Cystic Fibrosis
Conditions
Keywords
Fibrosis, Pancreatic 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 efficacy and safety of ivacaftor in subjects with cystic fibrosis aged 12 years and older who have the 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 phase 3 study in subjects with cystic fibrosis (CF) age 12 years and older who have a G551D-CFTR mutation and percent predicted forced expiratory volumn in 1 second (FEV1) between 40% and 90%. Based on in vitro studies and pharmacologic, pharmacokinetic (PK), and safety profiles, ivacaftor was selected for clinical development as a possible treatment for patients with CF. Patients with the G551D mutation were the targeted population for this study because ivacaftor is a potentiator of the gating function of the CFTR protein, and the most prevalent mutation with a gating defect in CF is the G551D mutation. This study was designed to further evaluate the efficacy of ivacaftor in subjects with CF who have a G551D-CFTR gene mutation and to evaluate safety in this population over a longer period than previously studied.
Interventions
DRUGIvacaftor
150-mg tablets given orally q12h for up to 48 weeks
DRUGPlacebo
Tablet given orally q12h for up to 48 weeks
Sponsors
Cystic Fibrosis Foundation
Vertex Pharmaceuticals Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele * Forced expiratory volume in 1 second (FEV1) of 40% to 90% (inclusive) of predicted normal for age, gender, and height at Screening. * No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator * Willing to use highly effective birth control methods during the study
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 * Acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 4 weeks 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 * Abnormal renal function at Screening * History of solid organ or hematological transplantation * Pregnant, planning a pregnancy, breast-feeding, or unwilling to follow contraception requirements * Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days prior to Screening * Use of inhaled hypertonic saline treatment * Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP 3A4)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Mean Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24 | baseline through 24 weeks | Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Mean Change From Baseline in Percent Predicted FEV1 Through Week 48 | baseline through 48 weeks | Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. |
| Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled) | baseline through 24 weeks and 48 weeks | 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). |
| Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48 | baseline through 24 weeks and 48 weeks | 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-to-first Pulmonary Exacerbation Through Week 24 and Week 48 | baseline through 24 weeks and 48 weeks | Pulmonary exacerbation was defined as a change in antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of signs/symptoms such as change in sputum; new or increased hemoptysis; increased cough or dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees C; anorexia or weight loss; sinus pain/tenderness and discharge; change in physical examination of the chest; decreased pulmonary function by 10%; and radiographic changes indicative of pulmonary infection. |
| Absolute Change From Baseline in Weight at Week 24 and Week 48 | baseline to 24 weeks and 48 weeks | As malnutrition is common in patients with cystic fibrosis (CF) because of increased energy expenditures due to lung disease and fat malabsorption, body weight is an important clinical measure of nutritional status. |
Countries
Australia, Canada, Czechia, France, Germany, Ireland, United Kingdom, United States
Participant flow
Recruitment details
The study started on 10 June 2009 (signing of first informed consent). After obtaining consent and assent (where applicable), screening evaluations were completed during a period of 2 to 5 weeks (Day -35 to Day -15) before the first dose of study drug.
Pre-assignment details
A total of 167 subjects were randomized; 161 subjects received at least 1 dose of the study drug. A 2-week run-in period was included to establish the baseline assessments on Day 1 after ensuring that subjects were properly taking their cystic fibrosis (CF) medication regimens.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Oral tablet every 12 hours (q12h) for up to 48 weeks. | 78 |
| 150 mg Ivacaftor q12h Oral tablet of 150 mg of ivacaftor q12h for up to 48 weeks. | 83 |
| Total | 161 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
| Overall Study | Increased Lab Draws, Difficult Lab Stick | 1 | 0 |
| Overall Study | Noncompliance with Study Requirements | 0 | 2 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Pregnancy | 0 | 1 |
| Overall Study | Prohibited Medication | 2 | 1 |
| Overall Study | Withdrawal of Consent | 1 | 1 |
| Overall Study | Wrong Genotype | 1 | 0 |
Baseline characteristics
| Characteristic | Total | 150 mg Ivacaftor q12h | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 36 Participants | 19 Participants | 17 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 125 Participants | 64 Participants | 61 Participants |
| Age Continuous | 25.5 years STANDARD_DEVIATION 9.54 | 26.2 years STANDARD_DEVIATION 9.85 | 24.7 years STANDARD_DEVIATION 9.21 |
| Body Mass Index | 21.8 kilograms per square meter STANDARD_DEVIATION 3.56 | 21.7 kilograms per square meter STANDARD_DEVIATION 3.65 | 21.9 kilograms per square meter STANDARD_DEVIATION 3.49 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 158 Participants | 81 Participants | 77 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 1 Participants |
| Percent Predicted FEV1, Categorical < 70% predicted FEV1 | 94 participants | 49 participants | 45 participants |
| Percent Predicted FEV1, Categorical ≥ 70% predicted FEV1 | 67 participants | 34 participants | 33 participants |
| Percent Predicted Forced Expiratory Volume in 1 Second (FEV1), Continuous | 63.6 percentage STANDARD_DEVIATION 16.43 | 63.5 percentage STANDARD_DEVIATION 16.14 | 63.7 percentage STANDARD_DEVIATION 16.83 |
| Race/Ethnicity, Customized Not Allowed to Ask Per Local Regulations | 3 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized White | 158 participants | 81 participants | 77 participants |
| Region of Enrollment Australia | 19 participants | 10 participants | 9 participants |
| Region of Enrollment Europe | 42 participants | 23 participants | 19 participants |
| Region of Enrollment North America | 100 participants | 50 participants | 50 participants |
| Sex: Female, Male Female | 84 Participants | 44 Participants | 40 Participants |
| Sex: Female, Male Male | 77 Participants | 39 Participants | 38 Participants |
| Sweat Chloride | 100.2 millimoles per liter STANDARD_DEVIATION 10.28 | 100.4 millimoles per liter STANDARD_DEVIATION 10 | 100.1 millimoles per liter STANDARD_DEVIATION 10.63 |
| Weight | 61.5 kilograms STANDARD_DEVIATION 14.06 | 61.7 kilograms STANDARD_DEVIATION 14.26 | 61.2 kilograms STANDARD_DEVIATION 13.93 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 78 / 78 | 82 / 83 |
| serious Total, serious adverse events | 33 / 78 | 20 / 83 |
Outcome results
Primary
Absolute Mean Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24
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 24 weeks
Population: All randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Mean Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24 | -0.2 percent of predicted volume (L) | Standard Error 0.7 |
| 150 mg Ivacaftor q12h | Absolute Mean Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24 | 10.4 percent of predicted volume (L) | Standard Error 0.7 |
Comparison: The primary analysis for the primary efficacy variable was based on a Mixed-Effects Model for Repeated Measures (MMRM). The model included absolute change from baseline in percent predicted forced expiratory volume in 1 second (FEV1) as the dependent variable, treatment (ivacaftor versus placebo) and visit (Day 15, Week 8, Week 16, and Week 24) as fixed effects, and subject as a random effect, with adjustment for the continuous baseline values of age and percent predicted FEV1.p-value: <0.000195% CI: [8.6, 12.6]Mixed Models Analysis
Secondary
Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (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).
Time frame: baseline through 24 weeks and 48 weeks
Population: All randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled) | Change from Baseline Through Week 24 | -2.1 score on a scale | Standard Error 1.3 |
| Placebo | Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled) | Change from Baseline Through Week 48 | -2.7 score on a scale | Standard Error 1.2 |
| 150 mg Ivacaftor q12h | Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled) | Change from Baseline Through Week 24 | 6.0 score on a scale | Standard Error 1.2 |
| 150 mg Ivacaftor q12h | Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled) | Change from Baseline Through Week 48 | 6.0 score on a scale | Standard Error 1.1 |
Comparison: Through Week 24: Analysis for the respiratory domain score endpoint was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were from Mixed-Effects Model for Repeated Measures (MMRM) with dependent variable absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous baseline value for age, domain score, and percent predicted FEV1, using unstructured covariance matrix.p-value: <0.000195% CI: [4.7, 11.4]Mixed Models Analysis
Comparison: Through Week 48: Analysis for the CFQ-R respiratory domain score endpoint was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were from MMRM with dependent variable absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous baseline value for age,sweat chloride, and percent predicted FEV1,using unstructured covariance matrix.p-value: <0.000195% CI: [5.3, 11.9]Mixed Models Analysis
Secondary
Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48
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 24 weeks and 48 weeks
Population: All randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame..
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48 | Change from Baseline Through Week 24 | -0.8 millimoles per liter | Standard Error 1.3 |
| Placebo | Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48 | Change from Baseline Through Week 48 | -0.6 millimoles per liter | Standard Error 1.3 |
| 150 mg Ivacaftor q12h | Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48 | Change from Baseline Through Week 48 | -48.7 millimoles per liter | Standard Error 1.2 |
| 150 mg Ivacaftor q12h | Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48 | Change from Baseline Through Week 24 | -48.7 millimoles per liter | Standard Error 1.2 |
Comparison: Through Week 24: Analysis for this variable was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were from Mixed-Effects Model for Repeated Measures (MMRM) with dependent variable absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous baseline value for age, sweat chloride, and percent predicted FEV1, using unstructured covariance matrix.p-value: <0.000195% CI: [-51.3, -44.5]Mixed Models Analysis
Comparison: Through Week 48: Analysis for this variable was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were from Mixed-Effects Model for Repeated Measures (MMRM) with dependent variable absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous baseline value for age, sweat chloride, and percent predicted FEV1, using unstructured covariance matrix.p-value: <0.000195% CI: [-51.5, -44.7]Mixed Models Analysis
Secondary
Absolute Change From Baseline in Weight at Week 24 and Week 48
As malnutrition is common in patients with cystic fibrosis (CF) because of increased energy expenditures due to lung disease and fat malabsorption, body weight is an important clinical measure of nutritional status.
