Cystic Fibrosis
Conditions
Brief summary
To evaluate the efficacy of ivacaftor treatment, as measured by lung clearance index (LCI), in subjects with cystic fibrosis (CF) who have a specified CF transmembrane conductance regulator (CFTR) gating mutation
Interventions
DRUGivacaftor
DRUGPlacebo
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
3 Years to 5 Years
Healthy volunteers
No
Inclusion criteria
* Male or female with confirmed diagnosis of CF. * Must have 1 of the following CFTR gating mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D. * Hematology, serum chemistry, and coagulation at Screening with no clinically significant abnormalities or concomitant diagnosis that would interfere with the LCI and CT scan study assessments, as judged by the investigator.
Exclusion criteria
* An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before Day 1 * Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject (in the opinion of the investigator) * Abnormal liver function, at Screening, defined as ≥3 × upper limit of normal (ULN), of any 3 or more of the following: serum aspartate transaminase (AST), serum alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), serum alkaline phosphatase (ALP), and total bilirubin * History of solid organ or hematological transplantation * Any clinically significant non-CF-related illness within 2 weeks before Day 1 * Use of any moderate or strong inducers or inhibitors of cytochrome P450 (CYP) 3A within 2 weeks before Day 1 * Participation in a clinical study involving administration of either an investigational or a marketed drug within 30 days or 5 terminal half-lives (whichever is longer or as determined by the local requirements) before Screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Lung Clearance Index (LCI2.5) Through 8 Weeks of Treatment (Average of Week 4 and Week 8 LCI2.5) | Baseline Through Week 8 for each treatment period, Up to 24 Weeks | LCI2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Immunoreactive Trypsinogen Levels at Week 8 | Baseline and Week 8 of each treatment period, Up to 24 Weeks | Serum samples were collected for evaluation of change in immunoreactive trypsinogen levels at Week 8. |
| Absolute Change From Baseline in Fecal Elastase-1 Levels at Week 8 | Baseline and Week 8 of each treatment period, Up to 24 Weeks | Fecal elastase-1 was used clinically to diagnose pancreatic exocrine insufficiency in participants with cystic fibrosis. |
| Absolute Change From Baseline in Weight at Week 8 | Baseline and Week 8 of each treatment period, Up to 24 Weeks | — |
| Absolute Change From Baseline in Body Mass Index (BMI) at Week 8 | Baseline and Week 8 of each treatment period, Up to 24 Weeks | BMI was defined as weight in kilogram (kg) divided by height in square meter (m\^2). |
| Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline up to Month 15 | — |
Countries
Australia, Canada, United Kingdom
Participant flow
Pre-assignment details
Study consisted of 2 parts: Part 1- Double Blind (DB) Crossover Treatment Period and Part 2- Open Label (OL) Period.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 Sequence 1: Ivacaftor First, Then Placebo Ivacaftor administered every 12 hours for 8 weeks in treatment period 1 followed by placebo matched to Ivacaftor administered every 12 hours for 8 weeks in treatment period 2. Washout period of 8 weeks occurred between treatment period 1 and treatment period 2. For ivacaftor, the dose was either 50 milligram (mg) or 75 mg, as determined by the participant's body weight on Day 1. | 8 |
| Part 1 Sequence 2: Placebo First, Then Ivacaftor Placebo matched to Ivacaftor administered every 12 hours for 8 weeks in treatment period 1 followed by Ivacaftor administered every 12 hours for 8 weeks in treatment period 2. Washout period of 8 weeks occurred between treatment period 1 and treatment period 2. For ivacaftor, the dose was either 50 mg or 75 mg, as determined by the participant's body weight on Day 1. | 6 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part 1 Treatment Period 2 (8 Weeks) | Availability of commercial drug | 1 | 1 | 0 |
| Part 2 Open Label Period (32 Weeks) | Availability of commercial drug | 0 | 0 | 9 |
| Part 2 Open Label Period (32 Weeks) | Other | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Part 1 Sequence 2: Placebo First, Then Ivacaftor | Total | Part 1 Sequence 1: Ivacaftor First, Then Placebo |
|---|---|---|---|
| Age, Continuous | 4.2 years STANDARD_DEVIATION 1 | 3.9 years STANDARD_DEVIATION 0.9 | 3.6 years STANDARD_DEVIATION 0.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 14 Participants | 8 Participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Male | 5 Participants | 9 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 | 0 / 10 |
| other Total, other adverse events | 11 / 13 | 11 / 13 | 6 / 10 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 | 0 / 10 |
Outcome results
Primary
Absolute Change From Baseline in Lung Clearance Index (LCI2.5) Through 8 Weeks of Treatment (Average of Week 4 and Week 8 LCI2.5)
LCI2.5 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 Through Week 8 for each treatment period, Up to 24 Weeks
Population: Full Analysis Set (FAS) was used which included all randomized participants who had mutation on at least 1 allele, received at least 1 dose of study drug (Ivacaftor or placebo) and had at least 1 post-baseline assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Crossover Part) | Absolute Change From Baseline in Lung Clearance Index (LCI2.5) Through 8 Weeks of Treatment (Average of Week 4 and Week 8 LCI2.5) | -0.07 Lung clearance index | Standard Deviation 0.93 |
| Ivacaftor (Crossover Part) | Absolute Change From Baseline in Lung Clearance Index (LCI2.5) Through 8 Weeks of Treatment (Average of Week 4 and Week 8 LCI2.5) | -0.53 Lung clearance index | Standard Deviation 1.23 |
p-value: 0.2121t-test, 2 sided
Secondary
Absolute Change From Baseline in Body Mass Index (BMI) at Week 8
BMI was defined as weight in kilogram (kg) divided by height in square meter (m\^2).
