Cystic Fibrosis
Conditions
Keywords
G551D mutation, Fibrosis, Pancreatic Diseases, Digestive System Diseases, Lung Diseases, Respiratory Tract Diseases, Genetic Diseases, Inborn, Infant, Newborn, Diseases, Pathologic Processes
Brief summary
The purpose of this study was to evaluate the safety and tolerability of ivacaftor in patients with cystic fibrosis (CF) who were aged 18 years or older and have a G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ivacaftor is a potent and selective CFTR potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. Potentiators are pharmacological agents that increase the chloride ion transport properties of the channel in the presence of cyclic AMP-dependent protein kinase A (PKA) activation.
Detailed description
This was a double-blind, placebo-controlled, cross-over, multiple dose study of up to 28 days of dosing, in subjects with cystic fibrosis (CF) who have a G551D-CTFR gene mutation. Enrollment of 39 subjects occurred at 15 centers in the US, Canada, and Germany. The study was conducted in 2 parts: * Part 1 consisted of Group A and Group B. Subjects in Group A (10 subjects) were randomized to receive 25 mg of ivacaftor every 12 hours \[q12h\] (4 subjects), 75 mg of ivacaftor q12h (4 subjects), or placebo (2 subjects) for 14 days. Following a 7- to 28-day washout period, subjects who received active study drug crossed over to the alternate dose strength of ivacaftor for an additional 14 days. Placebo subjects continued to receive placebo for an additional 14 days. Subjects in Group B (10 subjects) were randomized to receive 75 mg of ivacaftor q12h (4 subjects), 150 mg of ivacaftor q12h (4 subjects), or placebo (2 subjects) for 14 days. Following a 7- to 28-day washout period, the subjects who received active study drug crossed over to the alternate dose strength of ivacaftor for an additional 14 days. Placebo subjects continued to receive placebo for an additional 14 days. * Part 2 consisted of Group C; these subjects did not participate in Part 1. Subjects were randomized to receive 150 mg of ivacaftor q12h (7 subjects), 250 mg of ivacaftor q12h (7 subjects), or placebo (4 subjects) for a total of 28 days. Ivacaftor doses studied in Part 2 were selected following an interim pharmacokinetic/pharmacodynamic (PK/PD) and statistical analyses of data from Part 1. The 2 doses selected for Part 2 were anticipated to enable better definition of the optimal therapeutic dose.
Interventions
DRUGIvacaftor 25 mg/75 mg
25 mg or 75 mg q12h for a total of 28 days (Part 1)
DRUGIvacaftor 75 mg/150 mg
75 mg or 150 mg q12h for a total of 28 days (Part 1)
DRUGIvacaftor 150 mg or 250 mg
150 mg or 250 mg of ivacaftor q12h for 28 days (Part 2)
DRUGPlacebo
Given q12h for 28 days each in Part 1 and Part 2 of the study
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
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Weighing at least 40 kg * Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele * Forced expiratory volume in 1 second (FEV1) of at least 40% of predicted normal for age, gender, and height * Willing to remain on stable medication regimen for the duration of study participation * No significant clinical laboratory abnormalities, not pregnant, and willing to use at least 2 highly effective birth control methods during Part 1 and 1 highly effective birth control method during Part 2 of the study * No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator
Exclusion criteria
* History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject * Ongoing acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 14 days of Day 1 of the study * History of alcohol, medication or illicit drug abuse within one year prior to Day 1 * Abnormal liver function ≥ 3x the upper limit of normal * History of abnormal renal function (creatinine clearance \< 50 mL/min using Cockcroft-Gault equation) * History of solid organ or hematological transplantation * Pregnant or breast-feeding (for women) * Ongoing participation in another therapeutic clinical trial, or prior participation in an investigational drug study without appropriate washout * Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP3A4)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Adverse Events (Combined Part 1 and Part 2) | Baseline to Follow-up | Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug). Serious adverse events that were ongoing at the follow-up visit were followed until the event resolved, returned to baseline, or was determined to be a stable or chronic condition. |
| Number of Adverse Events (Combined Part 1 and Part 2) | Baseline to Follow-up | Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug). Serious adverse events that were ongoing at the follow-up visit were followed until the event resolved, returned to baseline, or was determined to be a stable or chronic condition. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | 14 days and 28 days | The transepithelial nasal potential difference (NPD) is a direct measure of transepithelial ion transport. NPD under conditions of zero chloride concentration perfusion solution in the presence of isoproterenol was of primary interest. |
| Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | 14 days and 28 days | Spirometry is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. Relative change reflects the percent change from the baseline values \[100% \* (X-Y)/Y\], where X and Y are post-baseline and baseline values, respectively. |
| Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score) | 14 days and 28 days | 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). |
| Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2) | 14 days and 28 days | 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. |
Countries
Canada, Germany, United States
Participant flow
Recruitment details
Part 1 started on 10 May 2007 (signing of first informed consent). After obtaining consent, Part 1 screening evaluations were completed during Day -28 to Day -2. Part 2 started on 28 May 2008 (signing of first informed consent). Part 2 screening evaluations were also completed during Day -28 to Day -2 before the first dose of study drug.
