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

Primary Purpose

Cystic Fibrosis

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Lumacaftor
Ivacaftor
Sponsored by
Vertex Pharmaceuticals Incorporated
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cystic Fibrosis

Eligibility Criteria

6 Years - 11 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Lumacaftor/Ivacaftor (LUM/IVA)

Arm Description

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.

Outcomes

Primary Outcome Measures

Part A: Observed Plasma Concentration of Lumacaftor (LUM) and Ivacaftor (IVA) at Hour 4 Post-dose (C4h) on Day 1
Part A: Observed Plasma Concentration of Lumacaftor (LUM) and Ivacaftor (IVA) at Hour 4 Post-dose (C4h) on Day 14
Part A: Area Under the Plasma Concentration-Time Curve From Time 0 to End of Dosing Interval (AUCtau) of Lumacaftor (LUM) and Ivacaftor (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.
Part B: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
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

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
Part A: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
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.
Part B: Average Absolute Change From Baseline in Sweat Chloride at Day 15 and at 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.
Part B: Absolute Change in Sweat Chloride From Week 24 at Week 26
Sweat samples were collected using an approved collection device. Change = Week 26 minus Week 24.
Part B: Absolute Change From Baseline in Body Mass Index (BMI) at Week 24
BMI was defined as weight in kilogram (kg) divided by height*height in square meter (m^2).
Part B: Absolute Change From Baseline in BMI-for-age Z-score at 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.
Part B: Absolute Change From Baseline in Weight at Week 24
Part B: Absolute Change From Baseline in Weight-for-age Z-score at 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.
Part B: Absolute Change From Baseline in Height at Week 24
Part B: Absolute Change From Baseline in Height-for-age Z-score at 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.
Part B: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at 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.
Part B: Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domains at 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.
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 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.

Full Information

First Posted
July 8, 2013
Last Updated
May 23, 2017
Sponsor
Vertex Pharmaceuticals Incorporated
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1. Study Identification

Unique Protocol Identification Number
NCT01897233
Brief Title
Study of Lumacaftor in Combination With Ivacaftor in Subjects 6 Through 11 Years of Age With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation
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 Type
Interventional

2. Study Status

Record Verification Date
May 2017
Overall Recruitment Status
Completed
Study Start Date
July 2013 (undefined)
Primary Completion Date
October 2015 (Actual)
Study Completion Date
October 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Vertex Pharmaceuticals Incorporated

4. Oversight

Data Monitoring Committee
No

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cystic Fibrosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
62 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Lumacaftor/Ivacaftor (LUM/IVA)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Lumacaftor
Other Intervention Name(s)
VX-809
Intervention Type
Drug
Intervention Name(s)
Ivacaftor
Other Intervention Name(s)
VX-770
Primary Outcome Measure Information:
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
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
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)
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
Secondary Outcome Measure Information:
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
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
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
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
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
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
Title
Part B: Absolute Change From Baseline in Weight at Week 24
Time Frame
Baseline, Week 24
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
Title
Part B: Absolute Change From Baseline in Height at Week 24
Time Frame
Baseline, Week 24
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
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
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
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Years
Maximum Age & Unit of Time
11 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
City
Birmingham
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Alabama
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United States
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Tucson
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Long Beach
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Palo Alto
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Toronto
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Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
8474788
Citation
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. doi: 10.1002/ppul.1950150204.
Results Reference
background
PubMed Identifier
33331662
Citation
Southern KW, Murphy J, Sinha IP, Nevitt SJ. Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del). Cochrane Database Syst Rev. 2020 Dec 17;12(12):CD010966. doi: 10.1002/14651858.CD010966.pub3.
Results Reference
derived
PubMed Identifier
27805836
Citation
Milla CE, Ratjen F, Marigowda G, Liu F, Waltz D, Rosenfeld M; VX13-809-011 Part B Investigator Group *. Lumacaftor/Ivacaftor in Patients Aged 6-11 Years with Cystic Fibrosis and Homozygous for F508del-CFTR. Am J Respir Crit Care Med. 2017 Apr 1;195(7):912-920. doi: 10.1164/rccm.201608-1754OC.
Results Reference
derived

Learn more about this trial

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

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