure Participants	58
AEs	55 88.7%
SAEs	4 6.5%

5. Secondary Outcome

Title	Part A: Observed Plasma Concentration of Lumacaftor Metabolite (M28-LUM) and Ivacaftor Metabolites (M1-IVA and M6-IVA) at Hour 4 Post-dose (C4h) on Day 1 and 14
Time Frame	Day 1, Day 14

Outcome Measure Data

Analysis Population Description

The PK Set included all enrolled participants who received the study drug and for whom the primary PK data were considered to be sufficient and interpretable.

Arm/Group Title	Part A Overall Arm: LUM/IVA
Arm/Group Description	All participants aged 6 through 11 years who received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 14 days.
Measure Participants	10
M28-LUM (Day 1)	176 (79.0)
M1-IVA (Day 1)	3940 (1380)
M6-IVA (Day 1)	1810 (981)
M28-LUM (Day 14)	2040 (1230)
M1-IVA (Day 14)	2380 (1360)
M6-IVA (Day 14)	4240 (1990)

6. Secondary Outcome

Title	Part A: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	AE: any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, inpatient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. AEs with start date or increased severity on or after the first study drug dose through the end of Part A were considered treatment-emergent.
Time Frame	Day 1 up to Day 28

Outcome Measure Data

Analysis Population Description

The Safety Set included all participants who received at least 1 dose of study drug. Here "n" signifies those subjects who were evaluable for the specified cohort.

Arm/Group Title	Part A Overall Arm: LUM/IVA
Arm/Group Description	All participants aged 6 through 11 years who received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 14 days.
Measure Participants	10
Part A Cohort 1: AEs (n=5)	4 6.5%
Part A Cohort 1: SAEs (n=5)	0 0%
Part A Cohort 2: AEs (n=5)	3 4.8%
Part A Cohort 2: SAEs (n=5)	0 0%

7. Secondary Outcome

Title	Part B: Average Absolute Change From Baseline in Sweat Chloride at Day 15 and at Week 4
Description	Sweat samples were collected using an approved collection device. Baseline was defined as the average of the measurements at screening and on Day 1 pre-dose. Average of Day 15 and Week 4 measurements was taken and change was calculated as: Average (Day 15 and Week 4 measurement) minus Baseline measurement.
Time Frame	Baseline, Day 15 and Week 4

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all Part B enrolled participants who were exposed to any amount of Part B study drug. Here "Number of Participants" analyzed signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Part B: LUM/IVA
Arm/Group Description	Participants aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.
Measure Participants	57
Least Squares Mean (95% Confidence Interval) [millimole per liter (mmol/L)]	-19.7

8. Secondary Outcome

Title	Part B: Absolute Change in Sweat Chloride From Week 24 at Week 26
Description	Sweat samples were collected using an approved collection device. Change = Week 26 minus Week 24.
Time Frame	Week 24, Week 26

Outcome Measure Data

Analysis Population Description

The FAS included all Part B enrolled participants who were exposed to any amount of Part B study drug. Here "Number of Participants" analyzed signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Part B: LUM/IVA
Arm/Group Description	Participants aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.
Measure Participants	47
Least Squares Mean (95% Confidence Interval) [mmol/L]	21.3

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The FAS included all Part B enrolled participants who were exposed to any amount of Part B study drug. Here "Number of Participants" analyzed signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Part B: LUM/IVA
Arm/Group Description	Participants aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks
Measure Participants	56
Least Squares Mean (95% Confidence Interval) [kilogram per square meter (kg/m^2)]	0.64

10. Secondary Outcome

Title	Part B: Absolute Change From Baseline in BMI-for-age Z-score at Week 24
Description	BMI was defined as weight in kg divided by height*height in m^2. z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is, with range from -infinity to +infinity; where 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age z-score (BMI z-score). The BMI-for-age z-scores were calculated using National Center for Health Statistics growth charts.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

The FAS included all Part B enrolled participants who were exposed to any amount of Part B study drug. Here "Number of Participants" analyzed signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Part B: LUM/IVA
Arm/Group Description	Participants aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.
Measure Participants	56
Least Squares Mean (95% Confidence Interval) [z-score]	0.15

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The FAS included all Part B enrolled participants who were exposed to any amount of Part B study drug. Here "Number of Participants" analyzed signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Part B: LUM/IVA
Arm/Group Description	Participants aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.
Measure Participants	56
Least Squares Mean (95% Confidence Interval) [kilograms (kg)]	2.6

12. Secondary Outcome

Title	Part B: Absolute Change From Baseline in Weight-for-age Z-score at Week 24
Description	Z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is, with range from -infinity to +infinity; where 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. Weight, adjusted for age and sex, was analyzed as weight-for-age z-score (weight z-score). The weight-for-age z-scores were calculated using National Center for Health Statistics growth charts.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

The FAS included all Part B enrolled participants who were exposed to any amount of Part B study drug. Here "Number of Participants" analyzed signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Part B: LUM/IVA
Arm/Group Description	Participants aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.
Measure Participants	56
Least Squares Mean (95% Confidence Interval) [z-score]	0.13

13. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The FAS included all Part B enrolled participants who were exposed to any amount of Part B study drug. Here "Number of Participants" analyzed signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Part B: LUM/IVA
Arm/Group Description	Participants aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.
Measure Participants	56
Least Squares Mean (95% Confidence Interval) [centimeter (cm)]	2.9

14. Secondary Outcome

Title	Part B: Absolute Change From Baseline in Height-for-age Z-score at Week 24
Description	Z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is, with range from -infinity to +infinity; where 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. Height, adjusted for age and sex, was analyzed as height-for-age z-score (height z-score). The height-for-age z-scores were calculated using National Center for Health Statistics growth charts.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

The FAS included all Part B enrolled participants who were exposed to any amount of Part B study drug. Here "Number of Participants" analyzed signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Part B: LUM/IVA
Arm/Group Description	Participants aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.
Measure Participants	56
Least Squares Mean (95% Confidence Interval) [z-score]	0.03

15. Secondary Outcome

Title	Part B: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Week 24
Description	The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

The FAS included all Part B enrolled participants who were exposed to any amount of Part B study drug. Here "Number of Participants" analyzed signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Part B: LUM/IVA
Arm/Group Description	Participants aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.
Measure Participants	56
Least Squares Mean (95% Confidence Interval) [Units on a scale]	5.4

16. Secondary Outcome

Title	Part B: Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domains at Week 24
Description	The TSQM is a 14-item self-administered questionnaire which measures participants' experiences with their medication on four dimensions: effectiveness, side effects, convenience and global satisfaction. For each dimension, responses are added and transformed to a scale from 0 to 100, where higher scores indicate greater satisfaction.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

The FAS included all Part B enrolled participants who were exposed to any amount of Part B study drug. Here "Number of Participants" analyzed signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Part B: LUM/IVA
Arm/Group Description	Participants aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.
Measure Participants	50
Change at Week 24: Effectiveness	9.2
Change at Week 24: Side Effects	-0.3
Change at Week 24: Convenience	11.1
Change at Week 24: Global Score	3.6

17. Secondary Outcome

Title	Part B: Pre-dose Concentration (Ctrough) and 3 to 6 Hours Post-dose Concentration (C3-6hr) of Lumacaftor, Lumacaftor Metabolite (M28-LUM), Ivacaftor and Ivacaftor Metabolites (M1-IVA and M6-IVA)
Description	Ctrough and C3-6hr for lumacaftor, M28 lumacaftor (lumacaftor metabolite), ivacaftor, M1 ivacaftor (ivacaftor metabolite), and M6 ivacaftor (ivacaftor metabolite) were calculated. Ctrough was observed pre-dose concentration. C3-6hr was observed concentration at 3 to 6 hours post- dose.
Time Frame	For Ctrough: pre-morning dose on Week 4, Week 6 and Week 24; For C3-6hr: 3 to 6 hours post-morning dose on Day 1, 15 and Week 4

Outcome Measure Data

Analysis Population Description

The PK Set included all enrolled participants who received the study drug and for whom the primary PK data were considered to be sufficient and interpretable. Here "n" signifies those participants who were evaluable at the specified time point for the given category.

Arm/Group Title	Part B: LUM/IVA
Arm/Group Description	Participants aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.
Measure Participants	58
C3-6h LUM (Day 1) (n=57)	17100 (6260)
C3-6h IVA (Day 1) (n=57)	1980 (850)
C3-6h M28-LUM (Day 1) (n=57)	186 (96.3)
C3-6h M1-IVA (Day 1) (n=57)	4170 (1940)
C3-6h M6-IVA (Day 1) (n=57)	2040 (1650)
C3-6h LUM (Day 15) (n=55)	21400 (6850)
C3-6h IVA (Day 15) (n=55)	751 (433)
C3-6h M28-LUM (Day 15) (n=55)	1660 (843)
C3-6h M1-IVA (Day 15) (n=55)	2670 (1330)
C3-6h M6-IVA (Day 15) (n=55)	4360 (2340)
C3-6h LUM (Week 4) (n=54)	22000 (8470)
C3-6h IVA (Week 4) (n=54)	779 (389)
C3-6h M28-LUM (Week 4) (n=54)	1730 (884)
C3-6h M1-IVA (Week 4) (n=54)	2800 (1410)
C3-6h M6-IVA (Week 4) (n=54)	4690 (3360)
Ctrough LUM (Week 4) (n=53)	12300 (6780)
Ctrough IVA (Week 4) (n=53)	171 (228)
Ctrough M28-LUM (Week 4) (n=53)	1780 (903)
Ctrough M1-IVA (Week 4) (n=53)	684 (816)
Ctrough M6-IVA (Week 4) (n=53)	2490 (2150)
Ctrough LUM (Week 16) (n=53)	11500 (6020)
Ctrough IVA (Week 16) (n=52)	153 (150)
Ctrough M28-LUM (Week 16) (n=53)	1610 (859)
Ctrough M1-IVA (Week 16) (n=53)	690 (627)
Ctrough M6-IVA (Week 16) (n=53)	2360 (1570)
Ctrough LUM (Week 24) (n=51)	11400 (5300)
Ctrough IVA (Week 24) (n=51)	118 (87.2)
Ctrough M28-LUM (Week 24) (n=51)	1710 (947)
Ctrough M1-IVA (Week 24) (n=51)	493 (409)
Ctrough M6-IVA (Week 24) (n=51)	1790 (1180)

Adverse Events

Time Frame	Part A: Day 1 up to Day 28; Part B: Day 1 up to Week 26
Adverse Event Reporting Description	For Part A: MedDRA 16.0 and For Part B: MedDRA 18.1 was used.
Arm/Group Title	Part A Cohort 1: LUM/IVA		Part A Cohort 2: LUM/IVA		Part B: LUM/IVA
Arm/Group Description	Participants aged 6 through 8 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 14 days.		Participants aged 9 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 14 days.		Participants aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.
All Cause Mortality
	Part A Cohort 1: LUM/IVA		Part A Cohort 2: LUM/IVA		Part B: LUM/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Part A Cohort 1: LUM/IVA		Part A Cohort 2: LUM/IVA		Part B: LUM/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)		4/58 (6.9%)
Gastrointestinal disorders
Ileus	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Investigations
Alanine aminotransferase increased	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Aspartate aminotransferase increased	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Other (Not Including Serious) Adverse Events
	Part A Cohort 1: LUM/IVA		Part A Cohort 2: LUM/IVA		Part B: LUM/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/5 (80%)		3/5 (60%)		55/58 (94.8%)
Blood and lymphatic system disorders
Lymphadenopathy	1/5 (20%)		0/5 (0%)		1/58 (1.7%)
Normochromic normocytic anaemia	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Ear and labyrinth disorders
Ear pain	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Eye disorders
Eye pruritus	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Cataract	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Gastrointestinal disorders
Abdominal pain upper	1/5 (20%)		0/5 (0%)		8/58 (13.8%)
Abdominal pain	0/5 (0%)		0/5 (0%)		6/58 (10.3%)
Nausea	0/5 (0%)		0/5 (0%)		6/58 (10.3%)
Vomiting	0/5 (0%)		0/5 (0%)		6/58 (10.3%)
Constipation	1/5 (20%)		0/5 (0%)		5/58 (8.6%)
Diarrhoea	1/5 (20%)		0/5 (0%)		4/58 (6.9%)
Abdominal discomfort	0/5 (0%)		0/5 (0%)		3/58 (5.2%)
Flatulence	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Faecal volume increased	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Faeces soft	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Frequent bowel movements	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
General disorders
Fatigue	0/5 (0%)		0/5 (0%)		6/58 (10.3%)
Pyrexia	1/5 (20%)		0/5 (0%)		6/58 (10.3%)
Application site erythema	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Application site urticaria	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Application site vesicles	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Asthenia	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Malaise	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Vessel puncture site reaction	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Immune system disorders
Seasonal allergy	0/5 (0%)		0/5 (0%)		3/58 (5.2%)
House dust allergy	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Mycotic allergy	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	0/5 (0%)		0/5 (0%)		11/58 (19%)
Otitis media	0/5 (0%)		0/5 (0%)		3/58 (5.2%)
Pharyngitis streptococcal	0/5 (0%)		0/5 (0%)		3/58 (5.2%)
Sinusitis	0/5 (0%)		0/5 (0%)		3/58 (5.2%)
Upper respiratory tract infection	0/5 (0%)		0/5 (0%)		3/58 (5.2%)
Gastroenteritis viral	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Otitis externa	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Urinary tract infection	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Abscess limb	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Gastroenteritis	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Gastroenteritis bacterial	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Impetigo	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Influenza	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Oral candidiasis	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Staphylococcal skin infection	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Tinea infection	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Viral upper respiratory tract infection	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Injury, poisoning and procedural complications
Fall	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Sunburn	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Arthropod bite	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Contusion	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Foot fracture	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Laceration	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Ligament sprain	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Limb injury	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Skin abrasion	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Traumatic haematoma	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Upper limb fracture	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Investigations
Alanine aminotransferase increased	0/5 (0%)		0/5 (0%)		6/58 (10.3%)
Aspartate aminotransferase increased	0/5 (0%)		0/5 (0%)		3/58 (5.2%)
Pulmonary function test decreased	0/5 (0%)		0/5 (0%)		3/58 (5.2%)
Blood creatine phosphokinase increased	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Mean cell haemoglobin concentration decreased	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Blood alkaline phosphatase increased	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Blood bicarbonate decreased	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Blood creatinine decreased	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Blood urea increased	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Crystal urine present	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Eosinophil count decreased	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Gamma-glutamyltransferase increased	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Lipase increased	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Pseudomonas test positive	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Streptococcus test positive	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Weight decreased	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Forced Expiratory Volume Decreased	0/5 (0%)		1/5 (20%)		0/58 (0%)
Hepatic Enzyme Increased	1/5 (20%)		0/5 (0%)		0/58 (0%)
Metabolism and nutrition disorders
Increased appetite	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Decreased appetite	0/5 (0%)		0/5 (0%)		3/58 (5.2%)
Musculoskeletal and connective tissue disorders
Back pain	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Neck pain	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Muscle spasms	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Musculoskeletal chest pain	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Myalgia	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Pain in extremity	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Nervous system disorders
Headache	2/5 (40%)		1/5 (20%)		12/58 (20.7%)
Dizziness	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Lethargy	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Migraine	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Sinus headache	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Syncope	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Psychiatric disorders
Anxiety	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Attention deficit/hyperactivity disorder	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Insomnia	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Renal and urinary disorders
Enuresis	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Respiratory, thoracic and mediastinal disorders
Cough	1/5 (20%)		3/5 (60%)		29/58 (50%)
Nasal Congestion	0/5 (0%)		1/5 (20%)		12/58 (20.7%)
Sputum increased	0/5 (0%)		0/5 (0%)		8/58 (13.8%)
Rhinorrhoea	0/5 (0%)		0/5 (0%)		5/58 (8.6%)
Oropharyngeal pain	0/5 (0%)		0/5 (0%)		3/58 (5.2%)
Rales	0/5 (0%)		0/5 (0%)		3/58 (5.2%)
Dyspnoea exertional	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Haemoptysis	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Lower respiratory tract congestion	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Productive cough	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Sinus congestion	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Wheezing	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Dyspnoea	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Increased viscosity of upper respiratory secretion	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Nasal polyps	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Paranasal sinus hypersecretion	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Pharyngeal erythema	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Respiration abnormal	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Rhonchi	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Sneezing	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Upper respiratory tract congestion	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Upper-airway cough syndrome	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Skin and subcutaneous tissue disorders
Rash	0/5 (0%)		0/5 (0%)		4/58 (6.9%)
Dermatitis contact	0/5 (0%)		0/5 (0%)		3/58 (5.2%)
Pruritus	0/5 (0%)		0/5 (0%)		2/58 (3.4%)
Dandruff	0/5 (0%)		0/5 (0%)		1/58 (1.7%)
Urticaria	0/5 (0%)		0/5 (0%)		1/58 (1.7%)

Limitations/Caveats

Due to limited sampling and instances of missing data, C4h was reported instead of Cmax as an approximation of maximum concentration. Sparse PK sampling scheme was optimized around parent compounds which limited the estimation of AUC for metabolites.

More Information

Certain Agreements

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

PI is free to publish results of the study after (1) the first multi-center publication, (2) if the sponsor elects not to publish the results, or (3) 18 months after close of the study, whichever occurs first. Proposed publications are to be submitted to the sponsor for review and comment for a period of at least 45 days (which may be extended under certain circumstances related to protection of intellectual property); the sponsor cannot require changes to the proposed publications.