Pre-assignment details
In Part 1, 21 subjects were randomized but 1 subject was excluded prior to dosing because the subject needed a protocol-prohibited medication. In Part 2, 20 subjects were randomized but 1 subject withdrew consent to the study prior to dosing.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Placebo Part 1: placebo every 12 hours (q12h); 14 days/14 days. | 4 |
| Part 1: 25 mg/75 mg Part 1: Ivacaftor (25 mg/75 mg) every 12 hours (q12h); 14 days/14 days. | 4 |
| Part 1: 75 mg/25 mg Part 1: Ivacaftor (75 mg/25 mg) every 12 hours (q12h); 14 days/14 days. | 4 |
| Part 1: 75 mg/150 mg Part 1: Ivacaftor (75 mg/150 mg) every 12 hours (q12h); 14 days/14 days. | 4 |
| Part 1: 150 mg/75 mg Part 1: Ivacaftor (150 mg/75 mg) every 12 hours (q12h); 14 days/14 days. | 4 |
| Part 2: 150 mg Part 2: Ivacaftor (150 mg) q12h; 28 days | 8 |
| Part 2: 250 mg Part 2: Ivacaftor (250 mg) q12h; 28 days | 7 |
| Part 2: Placebo Part 2: placebo q12h; 28 days | 4 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Part 2 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Part 1: Placebo | Part 1: 25 mg/75 mg | Part 1: 75 mg/25 mg | Part 1: 75 mg/150 mg | Part 1: 150 mg/75 mg | Part 2: 150 mg | Part 2: 250 mg | Part 2: Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | 34.5 years STANDARD_DEVIATION 14.66 | 33.5 years STANDARD_DEVIATION 12.5 | 38.5 years STANDARD_DEVIATION 11.82 | 26.3 years STANDARD_DEVIATION 7.85 | 23.5 years STANDARD_DEVIATION 6.45 | 25.6 years STANDARD_DEVIATION 7.98 | 26.0 years STANDARD_DEVIATION 7.07 | 26.8 years STANDARD_DEVIATION 10.69 | 28.7 years STANDARD_DEVIATION 10.03 |
| Body Mass Index | 24.195 kilograms per square meter STANDARD_DEVIATION 3.2002 | 22.455 kilograms per square meter STANDARD_DEVIATION 2.3133 | 23.653 kilograms per square meter STANDARD_DEVIATION 3.6216 | 20.960 kilograms per square meter STANDARD_DEVIATION 2.2522 | 20.788 kilograms per square meter STANDARD_DEVIATION 4.1527 | 21.896 kilograms per square meter STANDARD_DEVIATION 0.977 | 22.703 kilograms per square meter STANDARD_DEVIATION 1.398 | 22.035 kilograms per square meter STANDARD_DEVIATION 0.6999 | 22.3 kilograms per square meter STANDARD_DEVIATION 2.37 |
| Genotype G551D/1078 DEL T | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Genotype G551D/3849 AND 10KBC | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Genotype G551D/6214 + 1G > 7T | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Genotype G551D/DELTA F508 | 3 participants | 4 participants | 4 participants | 2 participants | 3 participants | 7 participants | 5 participants | 4 participants | 32 participants |
| Genotype G551D/G542X | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Genotype G551D/G551D | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Genotype G551D/N1303K | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Genotype G551D/R553X | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) | 64.902 percentage of volume in liters STANDARD_DEVIATION 22.6821 | 71.073 percentage of volume in liters STANDARD_DEVIATION 27.2307 | 54.885 percentage of volume in liters STANDARD_DEVIATION 9.6772 | 68.284 percentage of volume in liters STANDARD_DEVIATION 24.7014 | 49.270 percentage of volume in liters STANDARD_DEVIATION 7.5615 | 70.443 percentage of volume in liters STANDARD_DEVIATION 25.4442 | 72.674 percentage of volume in liters STANDARD_DEVIATION 21.5223 | 79.351 percentage of volume in liters STANDARD_DEVIATION 28.7018 | 67.3 percentage of volume in liters STANDARD_DEVIATION 22.17 |
| Race/Ethnicity, Customized Caucasian | 4 participants | 4 participants | 4 participants | 4 participants | 4 participants | 8 participants | 7 participants | 4 participants | 39 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 0 Participants | 3 Participants | 3 Participants | 5 Participants | 3 Participants | 1 Participants | 20 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 4 Participants | 1 Participants | 1 Participants | 3 Participants | 4 Participants | 3 Participants | 19 Participants |
| Weight | 70.05 kilograms STANDARD_DEVIATION 16.507 | 66.05 kilograms STANDARD_DEVIATION 12.628 | 73.43 kilograms STANDARD_DEVIATION 14.366 | 57.48 kilograms STANDARD_DEVIATION 8.663 | 59.35 kilograms STANDARD_DEVIATION 18.401 | 61.19 kilograms STANDARD_DEVIATION 9.857 | 64.46 kilograms STANDARD_DEVIATION 13.027 | 63.50 kilograms STANDARD_DEVIATION 7.391 | 64.1 kilograms STANDARD_DEVIATION 12.42 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 8 | 4 / 8 | 13 / 16 | 13 / 16 | 6 / 7 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 16 | 1 / 16 | 0 / 7 |
Outcome results
Primary
Number of Adverse Events (Combined Part 1 and Part 2)
Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug). Serious adverse events that were ongoing at the follow-up visit were followed until the event resolved, returned to baseline, or was determined to be a stable or chronic condition.
Time frame: Baseline to Follow-up
Population: All randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Adverse Events (Combined Part 1 and Part 2) | Number of Adverse Events (AEs) | 32 events |
| Placebo | Number of Adverse Events (Combined Part 1 and Part 2) | Number of Related or Possibly Related AEs | 11 events |
| Placebo | Number of Adverse Events (Combined Part 1 and Part 2) | Number of Serious Adverse Events (SAEs) | 0 events |
| Placebo | Number of Adverse Events (Combined Part 1 and Part 2) | Number of Related or Possibly Related SAEs | 0 events |
| Ivacaftor | Number of Adverse Events (Combined Part 1 and Part 2) | Number of Related or Possibly Related SAEs | 0 events |
| Ivacaftor | Number of Adverse Events (Combined Part 1 and Part 2) | Number of Adverse Events (AEs) | 179 events |
| Ivacaftor | Number of Adverse Events (Combined Part 1 and Part 2) | Number of Serious Adverse Events (SAEs) | 2 events |
| Ivacaftor | Number of Adverse Events (Combined Part 1 and Part 2) | Number of Related or Possibly Related AEs | 40 events |
Primary
Number of Subjects With Adverse Events (Combined Part 1 and Part 2)
Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug). Serious adverse events that were ongoing at the follow-up visit were followed until the event resolved, returned to baseline, or was determined to be a stable or chronic condition.
Time frame: Baseline to Follow-up
Population: All randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Subjects With Adverse Events (Combined Part 1 and Part 2) | Subjects with AEs | 7 participants |
| Placebo | Number of Subjects With Adverse Events (Combined Part 1 and Part 2) | Subjects with Related or Possibly Related AEs | 3 participants |
| Placebo | Number of Subjects With Adverse Events (Combined Part 1 and Part 2) | Subjects with SAEs | 0 participants |
| Placebo | Number of Subjects With Adverse Events (Combined Part 1 and Part 2) | Subjects with Related or Possibly Related SAEs | 0 participants |
| Ivacaftor | Number of Subjects With Adverse Events (Combined Part 1 and Part 2) | Subjects with Related or Possibly Related SAEs | 0 participants |
| Ivacaftor | Number of Subjects With Adverse Events (Combined Part 1 and Part 2) | Subjects with AEs | 26 participants |
| Ivacaftor | Number of Subjects With Adverse Events (Combined Part 1 and Part 2) | Subjects with SAEs | 1 participants |
| Ivacaftor | Number of Subjects With Adverse Events (Combined Part 1 and Part 2) | Subjects with Related or Possibly Related AEs | 13 participants |
Secondary
Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2)
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: 14 days and 28 days
Population: Due to the crossover design in Part 1, subjects were counted once for each period; therefore, the 4 unique subjects who received placebo were counted as 8 subjects in the analyses for Part 1.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2) | Change from Baseline in Sweat Chloride, Day ≥14 | 4.9 millimoles per liter |
| Placebo | Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2) | Change from Baseline in Sweat Chloride, Day 14 | 2.0 millimoles per liter |
| Ivacaftor | Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2) | Change from Baseline in Sweat Chloride, Day 14 | -33.8 millimoles per liter |
| Ivacaftor | Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2) | Change from Baseline in Sweat Chloride, Day ≥14 | -32.9 millimoles per liter |
| 75 mg Ivacaftor q12h | Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2) | Change from Baseline in Sweat Chloride, Day ≥14 | -40.8 millimoles per liter |
| 75 mg Ivacaftor q12h | Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2) | Change from Baseline in Sweat Chloride, Day 14 | -42.0 millimoles per liter |
