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

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

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.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Ivacaftor; Drug: Lumacaftor

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada
• United States
  • Alabama
    • Birmingham, Alabama, United States
  • Arizona
    • Tucson, Arizona, United States
  • California
    • Long Beach, California, United States
    • Palo Alto, California, United States
  • Colorado
    • Aurora, Colorado, United States
  • Georgia
    • Atlanta, Georgia, United States
  • Indiana
    • Indianapolis, Indiana, United States
  • Massachusetts
    • Boston, Massachusetts, United States
  • Missouri
    • Kansas City, Missouri, United States
    • Saint Louis, Missouri, United States
  • New York
    • Buffalo, New York, United States
    • Rochester, New York, United States
    • Syracuse, New York, United States
  • South Carolina
    • Charleston, South Carolina, United States
  • Texas
    • Austin, Texas, United States
  • Utah
    • Salt Lake City, Utah, United States
  • Virginia
    • Norfolk, Virginia, United States
  • Washington
    • Seattle, Washington, United States
  • Wisconsin
    • Milwaukee, Wisconsin, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 11 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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: Ivacaftor; Other Names: VX-770; Drug: Lumacaftor; Other Names: VX-809

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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.	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)
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.	Day 1 up to Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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.	Day 1 up to Day 28
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.	Baseline, Day 15 and Week 4
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.	Week 24, Week 26
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).	Baseline, Week 24
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.	Baseline, Week 24
Part B: Absolute Change From Baseline in Weight at Week 24		Baseline, 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.	Baseline, Week 24
Part B: Absolute Change From Baseline in Height at Week 24		Baseline, 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.	Baseline, Week 24
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.	Baseline, Week 24
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.	Baseline, Week 24
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.	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

Collaborators and Investigators

• Sponsor: Vertex Pharmaceuticals Incorporated

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (ACTUAL): October 1, 2015
• Study Completion (ACTUAL): October 1, 2015

Study Registration Dates

• First Submitted: July 8, 2013
• First Submitted That Met QC Criteria: July 8, 2013
• First Posted (ESTIMATE): July 11, 2013

Study Record Updates

• Last Update Posted (ACTUAL): June 20, 2017
• Last Update Submitted That Met QC Criteria: May 23, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Chloride Channel Agonists; Ivacaftor
• Other Study ID Numbers: VX13-809-011