Time frame: baseline to 24 weeks and 48 weeks
Population: All randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Absolute Change From Baseline in Weight at Week 24 and Week 48 | At Week 24 | 0.2 kilograms | Standard Error 0.4 |
| Placebo | Absolute Change From Baseline in Weight at Week 24 and Week 48 | At Week 48 | 0.4 kilograms | Standard Error 0.5 |
| 150 mg Ivacaftor q12h | Absolute Change From Baseline in Weight at Week 24 and Week 48 | At Week 24 | 3.0 kilograms | Standard Error 0.4 |
| 150 mg Ivacaftor q12h | Absolute Change From Baseline in Weight at Week 24 and Week 48 | At Week 48 | 3.1 kilograms | Standard Error 0.5 |
Comparison: At Week 24: Analysis for this variable was based on a linear mixed effects (LME) model with treatment as a fixed effect, and intercept, visit (days on study) and treatment by visit interaction as random effects, with adjustment for age group and baseline percent predicted forced expiratory volume in 1 second (FEV1) severity.p-value: <0.000195% CI: [1.8, 3.7]Mixed Models Analysis
Comparison: At Week 48: Analysis for this variable was based on a linear mixed effects (LME) model with treatment as a fixed effect and visit (days on study) and treatment by visit interaction as random effects, with adjustment for age group and baseline percent predicted forced expiratory volume in 1 second (FEV1) severity.p-value: 0.000195% CI: [1.3, 4.1]Mixed Models Analysis
Secondary
Absolute Mean Change From Baseline in Percent Predicted FEV1 Through Week 48
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 48 weeks
Population: All randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame..
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Mean Change From Baseline in Percent Predicted FEV1 Through Week 48 | -0.4 percent of predicted volume (L) | Standard Error 0.7 |
| 150 mg Ivacaftor q12h | Absolute Mean Change From Baseline in Percent Predicted FEV1 Through Week 48 | 10.1 percent of predicted volume (L) | Standard Error 0.7 |
Comparison: Analysis of this variable was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were obtained from Mixed-Effects Model for Repeated Measures (MMRM) with dependent variable absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for the continuous baseline values of age and percent predicted forced expiratory volume in 1 second (FEV1),using unstructured covariance matrix.p-value: <0.000195% CI: [8.5, 12.5]Mixed Models Analysis
Secondary
Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48
Pulmonary exacerbation was defined as a change in antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of signs/symptoms such as change in sputum; new or increased hemoptysis; increased cough or dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees C; anorexia or weight loss; sinus pain/tenderness and discharge; change in physical examination of the chest; decreased pulmonary function by 10%; and radiographic changes indicative of pulmonary infection.
Time frame: baseline through 24 weeks and 48 weeks
Population: All randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48 | 113 to 168 Days | 0.53 proportion of event-free participants |
| Placebo | Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48 | 281 to 336 Days | 0.41 proportion of event-free participants |
| Placebo | Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48 | 0 to 15 Days | 0.97 proportion of event-free participants |
| Placebo | Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48 | 169 to 224 Days | 0.51 proportion of event-free participants |
| Placebo | Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48 | 16 to 56 Days | 0.87 proportion of event-free participants |
| Placebo | Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48 | 225 to 280 Days | 0.44 proportion of event-free participants |
| Placebo | Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48 | 57 to 112 Days | 0.72 proportion of event-free participants |
| 150 mg Ivacaftor q12h | Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48 | 225 to 280 Days | 0.70 proportion of event-free participants |
| 150 mg Ivacaftor q12h | Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48 | 113 to 168 Days | 0.78 proportion of event-free participants |
| 150 mg Ivacaftor q12h | Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48 | 281 to 336 Days | 0.67 proportion of event-free participants |
| 150 mg Ivacaftor q12h | Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48 | 169 to 224 Days | 0.75 proportion of event-free participants |
| 150 mg Ivacaftor q12h | Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48 | 57 to 112 Days | 0.83 proportion of event-free participants |
| 150 mg Ivacaftor q12h | Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48 | 0 to 15 Days | 0.98 proportion of event-free participants |
| 150 mg Ivacaftor q12h | Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48 | 16 to 56 Days | 0.89 proportion of event-free participants |
Comparison: Time to first pulmonary exacerbation through Week 24 was analyzed using Cox regression. The model included a covariate for treatment and adjustments for the age group and percent predicted forced expiratory volume in 1 second (FEV1) severity at baseline.p-value: 0.001695% CI: [0.23, 0.71]Regression, Cox
Comparison: Time to first pulmonary exacerbation through Week 48 was analyzed using Cox regression. The model included a covariate for treatment and adjustments for the age group and percent predicted forced expiratory volume in 1 second (FEV1) severity at baseline.p-value: 0.001295% CI: [0.28, 0.73]Regression, Cox