| 150 mg Ivacaftor q12h | Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2) | Change from Baseline in Sweat Chloride, Day 14 | -46.0 millimoles per liter |
| 150 mg Ivacaftor q12h | Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2) | Change from Baseline in Sweat Chloride, Day ≥14 | -44.2 millimoles per liter |
| 250 mg Ivacaftor q12h | Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2) | Change from Baseline in Sweat Chloride, Day ≥14 | -28.2 millimoles per liter |
| 250 mg Ivacaftor q12h | Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2) | Change from Baseline in Sweat Chloride, Day 14 | -27.1 millimoles per liter |
Comparison: Within-dose group and between-dose group analyses were performed, using a linear mixed effect model with baseline, dose, and period as fixed effects and subject as a random effect.p-value: <0.05Mixed Models Analysis
Secondary
Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2)
The transepithelial nasal potential difference (NPD) is a direct measure of transepithelial ion transport. NPD under conditions of zero chloride concentration perfusion solution in the presence of isoproterenol was of primary interest.
Time frame: 14 days and 28 days
Population: Due to the crossover design in Part 1, subjects were counted once for each period; therefore, the 4 unique subjects who received placebo were counted as 8 subjects in the analyses for Part 1.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Zero Chloride + Isoproterenol, Day 14 | -0.3 millivolts |
| Placebo | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Zero Chloride + Isoproterenol, Day ≥ 14 | -0.5 millivolts |
| Placebo | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Amiloride, Day ≥ 14 | -0.7 millivolts |
| Placebo | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Amiloride, Day 14 | 0.3 millivolts |
| Ivacaftor | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Amiloride, Day 14 | -0.1 millivolts |
| Ivacaftor | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Zero Chloride + Isoproterenol, Day 14 | -1.4 millivolts |
| Ivacaftor | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Zero Chloride + Isoproterenol, Day ≥ 14 | -1.3 millivolts |
| Ivacaftor | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Amiloride, Day ≥ 14 | -0.3 millivolts |
| 75 mg Ivacaftor q12h | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Amiloride, Day ≥ 14 | -3.7 millivolts |
| 75 mg Ivacaftor q12h | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Amiloride, Day 14 | -4.2 millivolts |
| 75 mg Ivacaftor q12h | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Zero Chloride + Isoproterenol, Day 14 | -4.4 millivolts |
| 75 mg Ivacaftor q12h | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Zero Chloride + Isoproterenol, Day ≥ 14 | -4.5 millivolts |
| 150 mg Ivacaftor q12h | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Zero Chloride + Isoproterenol, Day 14 | -4.6 millivolts |
| 150 mg Ivacaftor q12h | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Zero Chloride + Isoproterenol, Day ≥ 14 | -5.3 millivolts |
| 150 mg Ivacaftor q12h | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Amiloride, Day 14 | -9.9 millivolts |
| 150 mg Ivacaftor q12h | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Amiloride, Day ≥ 14 | -8.8 millivolts |
| 250 mg Ivacaftor q12h | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Zero Chloride + Isoproterenol, Day ≥ 14 | -8.4 millivolts |
| 250 mg Ivacaftor q12h | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Zero Chloride + Isoproterenol, Day 14 | -7.6 millivolts |
| 250 mg Ivacaftor q12h | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Amiloride, Day ≥ 14 | -4.0 millivolts |
| 250 mg Ivacaftor q12h | Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2) | Amiloride, Day 14 | -5.5 millivolts |
Comparison: Within-dose group and between-dose group analyses were performed, using a linear mixed effect model with baseline, dose, and period as fixed effects and subject as a random effect.p-value: <0.05Mixed Models Analysis
Secondary
Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2)
Spirometry is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. Relative change reflects the percent change from the baseline values \[100% \* (X-Y)/Y\], where X and Y are post-baseline and baseline values, respectively.