Time frame: Baseline and Week 8 of each treatment period, Up to 24 Weeks
Population: FAS was used which included all randomized participants who had mutation on at least 1 allele, received at least 1 dose of study drug (Ivacaftor or placebo) and had at least 1 post-baseline assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Crossover Part) | Absolute Change From Baseline in Body Mass Index (BMI) at Week 8 | 0.13 Kilogram per meter square (kg/m^2) | Standard Deviation 0.79 |
| Ivacaftor (Crossover Part) | Absolute Change From Baseline in Body Mass Index (BMI) at Week 8 | 0.32 Kilogram per meter square (kg/m^2) | Standard Deviation 0.59 |
Secondary
Absolute Change From Baseline in Fecal Elastase-1 Levels at Week 8
Fecal elastase-1 was used clinically to diagnose pancreatic exocrine insufficiency in participants with cystic fibrosis.
Time frame: Baseline and Week 8 of each treatment period, Up to 24 Weeks
Population: FAS was used which included all randomized participants who had mutation on at least 1 allele, received at least 1 dose of study drug (Ivacaftor or placebo) and had at least 1 post-baseline assessment. Here Overall Number of Participants Analyzed signifies those participants who were evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Crossover Part) | Absolute Change From Baseline in Fecal Elastase-1 Levels at Week 8 | -17.0 microgram per gram (mcg/g) | Standard Deviation 55.4 |
| Ivacaftor (Crossover Part) | Absolute Change From Baseline in Fecal Elastase-1 Levels at Week 8 | 23.1 microgram per gram (mcg/g) | Standard Deviation 37.9 |
Secondary
Absolute Change From Baseline in Immunoreactive Trypsinogen Levels at Week 8
Serum samples were collected for evaluation of change in immunoreactive trypsinogen levels at Week 8.
Time frame: Baseline and Week 8 of each treatment period, Up to 24 Weeks
Population: FAS was used which included all randomized participants who had mutation on at least 1 allele, received at least 1 dose of study drug (Ivacaftor or placebo) and had at least 1 post-baseline assessment. Here Overall Number of Participants Analyzed signifies those participants who were evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Crossover Part) | Absolute Change From Baseline in Immunoreactive Trypsinogen Levels at Week 8 | -9.3 Nanogram per milliliter (ng/mL) | Standard Deviation 18.4 |
| Ivacaftor (Crossover Part) | Absolute Change From Baseline in Immunoreactive Trypsinogen Levels at Week 8 | -15.5 Nanogram per milliliter (ng/mL) | Standard Deviation 6.5 |
Secondary
Absolute Change From Baseline in Weight at Week 8
Time frame: Baseline and Week 8 of each treatment period, Up to 24 Weeks
Population: FAS was used which included all randomized participants who had mutation on at least 1 allele, received at least 1 dose of study drug (Ivacaftor or placebo) and had at least 1 post-baseline assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Crossover Part) | Absolute Change From Baseline in Weight at Week 8 | 0.9 Kilogram (kg) | Standard Deviation 1 |
| Ivacaftor (Crossover Part) | Absolute Change From Baseline in Weight at Week 8 | 1.1 Kilogram (kg) | Standard Deviation 0.9 |
Secondary
Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: Baseline up to Month 15
Population: The Safety Set was used which included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo (Crossover Part) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with any AEs | 11 Participants |
| Placebo (Crossover Part) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 0 Participants |
| Ivacaftor (Crossover Part) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with any AEs | 11 Participants |
| Ivacaftor (Crossover Part) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 0 Participants |
| Ivacaftor (Open Label Part) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with any AEs | 6 Participants |
| Ivacaftor (Open Label Part) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 0 Participants |