Trial Outcomes & Findings for Study of Lumacaftor in Combination With Ivacaftor in Subjects 6 Through 11 Years of Age With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation (NCT NCT01897233)

NCT ID: NCT01897233

Last Updated: 2017-06-20

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

62 participants

Primary outcome timeframe

4 hours post-morning dose on Day 1

Results posted on

2017-06-20

Participant Flow

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.

Participant milestones

Participant milestones
Measure	Lumacaftor/Ivacaftor (LUM/IVA) 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.
Part A (14 Days) STARTED	10
Part A (14 Days) Part A Cohort 1 (6 to 8 Years)	5
Part A (14 Days) Part A Cohort 2 (9 to 11 Years)	5
Part A (14 Days) COMPLETED	10
Part A (14 Days) NOT COMPLETED	0
Part B (24 Weeks) STARTED	58
Part B (24 Weeks) COMPLETED	54
Part B (24 Weeks) NOT COMPLETED	4

Reasons for withdrawal

Reasons for withdrawal
Measure	Lumacaftor/Ivacaftor (LUM/IVA) 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.
Part B (24 Weeks) Adverse Event	1
Part B (24 Weeks) Withdrawal by Subject	2
Part B (24 Weeks) Physician Decision	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Lumacaftor/Ivacaftor (LUM/IVA) n=62 Participants 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.
Age, Continuous Part A Cohort 1 (n=5)	6.6 years STANDARD_DEVIATION 0.89 • n=5 Participants
Age, Continuous Part A Cohort 2 (n=5)	9.6 years STANDARD_DEVIATION 0.89 • n=5 Participants
Age, Continuous Part B (n=58)	9.1 years STANDARD_DEVIATION 1.53 • n=5 Participants
Sex/Gender, Customized Part A Cohort 1 (n=5): Female	1 participants n=5 Participants
Sex/Gender, Customized Part A Cohort 1 (n=5): Male	4 participants n=5 Participants
Sex/Gender, Customized Part A Cohort 2 (n=5): Female	1 participants n=5 Participants
Sex/Gender, Customized Part A Cohort 2 (n=5): Male	4 participants n=5 Participants
Sex/Gender, Customized Part B (n=58): Female	31 participants n=5 Participants
Sex/Gender, Customized Part B (n=58): Male	27 participants n=5 Participants

PRIMARY outcome

Timeframe: 4 hours post-morning dose on Day 1

Population: 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.

Outcome measures

Outcome measures
Measure	Part A Overall Arm: LUM/IVA n=10 Participants 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.
Part A: Observed Plasma Concentration of Lumacaftor (LUM) and Ivacaftor (IVA) at Hour 4 Post-dose (C4h) on Day 1 LUM	15200 nanogram per milliliter (ng/mL) Standard Deviation 6740
Part A: Observed Plasma Concentration of Lumacaftor (LUM) and Ivacaftor (IVA) at Hour 4 Post-dose (C4h) on Day 1 IVA	1920 nanogram per milliliter (ng/mL) Standard Deviation 727

PRIMARY outcome

Timeframe: 4 hours post-morning dose on Day 14

Population: 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.

Outcome measures

Outcome measures
Measure	Part A Overall Arm: LUM/IVA n=10 Participants 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.
Part A: Observed Plasma Concentration of Lumacaftor (LUM) and Ivacaftor (IVA) at Hour 4 Post-dose (C4h) on Day 14 LUM	24500 ng/mL Standard Deviation 10400
Part A: Observed Plasma Concentration of Lumacaftor (LUM) and Ivacaftor (IVA) at Hour 4 Post-dose (C4h) on Day 14 IVA	622 ng/mL Standard Deviation 322

PRIMARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Part A Overall Arm: LUM/IVA n=10 Participants 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.
Part A: Area Under the Plasma Concentration-Time Curve From Time 0 to End of Dosing Interval (AUCtau) of Lumacaftor (LUM) and Ivacaftor (IVA) LUM	387600 ng*hr/mL Interval 280700.0 to 640800.0
Part A: Area Under the Plasma Concentration-Time Curve From Time 0 to End of Dosing Interval (AUCtau) of Lumacaftor (LUM) and Ivacaftor (IVA) IVA	6838 ng*hr/mL Interval 2689.0 to 12100.0

PRIMARY outcome

Timeframe: Day 1 up to Week 26

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

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.

Outcome measures

Outcome measures
Measure	Part A Overall Arm: LUM/IVA n=58 Participants 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.
Part B: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) AEs	55 participants
Part B: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) SAEs	4 participants

SECONDARY outcome

Timeframe: Day 1, Day 14

Population: 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.

Outcome measures

Outcome measures
Measure	Part A Overall Arm: LUM/IVA n=10 Participants 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.
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 M28-LUM (Day 1)	176 ng/mL Standard Deviation 79.0
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 M1-IVA (Day 1)	3940 ng/mL Standard Deviation 1380
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 M6-IVA (Day 1)	1810 ng/mL Standard Deviation 981
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 M28-LUM (Day 14)	2040 ng/mL Standard Deviation 1230
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 M1-IVA (Day 14)	2380 ng/mL Standard Deviation 1360
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 M6-IVA (Day 14)	4240 ng/mL Standard Deviation 1990

SECONDARY outcome

Timeframe: Day 1 up to Day 28

Population: 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.

Outcome measures

Outcome measures
Measure	Part A Overall Arm: LUM/IVA n=10 Participants 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.
Part A: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Part A Cohort 1: AEs (n=5)	4 participants
Part A: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Part A Cohort 1: SAEs (n=5)	0 participants
Part A: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Part A Cohort 2: AEs (n=5)	3 participants
Part A: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Part A Cohort 2: SAEs (n=5)	0 participants

SECONDARY outcome

Timeframe: Baseline, Day 15 and Week 4

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Part A Overall Arm: LUM/IVA n=57 Participants 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.
Part B: Average Absolute Change From Baseline in Sweat Chloride at Day 15 and at Week 4	-19.7 millimole per liter (mmol/L) Interval -23.2 to -16.3

SECONDARY outcome

Timeframe: Week 24, Week 26

Population: 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.

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

Outcome measures

Outcome measures
Measure	Part A Overall Arm: LUM/IVA n=47 Participants 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.
Part B: Absolute Change in Sweat Chloride From Week 24 at Week 26	21.3 mmol/L Interval 18.6 to 24.0

SECONDARY outcome

Timeframe: Baseline, Week 24

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

Outcome measures

Outcome measures
Measure	Part A Overall Arm: LUM/IVA n=56 Participants 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.
Part B: Absolute Change From Baseline in Body Mass Index (BMI) at Week 24	0.64 kilogram per square meter (kg/m^2) Interval 0.46 to 0.83

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Part A Overall Arm: LUM/IVA n=56 Participants 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.
Part B: Absolute Change From Baseline in BMI-for-age Z-score at Week 24	0.15 z-score Interval 0.08 to 0.22

SECONDARY outcome

Timeframe: Baseline, Week 24

Outcome measures

Outcome measures
Measure	Part A Overall Arm: LUM/IVA n=56 Participants 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.
Part B: Absolute Change From Baseline in Weight at Week 24	2.6 kilograms (kg) Interval 2.2 to 3.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Part A Overall Arm: LUM/IVA n=56 Participants 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.
Part B: Absolute Change From Baseline in Weight-for-age Z-score at Week 24	0.13 z-score Interval 0.07 to 0.19

SECONDARY outcome

Timeframe: Baseline, Week 24

Outcome measures

Outcome measures
Measure	Part A Overall Arm: LUM/IVA n=56 Participants 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.
Part B: Absolute Change From Baseline in Height at Week 24	2.9 centimeter (cm) Interval 2.6 to 3.2

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Part A Overall Arm: LUM/IVA n=56 Participants 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.
Part B: Absolute Change From Baseline in Height-for-age Z-score at Week 24	0.03 z-score Interval -0.02 to 0.09

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Part A Overall Arm: LUM/IVA n=56 Participants 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.
Part B: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Week 24	5.4 Units on a scale Interval 1.4 to 9.4

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Part A Overall Arm: LUM/IVA n=50 Participants 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.
Part B: Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domains at Week 24 Change at Week 24: Effectiveness	9.2 units on a scale Interval 4.3 to 14.1
Part B: Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domains at Week 24 Change at Week 24: Side Effects	-0.3 units on a scale Interval -1.4 to 0.8
Part B: Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domains at Week 24 Change at Week 24: Convenience	11.1 units on a scale Interval 7.1 to 15.1
Part B: Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domains at Week 24 Change at Week 24: Global Score	3.6 units on a scale Interval -2.0 to 9.1