Time frame: 14 days and 28 days
Population: Due to the crossover design in Part 1, subjects were counted once for each period; therefore, the 4 unique subjects who received placebo were counted as 8 subjects in the analyses for Part 1.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Absolute Change from Baseline, Day ≥ 14 | 2.1 percent predicted (%) |
| Placebo | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Relative Change from Baseline, Day ≥ 14 | 3.3 percent predicted (%) |
| Placebo | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Relative Change from Baseline, Day 14 | 2.0 percent predicted (%) |
| Placebo | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Absolute Change from Baseline, Day 14 | 0.5 percent predicted (%) |
| Ivacaftor | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Relative Change from Baseline, Day ≥ 14 | 4.1 percent predicted (%) |
| Ivacaftor | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Absolute Change from Baseline, Day ≥ 14 | 2.5 percent predicted (%) |
| Ivacaftor | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Relative Change from Baseline, Day 14 | 4.7 percent predicted (%) |
| Ivacaftor | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Absolute Change from Baseline, Day 14 | 2.7 percent predicted (%) |
| 75 mg Ivacaftor q12h | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Absolute Change from Baseline, Day ≥ 14 | 5.3 percent predicted (%) |
| 75 mg Ivacaftor q12h | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Relative Change from Baseline, Day ≥ 14 | 9.3 percent predicted (%) |
| 75 mg Ivacaftor q12h | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Relative Change from Baseline, Day 14 | 9.5 percent predicted (%) |
| 75 mg Ivacaftor q12h | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Absolute Change from Baseline, Day 14 | 5.1 percent predicted (%) |
| 150 mg Ivacaftor q12h | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Relative Change from Baseline, Day 14 | 10.8 percent predicted (%) |
| 150 mg Ivacaftor q12h | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Absolute Change from Baseline, Day ≥ 14 | 6.9 percent predicted (%) |
| 150 mg Ivacaftor q12h | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Absolute Change from Baseline, Day 14 | 6.9 percent predicted (%) |
| 150 mg Ivacaftor q12h | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Relative Change from Baseline, Day ≥ 14 | 10.6 percent predicted (%) |
| 250 mg Ivacaftor q12h | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Relative Change from Baseline, Day ≥ 14 | 9.4 percent predicted (%) |
| 250 mg Ivacaftor q12h | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Absolute Change from Baseline, Day 14 | 8.4 percent predicted (%) |
| 250 mg Ivacaftor q12h | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Absolute Change from Baseline, Day ≥ 14 | 6.7 percent predicted (%) |
| 250 mg Ivacaftor q12h | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2) | Relative Change from Baseline, Day 14 | 12.0 percent predicted (%) |
Comparison: Within-dose group and between-dose group analyses were performed, using a linear mixed effect model with baseline, dose, and period as fixed effects and subject as a random effect.p-value: <0.05Mixed Models Analysis
Secondary
Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score)
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).
Time frame: 14 days and 28 days
Population: Part 2 is a parallel study. Subjects were counted only once for each treatment group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score) | Change from Baseline in Respiratory Score, Day 14 | 2.8 score on a scale | Standard Deviation 7.2 |
| Placebo | Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score) | Baseline Respiratory Domain Score | 70.8 score on a scale | Standard Deviation 21.5 |
| Placebo | Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score) | Change from Baseline in Respiratory Score, Day 28 | 2.8 score on a scale | Standard Deviation 7.2 |
| Ivacaftor | Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score) | Baseline Respiratory Domain Score | 68.8 score on a scale | Standard Deviation 23.9 |
| Ivacaftor | Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score) | Change from Baseline in Respiratory Score, Day 14 | 6.3 score on a scale | Standard Deviation 6.9 |
| Ivacaftor | Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score) | Change from Baseline in Respiratory Score, Day 28 | 6.9 score on a scale | Standard Deviation 6.5 |
| 75 mg Ivacaftor q12h | Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score) | Baseline Respiratory Domain Score | 73.0 score on a scale | Standard Deviation 8.7 |
| 75 mg Ivacaftor q12h | Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score) | Change from Baseline in Respiratory Score, Day 28 | 11.9 score on a scale | Standard Deviation 14.1 |
| 75 mg Ivacaftor q12h | Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score) | Change from Baseline in Respiratory Score, Day 14 | 5.6 score on a scale | Standard Deviation 7.9 |