Safety and Pharmacokinetic Study of Lumacaftor/Ivacaftor in Subjects Aged 2 Through 5 Years With Cystic Fibrosis, Homozygous for F508del

A Phase 3, 2-Part, Open-label Study to Evaluate the Safety and Pharmacokinetics of Lumacaftor/Ivacaftor Combination Therapy in Subjects Aged 2 Through 5 Years 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 evaluating the pharmacokinetics (PK), safety, tolerability, and pharmacodynamics (PD) of multiple doses of lumacaftor/ivacaftor (LUM/IVA) in subjects 2 through 5 years of age (inclusive) with cystic fibrosis (CF), homozygous for F508del. Subjects who participate in Part A may participate in Part B, if they meet the eligibility criteria.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: LUM/IVA

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

Contacts and Locations

Study Locations

• Canada
  • Montréal, Canada
  • British Columbia
    • Vancouver, British Columbia, Canada
  • Ontario
    • Toronto, Ontario, Canada
• United States
  • California
    • Palo Alto, California, United States
  • Colorado
    • Aurora, Colorado, United States
  • Illinois
    • Chicago, Illinois, United States
  • Indiana
    • Indianapolis, Indiana, United States
  • Massachusetts
    • Boston, Massachusetts, United States
  • Minnesota
    • Minneapolis, Minnesota, United States
  • Missouri
    • Kansas City, Missouri, United States
  • New York
    • Buffalo, New York, United States
  • North Carolina
    • Chapel Hill, North Carolina, United States
  • Ohio
    • Cincinnati, Ohio, United States
    • Cleveland, Ohio, United States
    • Columbus, Ohio, United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
  • South Carolina
    • Charleston, South Carolina, United States
  • Texas
    • Houston, Texas, United States
  • Virginia
    • Norfolk, Virginia, United States
  • Washington
    • Seattle, Washington, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 5 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects who weigh ≥8 kilogram (kg) without shoes and wearing light clothing at the Screening Visit
• Subjects with confirmed diagnosis of CF at the Screening Visit
• Subjects who are homozygous for the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutation

Exclusion Criteria:

• Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject
• An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1
• A standard 12-lead ECG demonstrating QTc >450 millisecond (msec) at the Screening Visit.
• History of solid organ or hematological transplantation.
• Ongoing or prior participation in an investigational drug study (including studies investigating LUM and/or IVA) within 30 days of the Screening Visit.
• History of cataract/lens opacity or evidence of cataract/lens opacity determined to be clinically significant by a licensed ophthalmologist during the ophthalmologic examination at the Screening Visit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Lumacaftor/Ivacaftor (LUM/IVA); Part A (<14 kg): Participants weighing less than (<) 14 kilograms (kg) at screening received LUM 100 milligram (mg)/IVA 125 mg fixed-dose combination every 12 hours for 15 days in Part A. Part A (>=14 kg): Participants weighing greater than or equal to (>=) 14 kg at screening received LUM 150 mg/IVA 188 mg fixed-dose combination every 12 hours for 15 days in Part A. Part B (<14 kg): Participants weighing <14 kg at screening received LUM 100 mg/IVA 125 mg fixed-dose combination every 12 hours for 24 weeks in Part B. Part B (>=14 kg): Participants weighing >=14 kg at screening received LUM 150 mg/IVA 188 mg fixed-dose combination every 12 hours for 24 weeks in Part B.

Drug: LUM/IVA; Other Names: Orkambi; VX-809+VX-770

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Part A: Pre-dose Concentration (Ctrough) of LUM and IVA	Day 15
Part B: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	Day 1 up to Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part B: Absolute Change From Baseline in Weight at Week 24		Baseline, Week 24
Part A: Pre-dose Concentration (Ctrough) of LUM and IVA Metabolites		Day 15
Part A: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)		Day 1 up to Day 25
Part B: Absolute Change From Baseline in Sweat Chloride at Week 24	Sweat samples were collected using an approved collection device.	Baseline, Week 24
Part B: Absolute Change From Baseline in Body Mass Index (BMI) at Week 24	BMI was defined as weight in kilograms (kg) divided by height in square meter (m^2).	Baseline, Week 24
Part B: Absolute Change From Baseline in Body Mass Index (BMI) For-Age Z-Score at Week 24	BMI was defined as weight in kg divided by height in m^2. z-score is a statistical measure to describe whether a mean was above or below the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age z-score (BMI z-score).	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 describe whether a mean was above or below the standard. Weight, adjusted for age and sex, was analyzed as weight-for-age z-score (Weight z-score).	Baseline, Week 24
Part B: Absolute Change From Baseline in Stature (Height) at Week 24		Baseline, Week 24
Part B: Absolute Change From Baseline in Stature-for-Age Z-Score	z-score is a statistical measure to describe whether a mean was above or below the standard. Stature (height), adjusted for age and sex, was analyzed as Stature-for-age z-score (Stature z-score).	Baseline, Week 24
Part B: Number of Pulmonary Exacerbations	Pulmonary exacerbation was defined as new or changed treatment with oral, inhaled, or intravenous antibiotics and fulfillment of pre-specified protocol defined criteria.	Through Week 24
Part B: Number of Participants With at Least One Pulmonary Exacerbation Pulmonary Exacerbation Through Week 24	Pulmonary exacerbation was defined as new or changed treatment with oral, inhaled, or intravenous antibiotics and fulfillment of pre-specified protocol defined criteria. Time to event data was not collected and instead, number of participants with first event were collected and are reported. Time-to-first pulmonary exacerbation was planned to be estimated using Kaplan-Meier (KM) estimates. However, due to less than 50% of events, time-to-first event data was not estimated. Instead, number of participants with at least one pulmonary exacerbation event were collected and are reported.	Through Week 24
Part B: Number of Cystic Fibrosis (CF)-Related Hospitalizations		Through Week 24
Part B: Absolute Change From Baseline in Fecal Elastase-1 (FE-1) Levels at Week 24		Baseline, Week 24
Part B: Absolute Change From Baseline in Serum Levels of Immunoreactive Trypsinogen (IRT) Through Week 24		Baseline, Through Week 24
Part B: Number of Participants With Microbiology Culture Status (Positive or Negative) at Week 24	Following microbial tests were performed: Burkholderia, Methicillin Resistant Staphylococcus Aureus (MRSA), Methicillin Susceptible Staphylococcus Aureus (MSSA), Pseudomonas Aeruginosa Mucoid (P. Aeruginosa Mucoid), P. Aeruginosa Non-Mucoid, P. Aeruginosa Small Colony Variant and Stenotrophomonas Maltophilia.	Baseline and Week 24
Part B: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Week 24	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.	Baseline, Week 24
Part B: Absolute Change in Sweat Chloride From Week 24 at Week 26	Sweat samples were collected using an approved collection device.	Week 24, Week 26
Part B: Acceptability/Palatability of LUM/IVA Granules Measured Using Hedonic Scale	The acceptability and palatability of LUM/IVA granules was assessed by a visual analog scale that incorporates a 5 point facial hedonic scale (Liked it Very Much, Liked it a Little, Not sure, Disliked it a Little, Disliked it Very Much). The assessment was conducted in 2 steps: assessment of approved food/liquid (Evaluation 1), and assessment of approved food/liquid with LUM/IVA granules (Evaluation 2).	Day 1
Part B: Absolute Change From Baseline in Lung Clearance Index (LCI) 2.5 at Week 24	Lung clearance index (LCI) is a measure of ventilation inhomogeneity that is derived from a multiple breath washout test using Nitrogen (N2). LCI 2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value.	Baseline, Week 24
Part B: Absolute Change From Baseline in Lung Clearance Index (LCI) 5.0 at Week 24	LCI is a measure of ventilation inhomogeneity that is derived from a multiple breath washout test using Nitrogen (N2). LCI 5.0 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/20th of its starting value.	Baseline, Week 24
Part B: Pre-dose Concentration (Ctrough) of LUM and IVA and Its Metabolites		Week 24

Collaborators and Investigators

• Sponsor: Vertex Pharmaceuticals Incorporated

Publications and helpful links

General Publications

• McNamara JJ, McColley SA, Marigowda G, Liu F, Tian S, Owen CA, Stiles D, Li C, Waltz D, Wang LT, Sawicki GS. Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2-5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study. Lancet Respir Med. 2019 Apr;7(4):325-335. doi: 10.1016/S2213-2600(18)30460-0. Epub 2019 Jan 24.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2016
• Primary Completion (Actual): September 1, 2017
• Study Completion (Actual): September 1, 2017

Study Registration Dates

• First Submitted: May 25, 2016
• First Submitted That Met QC Criteria: June 10, 2016
• First Posted (Estimate): June 13, 2016

Study Record Updates

• Last Update Posted (Actual): October 30, 2018
• Last Update Submitted That Met QC Criteria: September 30, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: CF
• 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
• Other Study ID Numbers: VX15-809-115; 2016-001004-33 (EudraCT Number)