SECONDARY outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Part A Overall Arm: LUM/IVA n=58 Participants 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.
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) C3-6h LUM (Day 1) (n=57)	17100 ng/mL Standard Deviation 6260
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) C3-6h IVA (Day 1) (n=57)	1980 ng/mL Standard Deviation 850
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) C3-6h M28-LUM (Day 1) (n=57)	186 ng/mL Standard Deviation 96.3
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) C3-6h M1-IVA (Day 1) (n=57)	4170 ng/mL Standard Deviation 1940
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) C3-6h M6-IVA (Day 1) (n=57)	2040 ng/mL Standard Deviation 1650
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) C3-6h LUM (Day 15) (n=55)	21400 ng/mL Standard Deviation 6850
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) C3-6h IVA (Day 15) (n=55)	751 ng/mL Standard Deviation 433
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) C3-6h M28-LUM (Day 15) (n=55)	1660 ng/mL Standard Deviation 843
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) C3-6h M1-IVA (Day 15) (n=55)	2670 ng/mL Standard Deviation 1330
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) C3-6h M6-IVA (Day 15) (n=55)	4360 ng/mL Standard Deviation 2340
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) C3-6h LUM (Week 4) (n=54)	22000 ng/mL Standard Deviation 8470
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) C3-6h IVA (Week 4) (n=54)	779 ng/mL Standard Deviation 389
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) C3-6h M28-LUM (Week 4) (n=54)	1730 ng/mL Standard Deviation 884
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) C3-6h M1-IVA (Week 4) (n=54)	2800 ng/mL Standard Deviation 1410
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) C3-6h M6-IVA (Week 4) (n=54)	4690 ng/mL Standard Deviation 3360
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) Ctrough LUM (Week 4) (n=53)	12300 ng/mL Standard Deviation 6780
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) Ctrough IVA (Week 4) (n=53)	171 ng/mL Standard Deviation 228
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) Ctrough M28-LUM (Week 4) (n=53)	1780 ng/mL Standard Deviation 903
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) Ctrough M1-IVA (Week 4) (n=53)	684 ng/mL Standard Deviation 816
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) Ctrough M6-IVA (Week 4) (n=53)	2490 ng/mL Standard Deviation 2150
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) Ctrough LUM (Week 16) (n=53)	11500 ng/mL Standard Deviation 6020
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) Ctrough IVA (Week 16) (n=52)	153 ng/mL Standard Deviation 150
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) Ctrough M28-LUM (Week 16) (n=53)	1610 ng/mL Standard Deviation 859
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) Ctrough M1-IVA (Week 16) (n=53)	690 ng/mL Standard Deviation 627
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) Ctrough M6-IVA (Week 16) (n=53)	2360 ng/mL Standard Deviation 1570
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) Ctrough LUM (Week 24) (n=51)	11400 ng/mL Standard Deviation 5300
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) Ctrough IVA (Week 24) (n=51)	118 ng/mL Standard Deviation 87.2
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) Ctrough M28-LUM (Week 24) (n=51)	1710 ng/mL Standard Deviation 947
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) Ctrough M1-IVA (Week 24) (n=51)	493 ng/mL Standard Deviation 409
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) Ctrough M6-IVA (Week 24) (n=51)	1790 ng/mL Standard Deviation 1180

Adverse Events

Part A Cohort 1: LUM/IVA

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Part A Cohort 2: LUM/IVA

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Part B: LUM/IVA

Serious events: 4 serious events

Other events: 55 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Part A Cohort 1: LUM/IVA n=5 participants at risk 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: LUM/IVA n=5 participants at risk 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: LUM/IVA n=58 participants at risk Participants aged 6 through 11 years received LUM 200 mg in fixed-dose combination with IVA 250 mg orally q12h for 24 weeks.
Infections and infestations Infective pulmonary exacerbation of cystic fibrosis	0.00% 0/5 • Part A: Day 1 up to Day 28; Part B: Day 1 up to Week 26 For Part A: MedDRA 16.0 and For Part B: MedDRA 18.1 was used.	0.00% 0/5 • Part A: Day 1 up to Day 28; Part B: Day 1 up to Week 26 For Part A: MedDRA 16.0 and For Part B: MedDRA 18.1 was used.	3.4% 2/58 • Part A: Day 1 up to Day 28; Part B: Day 1 up to Week 26 For Part A: MedDRA 16.0 and For Part B: MedDRA 18.1 was used.
Gastrointestinal disorders Ileus	0.00% 0/5 • Part A: Day 1 up to Day 28; Part B: Day 1 up to Week 26 For Part A: MedDRA 16.0 and For Part B: MedDRA 18.1 was used.	0.00% 0/5 • Part A: Day 1 up to Day 28; Part B: Day 1 up to Week 26 For Part A: MedDRA 16.0 and For Part B: MedDRA 18.1 was used.	1.7% 1/58 • Part A: Day 1 up to Day 28; Part B: Day 1 up to Week 26 For Part A: MedDRA 16.0 and For Part B: MedDRA 18.1 was used.
Investigations Alanine aminotransferase increased	0.00% 0/5 • Part A: Day 1 up to Day 28; Part B: Day 1 up to Week 26 For Part A: MedDRA 16.0 and For Part B: MedDRA 18.1 was used.	0.00% 0/5 • Part A: Day 1 up to Day 28; Part B: Day 1 up to Week 26 For Part A: MedDRA 16.0 and For Part B: MedDRA 18.1 was used.	1.7% 1/58 • Part A: Day 1 up to Day 28; Part B: Day 1 up to Week 26 For Part A: MedDRA 16.0 and For Part B: MedDRA 18.1 was used.
Investigations Aspartate aminotransferase increased	0.00% 0/5 • Part A: Day 1 up to Day 28; Part B: Day 1 up to Week 26 For Part A: MedDRA 16.0 and For Part B: MedDRA 18.1 was used.	0.00% 0/5 • Part A: Day 1 up to Day 28; Part B: Day 1 up to Week 26 For Part A: MedDRA 16.0 and For Part B: MedDRA 18.1 was used.	1.7% 1/58 • Part A: Day 1 up to Day 28; Part B: Day 1 up to Week 26 For Part A: MedDRA 16.0 and For Part B: MedDRA 18.1 was used.

Other adverse events

Additional Information

Medical Monitor

Vertex Pharmaceuticals Incorporated

Phone: 617-341-6777

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER