Cystic Fibrosis
Conditions
Brief summary
The purpose of this study is to evaluate the effect of ivacaftor (VX-770) on lung clearance index (LCI) in subjects aged 6 years and older with cystic fibrosis (CF) who have the G551D-CFTR mutation on at least 1 allele.
Detailed description
Currently, limited objective measures are available to quantify lung function in CF patients with mild lung disease. Lung clearance index (LCI) derived from inert gas multiple-breath washout (MBW) testing hold considerable promise to evaluate early lung disease as studies have detected abnormalities in a high percentage of CF patients with normal spirometry in both infants and children. This study explored the effect of ivacaftor on LCI and the efficacy of ivacaftor on other clinical and biomarker endpoints of CF lung disease in subjects aged 6 years and older with CF who have the G551D-CFTR mutation on at least 1 allele.
Interventions
DRUGIvacaftor
150 mg tablet, oral use, twice daily every 12 hours (q12h)
DRUGPlacebo
Tablet, oral use, twice daily every 12 hours (q12h)
Sponsors
Cystic Fibrosis Foundation
Vertex Pharmaceuticals Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female subjects with confirmed diagnosis of CF * Must have the G551D-CFTR mutation in at least 1 allele * FEV1 \>90% of predicted normal for age, gender, and height
Exclusion criteria
* Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening * Use of inhaled hypertonic saline treatment within 2 weeks of the Period 1, Day 1 visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Lung Clearance Index (LCI) | Baseline through Day 29 | Lung clearance index (LCI) is a measure of ventilation inhomogeneity that is derived from a multiple-breath washout test. The LCI was calculated as the number of lung volume turnovers (cumulative expired volume divided by the functional residual capacity \[FRC\]) required to reduce end-tidal SF6 concentration to 1/40th of the starting value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Percent Predicted FEV1 | Baseline through Day 29 | Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. |
| Change From Baseline in Sweat Chloride | Baseline through Day 29 | The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity. |
| Change From Baseline in CF Questionnaire-Revised (CFQ-R) Score (Respiratory Domain Score, Pooled) | Baseline through Day 29 | The CFQ-R is a health-related quality of life measure for subjects with cystic fibrosis. Each domain is scored from 0 (worst) to 100 (best). A difference of at least 4 points in the respiratory domain score of the CFQ-R is considered a minimal clinically important difference (MCID). The primary analytical focus was the respiratory health domain, which was analyzed by combining all self-response questionnaire versions from different age groups (e.g., Adult/Adolescent and Child versions). |
Countries
Canada, United Kingdom, United States
Participant flow
Recruitment details
The study started on 14 February 2011 (signing of first informed consent). After obtaining informed consent and assent (where applicable), screening evaluations were completed at any time during the period 10 to 18 days (Days -18 to -10) before first dose of study drug (Day 1).
Pre-assignment details
A total of 21 subjects were randomized; 20 subjects received at least 1 dose of the study drug.
Participants by arm
| Arm | Count |
|---|---|
| Ivacaftor Then Placebo Ivacaftor administered in Treatment Period 1 and placebo administered in Treatment Period 2. | 10 |
| Placebo Then Ivacaftor Placebo administered in Treatment Period 1 and ivacaftor administered in Treatment Period 2. | 10 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Illness after randomization | 1 | 0 |
| Washout | Adverse Event | 1 | 1 |
| Washout | Extended Washout | 0 | 1 |
Baseline characteristics
| Characteristic | Ivacaftor Then Placebo | Total | Placebo Then Ivacaftor |
|---|---|---|---|
| Age, Categorical <=18 years | 9 Participants | 16 Participants | 7 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 4 Participants | 3 Participants |
| Age Continuous | 13.4 years STANDARD_DEVIATION 7.12 | 16.6 years STANDARD_DEVIATION 10.92 | 19.8 years STANDARD_DEVIATION 13.35 |
| Body Mass Index | 19.36 kilograms per square meter STANDARD_DEVIATION 3.707 | 21.01 kilograms per square meter STANDARD_DEVIATION 5.687 | 22.66 kilograms per square meter STANDARD_DEVIATION 6.964 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 20 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 148.9 centimeters STANDARD_DEVIATION 19.54 | 152.5 centimeters STANDARD_DEVIATION 18.61 | 156.0 centimeters STANDARD_DEVIATION 17.92 |
| Lung Clearance Index (LCI) | 9.17 ratio STANDARD_DEVIATION 1.657 | 9.03 ratio STANDARD_DEVIATION 1.528 | 8.88 ratio STANDARD_DEVIATION 1.462 |
| Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) | 101.83 percentage STANDARD_DEVIATION 11.587 | 97.20 percentage STANDARD_DEVIATION 10.595 | 92.58 percentage STANDARD_DEVIATION 7.427 |
| 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 | 10 Participants | 20 Participants | 10 Participants |
| Region of Enrollment Europe | 4 participants | 9 participants | 5 participants |
| Region of Enrollment North America | 6 participants | 11 participants | 5 participants |
| Sex: Female, Male Female | 6 Participants | 10 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 10 Participants | 6 Participants |
| Sweat Chloride | 97.10 millimoles per liter STANDARD_DEVIATION 7.4 | 91.92 millimoles per liter STANDARD_DEVIATION 14.933 | 86.17 millimoles per liter STANDARD_DEVIATION 19.219 |
| Weight | 45.06 kilograms STANDARD_DEVIATION 20.018 | 51.92 kilograms STANDARD_DEVIATION 26.119 | 58.78 kilograms STANDARD_DEVIATION 30.576 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 19 | 13 / 18 |
| serious Total, serious adverse events | 1 / 19 | 2 / 18 |
Outcome results
Primary
Absolute Change From Baseline in Lung Clearance Index (LCI)
Lung clearance index (LCI) is a measure of ventilation inhomogeneity that is derived from a multiple-breath washout test. The LCI was calculated as the number of lung volume turnovers (cumulative expired volume divided by the functional residual capacity \[FRC\]) required to reduce end-tidal SF6 concentration to 1/40th of the starting value.
Time frame: Baseline through Day 29
Population: All randomized subjects who received at least 1 dose of study drug (placebo or ivacaftor) and had available assessments during the time frame.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Lung Clearance Index (LCI) | 0.77 ratio | Standard Error 0.291 |
| Ivacaftor | Absolute Change From Baseline in Lung Clearance Index (LCI) | -1.30 ratio | Standard Error 0.303 |
Comparison: The primary analysis for the primary efficacy variable was based on a mixed effect model. The model included the absolute change from the baseline in each period as the dependent variable, sequence, treatment, and period as fixed effects, study baseline LCI as the covariate, and subject nested within sequence as the random effect.p-value: 0.000495% CI: [-2.98, -1.15]Mixed Models Analysis
Secondary
Absolute Change From Baseline in Percent Predicted FEV1
Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.
Time frame: Baseline through Day 29
Population: All randomized subjects who received at least 1 dose of study drug (placebo or ivacaftor) and had available assessments during the time frame.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Percent Predicted FEV1 | 0.00 percent | Standard Error 1.916 |
| Ivacaftor | Absolute Change From Baseline in Percent Predicted FEV1 | 7.00 percent | Standard Error 1.978 |
Comparison: Analysis for this efficacy variable was performed in a similar way as the analysis for the primary efficacy variable.p-value: 0.011795% CI: [1.8, 12.21]Mixed Models Analysis
Secondary
Change From Baseline in CF Questionnaire-Revised (CFQ-R) Score (Respiratory Domain Score, Pooled)
The CFQ-R is a health-related quality of life measure for subjects with cystic fibrosis. Each domain is scored from 0 (worst) to 100 (best). A difference of at least 4 points in the respiratory domain score of the CFQ-R is considered a minimal clinically important difference (MCID). The primary analytical focus was the respiratory health domain, which was analyzed by combining all self-response questionnaire versions from different age groups (e.g., Adult/Adolescent and Child versions).
Time frame: Baseline through Day 29
Population: All randomized subjects who received at least 1 dose of study drug (placebo or ivacaftor) and had available assessments during the time frame.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in CF Questionnaire-Revised (CFQ-R) Score (Respiratory Domain Score, Pooled) | 1.33 score on a scale | Standard Error 3.067 |
| Ivacaftor | Change From Baseline in CF Questionnaire-Revised (CFQ-R) Score (Respiratory Domain Score, Pooled) | 5.32 score on a scale | Standard Error 3.166 |
Comparison: The raw scores in CFQ-R were summarized into different domains of health (12 domains for adolescents and adults 14 years of age and older, 8 domains for children ages 12 and 13 years, 8 domains for children ages 6 to 11 years, and 11 domains for parents/caregivers). Each domain was analyzed in a similar way as for the primary efficacy variable. The primary analytical focus was the respiratory health domain which was analyzed by combining all self-response questionnaire versions.p-value: 0.379695% CI: [-5.4, 13.39]Mixed Models Analysis
Secondary
Change From Baseline in Sweat Chloride
The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity.
Time frame: Baseline through Day 29
Population: All randomized subjects who received at least 1 dose of study drug (placebo or ivacaftor) and had available assessments during the time frame.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Sweat Chloride | 0.11 millimoles per liter | Standard Error 2.351 |
| Ivacaftor | Change From Baseline in Sweat Chloride | -45.74 millimoles per liter | Standard Error 2.632 |
Comparison: Analysis for change from baseline in average sweat chloride was similar to the analysis of the primary efficacy variable.p-value: <0.000195% CI: [-53.54, -38.16]Mixed Models Analysis