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

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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:
Information provided by (Responsible Party):
Vertex Pharmaceuticals Incorporated

Tracking Information
First Submitted Date  ICMJE May 25, 2016
First Posted Date  ICMJE June 13, 2016
Results First Submitted Date  ICMJE September 30, 2018
Results First Posted Date  ICMJE October 30, 2018
Last Update Posted Date October 30, 2018
Actual Study Start Date  ICMJE May 2016
Actual Primary Completion Date September 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 30, 2018)
  • Part A: Pre-dose Concentration (Ctrough) of LUM and IVA [ Time Frame: Day 15 ]
  • Part B: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Day 1 up to Week 26 ]
Original Primary Outcome Measures  ICMJE
 (submitted: June 10, 2016)
  • Part A: Pharmacokinetic (PK) parameters of lumacaftor (LUM) and ivacaftor (IVA): estimated peak concentrations (Cmax) [ Time Frame: up to 15 Days ]
  • Part A: Pharmacokinetic (PK) parameters of lumacaftor (LUM) and ivacaftor (IVA): estimated trough concentrations (Ctrough) [ Time Frame: up to 15 Days ]
  • Part B: Safety and Tolerability assessments as determined by number of subjects with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Baseline up to 28 days after last dose (up to 28 weeks) ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 30, 2018)
  • Part A: Pre-dose Concentration (Ctrough) of LUM and IVA Metabolites [ Time Frame: Day 15 ]
  • Part A: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Day 1 up to Day 25 ]
  • 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.
  • 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).
  • 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).
  • Part B: Absolute Change From Baseline in Weight at Week 24 [ Time Frame: Baseline, Week 24 ]
  • 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).
  • Part B: Absolute Change From Baseline in Stature (Height) at Week 24 [ Time Frame: Baseline, Week 24 ]
  • 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).
  • 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.
  • 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.
  • Part B: Number of Cystic Fibrosis (CF)-Related Hospitalizations [ Time Frame: Through Week 24 ]
  • Part B: Absolute Change From Baseline in Fecal Elastase-1 (FE-1) Levels at Week 24 [ Time Frame: Baseline, Week 24 ]
  • Part B: Absolute Change From Baseline in Serum Levels of Immunoreactive Trypsinogen (IRT) Through Week 24 [ Time Frame: Baseline, Through Week 24 ]
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • Part B: Pre-dose Concentration (Ctrough) of LUM and IVA and Its Metabolites [ Time Frame: Week 24 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: June 10, 2016)
  • Part A: PK parameters of LUM and IVA metabolites: estimated peak concentrations (Cmax) of lumacaftor and ivacaftor metabolites [ Time Frame: up to 15 days ]
  • Part A: PK parameters of LUM and IVA metabolites: estimated trough concentrations (Ctrough) of lumacaftor and ivacaftor metabolites [ Time Frame: up to 15 days ]
  • Part A: Safety and Tolerability assessments as determined by number of subjects with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Baseline up to 10 +/- 3 days after the last dose (up to 25 +/- 3 days) ]
  • Part B: Absolute change from baseline in sweat chloride level [ Time Frame: Baseline, Week 24 ]
  • Part B: Absolute change from baseline in body mass index (BMI) and BMI for age z score [ Time Frame: Baseline, Week 24 ]
  • Part B: Absolute change from baseline in weight and weight for age z score [ Time Frame: Baseline, Week 24 ]
  • Part B: Absolute change from baseline in stature and stature for age z score [ Time Frame: Baseline, Week 24 ]
  • Part B: Absolute change from baseline in lung clearance index (LCI)2.5 [ Time Frame: Baseline, Week 24 ]
  • Part B: Absolute change from baseline in LCI5.0 [ Time Frame: Baseline, Week 24 ]
  • Part B: Time-to-first pulmonary exacerbation [ Time Frame: through Week 24 ]
  • Part B: Number of Pulmonary Exacerbations [ Time Frame: Through Week 24 ]
  • Part B: Number of CF-related hospitalizations [ Time Frame: Through Week 24 ]
  • Part B; Absolute change from Baseline in fecal elastase-1 (FE-1) levels [ Time Frame: Baseline, Week 24 ]
  • Part B: Absolute change in serum levels of immunoreactive trypsinogen (IRT) [ Time Frame: from baseline through Week 24 ]
  • Part B: Changes in sputum microbiology cultures [ Time Frame: from baseline through Week 24 ]
  • Part B: Absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) [ Time Frame: Baseline, Week 24 ]
  • Part B: Acceptability/Palatability of LUM/IVA Granules Measured Using Hedonic Scale [ Time Frame: Day 1 ]
  • Part B: PK parameters of LUM, IVA, and their respective metabolites: estimated trough concentrations (Ctrough) of LUM and IVA and their metabolites [ Time Frame: up to 24 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Pharmacokinetic Study of Lumacaftor/Ivacaftor in Subjects Aged 2 Through 5 Years With Cystic Fibrosis, Homozygous for F508del
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cystic Fibrosis
Intervention  ICMJE Drug: LUM/IVA
Other Names:
  • Orkambi
  • VX-809+VX-770
Study Arms  ICMJE 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.

Intervention: Drug: LUM/IVA
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 30, 2018)
62
Original Estimated Enrollment  ICMJE
 (submitted: June 10, 2016)
68
Actual Study Completion Date  ICMJE September 2017
Actual Primary Completion Date September 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 5 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02797132
Other Study ID Numbers  ICMJE VX15-809-115
2016-001004-33 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Vertex Pharmaceuticals Incorporated
Study Sponsor  ICMJE Vertex Pharmaceuticals Incorporated
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Vertex Pharmaceuticals Incorporated
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP