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

• ClinicalTrials.gov Identifier: NCT02797132
• Recruitment Status: Completed
• First Posted: June 13, 2016
• Results First Posted: October 30, 2018
• Last Update Posted: October 30, 2018
• Sponsor: Vertex Pharmaceuticals Incorporated
• Information provided by (Responsible Party): Vertex Pharmaceuticals Incorporated

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis	Drug: LUM/IVA	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 62 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: May 2016
• Actual Primary Completion Date: September 2017
• Actual Study Completion Date: September 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Part A: Pre-dose Concentration (Ctrough) of LUM and IVA Metabolites [ Time Frame: Day 15 ]
2. Part A: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Day 1 up to Day 25 ]
3. Part B: Absolute Change From Baseline in Sweat Chloride at Week 24 [ Time Frame: Baseline, Week 24 ]
   Sweat samples were collected using an approved collection device.
4. Part B: Absolute Change From Baseline in Body Mass Index (BMI) at Week 24 [ Time Frame: Baseline, Week 24 ]
   BMI was defined as weight in kilograms (kg) divided by height in square meter (m^2).
5. Part B: Absolute Change From Baseline in Body Mass Index (BMI) For-Age Z-Score at Week 24 [ Time Frame: Baseline, 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).
6. Part B: Absolute Change From Baseline in Weight at Week 24 [ Time Frame: Baseline, Week 24 ]
7. Part B: Absolute Change From Baseline in Weight-for-age Z-Score at Week 24 [ Time Frame: Baseline, 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).
8. Part B: Absolute Change From Baseline in Stature (Height) at Week 24 [ Time Frame: Baseline, Week 24 ]
9. Part B: Absolute Change From Baseline in Stature-for-Age Z-Score [ Time Frame: Baseline, Week 24 ]
   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).
10. Part B: Number of Pulmonary Exacerbations [ Time Frame: 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.
11. Part B: Number of Participants With at Least One Pulmonary Exacerbation Pulmonary Exacerbation Through Week 24 [ Time Frame: 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.
12. Part B: Number of Cystic Fibrosis (CF)-Related Hospitalizations [ Time Frame: Through Week 24 ]
13. Part B: Absolute Change From Baseline in Fecal Elastase-1 (FE-1) Levels at Week 24 [ Time Frame: Baseline, Week 24 ]
14. Part B: Absolute Change From Baseline in Serum Levels of Immunoreactive Trypsinogen (IRT) Through Week 24 [ Time Frame: Baseline, Through Week 24 ]
15. Part B: Number of Participants With Microbiology Culture Status (Positive or Negative) at Week 24 [ Time Frame: Baseline and 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.
16. Part B: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Week 24 [ Time Frame: Baseline, Week 24 ]
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
17. Part B: Absolute Change in Sweat Chloride From Week 24 at Week 26 [ Time Frame: Week 24, Week 26 ]
    Sweat samples were collected using an approved collection device.
18. Part B: Acceptability/Palatability of LUM/IVA Granules Measured Using Hedonic Scale [ Time Frame: Day 1 ]
    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).
19. Part B: Absolute Change From Baseline in Lung Clearance Index (LCI) 2.5 at Week 24 [ Time Frame: Baseline, 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.
20. Part B: Absolute Change From Baseline in Lung Clearance Index (LCI) 5.0 at Week 24 [ Time Frame: Baseline, 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.
21. Part B: Pre-dose Concentration (Ctrough) of LUM and IVA and Its Metabolites [ Time Frame: Week 24 ]

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, California

Palo Alto, California, United States

United States, Colorado

Aurora, Colorado, United States

United States, Illinois

Chicago, Illinois, United States

United States, Indiana

Indianapolis, Indiana, United States

United States, Massachusetts

Boston, Massachusetts, United States

United States, Minnesota

Minneapolis, Minnesota, United States

United States, Missouri

Kansas City, Missouri, United States

United States, New York

Buffalo, New York, United States

United States, North Carolina

Chapel Hill, North Carolina, United States

United States, Ohio

Cincinnati, Ohio, United States

Cleveland, Ohio, United States

Columbus, Ohio, United States

United States, Pennsylvania

Philadelphia, Pennsylvania, United States

United States, South Carolina

Charleston, South Carolina, United States

United States, Texas

Houston, Texas, United States

United States, Virginia

Norfolk, Virginia, United States

United States, Washington

Seattle, Washington, United States

Canada, British Columbia

Vancouver, British Columbia, Canada

Canada, Ontario

Toronto, Ontario, Canada

Canada

Montréal, Canada

Sponsors and Collaborators

Vertex Pharmaceuticals Incorporated

  Study Documents (Full-Text)

Documents provided by Vertex Pharmaceuticals Incorporated:

Study Protocol  [PDF] April 13, 2017

Statistical Analysis Plan  [PDF] September 23, 2016

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT02797132
• Other Study ID Numbers: VX15-809-115; 2016-001004-33 ( EudraCT Number )
• First Posted: June 13, 2016
• Results First Posted: October 30, 2018
• Last Update Posted: October 30, 2018
• Last Verified: September 2018

Keywords provided by Vertex Pharmaceuticals Incorporated:

CF

Additional relevant MeSH terms:

Cystic Fibrosis; Fibrosis; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases