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

Back to results

Primary Purpose

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

LUM/IVA

About this trial

This is an interventional treatment trial for Cystic Fibrosis focused on measuring CF

Eligibility Criteria

2 Years - 5 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Lumacaftor/Ivacaftor (LUM/IVA)

Arm Description

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.

Outcomes

Primary Outcome Measures

Part A: Pre-dose Concentration (Ctrough) of LUM and IVA

Part B: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary Outcome Measures

Part A: Pre-dose Concentration (Ctrough) of LUM and IVA Metabolites

Part A: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Part B: Absolute Change From Baseline in Sweat Chloride at 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

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

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

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).

Part B: Absolute Change From Baseline in Stature (Height) at 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).

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.

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.

Part B: Number of Cystic Fibrosis (CF)-Related Hospitalizations

Part B: Absolute Change From Baseline in Fecal Elastase-1 (FE-1) Levels at Week 24

Part B: Absolute Change From Baseline in Serum Levels of Immunoreactive Trypsinogen (IRT) 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.

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.

Part B: Absolute Change in Sweat Chloride From Week 24 at Week 26

Sweat samples were collected using an approved collection device.

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).

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.

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.

Part B: Pre-dose Concentration (Ctrough) of LUM and IVA and Its Metabolites

Full Information

NCT ID

NCT02797132

First Posted

May 25, 2016

Last Updated

September 30, 2018

Sponsor

Vertex Pharmaceuticals Incorporated

1. Study Identification

Unique Protocol Identification Number

NCT02797132

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2018

Overall Recruitment Status

Completed

Study Start Date

May 2016 (Actual)

Primary Completion Date

September 2017 (Actual)

Study Completion Date

September 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Vertex Pharmaceuticals Incorporated

4. Oversight

Data Monitoring Committee

Yes

5. 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.

6. Conditions and Keywords

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

Cystic Fibrosis

Keywords

CF

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 (<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 Type

Drug

Intervention Name(s)

LUM/IVA

Other Intervention Name(s)

Orkambi, VX-809+VX-770

Primary Outcome Measure Information:

Title

Part A: Pre-dose Concentration (Ctrough) of LUM and IVA

Time Frame

Day 15

Title

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 Measure Information:

Title

Part A: Pre-dose Concentration (Ctrough) of LUM and IVA Metabolites

Time Frame

Day 15

Title

Part A: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time Frame

Day 1 up to Day 25

Title

Part B: Absolute Change From Baseline in Sweat Chloride at Week 24

Description

Sweat samples were collected using an approved collection device.

Time Frame

Baseline, Week 24

Title

Part B: Absolute Change From Baseline in Body Mass Index (BMI) at Week 24

Description

BMI was defined as weight in kilograms (kg) divided by height in square meter (m^2).

Time Frame

Baseline, Week 24

Title

Part B: Absolute Change From Baseline in Body Mass Index (BMI) For-Age Z-Score at Week 24

Description

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).

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 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).

Time Frame

Baseline, Week 24

Title

Part B: Absolute Change From Baseline in Stature (Height) at Week 24

Time Frame

Baseline, Week 24

Title

Part B: Absolute Change From Baseline in Stature-for-Age Z-Score

Description

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).

Time Frame

Baseline, Week 24

Title

Part B: Number of Pulmonary Exacerbations

Description

Pulmonary exacerbation was defined as new or changed treatment with oral, inhaled, or intravenous antibiotics and fulfillment of pre-specified protocol defined criteria.

Time Frame

Through Week 24

Title

Part B: Number of Participants With at Least One Pulmonary Exacerbation Pulmonary Exacerbation Through Week 24

Description

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.

Time Frame

Through Week 24

Title

Part B: Number of Cystic Fibrosis (CF)-Related Hospitalizations

Time Frame

Through Week 24

Title

Part B: Absolute Change From Baseline in Fecal Elastase-1 (FE-1) Levels at Week 24

Time Frame

Baseline, Week 24

Title

Part B: Absolute Change From Baseline in Serum Levels of Immunoreactive Trypsinogen (IRT) Through Week 24

Time Frame

Baseline, Through Week 24

Title

Part B: Number of Participants With Microbiology Culture Status (Positive or Negative) at Week 24

Description

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.

Time Frame

Baseline and Week 24

Title

Part B: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Week 24

Description

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

Time Frame

Baseline, Week 24

Title

Part B: Absolute Change in Sweat Chloride From Week 24 at Week 26

Description

Sweat samples were collected using an approved collection device.

Time Frame

Week 24, Week 26

Title

Part B: Acceptability/Palatability of LUM/IVA Granules Measured Using Hedonic Scale

Description

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).

Time Frame

Day 1

Title

Part B: Absolute Change From Baseline in Lung Clearance Index (LCI) 2.5 at Week 24

Description

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.

Time Frame

Baseline, Week 24

Title

Part B: Absolute Change From Baseline in Lung Clearance Index (LCI) 5.0 at Week 24

Description

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.

Time Frame

Baseline, Week 24

Title

Part B: Pre-dose Concentration (Ctrough) of LUM and IVA and Its Metabolites

Time Frame

Week 24

10. Eligibility

Sex

All

Minimum Age & Unit of Time

2 Years

Maximum Age & Unit of Time

5 Years

Accepts Healthy Volunteers

No

Eligibility 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

Facility Information:

City

Palo Alto

State/Province

California

Country

United States

City

Aurora

State/Province

Colorado

Country

United States

City

Chicago

State/Province

Illinois

Country

United States

City

Indianapolis

State/Province

Indiana

Country

United States

City

Boston

State/Province

Massachusetts

Country

United States

City

Minneapolis

State/Province

Minnesota

Country

United States

City

Kansas City

State/Province

Missouri

Country

United States

City

Buffalo

State/Province

New York

Country

United States

City

Chapel Hill

State/Province

North Carolina

Country

United States

City

Cincinnati

State/Province

Ohio

Country

United States

City

Cleveland

State/Province

Ohio

Country

United States

City

Columbus

State/Province

Ohio

Country

United States

City

Philadelphia

State/Province

Pennsylvania

Country

United States

City

Charleston

State/Province

South Carolina

Country

United States

City

Houston

State/Province

Texas

Country

United States

City

Norfolk

State/Province

Virginia

Country

United States

City

Seattle

State/Province

Washington

Country

United States

City

Vancouver

State/Province

British Columbia

Country

Canada

City

Toronto

State/Province

Ontario

Country

Canada

City

Montréal

Country

Canada

12. IPD Sharing Statement

Citations:

PubMed Identifier

30686767

Citation

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.

Results Reference

derived

Cystic Fibrosis

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial