Cystic Fibrosis
Conditions
Keywords
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 efficacy and safety of ivacaftor in subjects with cystic fibrosis aged 6 to 11 years who have the G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ivacaftor is a potent and selective 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 adenosine monophosphate (AMP)-dependent protein kinase A (PKA) activation.
Detailed description
This is a Phase 3, 2-part, randomized, double-blind, placebo-controlled, parallel group multicenter study of orally administered ivacaftor in subjects with cystic fibrosis (CF) 6 to 11 years of age who have the G551D-CFTR mutation and a forced expiratory volume in 1 second (FEV1) between 90% and 105% predicted (using Knudson standards). 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 effect of the CFTR protein, and the most prevalent mutation with a gating defect in CF is the G551D mutation. This study was conducted in 2 parts. Part A was conducted to analyze the PK properties of ivacaftor and to determine the most appropriate dose to administer to subjects in Part B of this study. Part B explored the safety and efficacy of ivacaftor over long-term treatment in subjects 6 to 11 years of age.
Interventions
DRUGIvacaftor
150-mg tablet 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
6 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
* Weighing at least 15 kg * Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele * Forced expiratory volume in 1 second (FEV1) of 40% to 105% (inclusive) of predicted normal for age, gender, and height (Knudson standards) at Screening * Able to swallow tablets * As judged by the investigator, parent or legal guardian and subject must have been able to understand protocol requirements, restrictions, and instructions, and the parent or legal guardian should have been able to ensure that the subject complied with, and was likely to complete, the study as planned * Parent or legal guardian must have signed the informed consent form and corresponding assent must be obtained from the subject * Willing to use at least 1 highly effective birth control method during 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 * Acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 4 weeks of Day 1 of the study * Abnormal liver function ≥ 3x the upper limit of normal * Abnormal renal function at Screening * History of solid organ or hematological transplantation * 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 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 Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (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) Through Week 24 and Week 48 (Respiratory Domain Score, Children) | 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. |
| 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, France, Germany, Ireland, United Kingdom, United States
Participant flow
Recruitment details
Part A started on 05 August 2009 (signing of first informed consent). Screening evaluations were completed during Day -28 to Day -2. All subjects completing Part A were offered the opportunity to participate in Part B, which started on 12 March 2010. Screening evaluations were completed during Day -35 to Day -15 before the first dose of study drug.
Pre-assignment details
Nine subjects were dosed and included in Part A. In Part B, 52 subjects were enrolled and all were randomized to ivacaftor (26 subjects) or placebo (26 subjects). 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 | 26 |
| 150 mg Ivacaftor q12h Oral tablet of 150 mg of ivacaftor q12h for up to 48 weeks | 26 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Prohibited Medication | 1 | 0 |
| Overall Study | Withdrawal of Consent | 1 | 0 |
| Overall Study | Wrong Genotype | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | 150 mg Ivacaftor q12h | Total |
|---|---|---|---|
| Age Continuous | 8.9 years STANDARD_DEVIATION 1.86 | 8.9 years STANDARD_DEVIATION 2 | 8.9 years STANDARD_DEVIATION 1.91 |
| Age, Customized > 11 Years | 1 participants | 3 participants | 4 participants |
| Age, Customized 6 to 8 Years | 13 participants | 12 participants | 25 participants |
| Age, Customized 9 to 11 Years | 12 participants | 11 participants | 23 participants |
| Body Mass Index | 16.8 kilograms per square meter STANDARD_DEVIATION 1.75 | 17.1 kilograms per square meter STANDARD_DEVIATION 2.61 | 17.0 kilograms per square meter STANDARD_DEVIATION 2.21 |
| Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) < 70% | 8 participants | 4 participants | 12 participants |
| Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) ≥ 70% to ≤ 90% | 6 participants | 12 participants | 18 participants |
| Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) > 90% | 12 participants | 10 participants | 22 participants |
| Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) | 83.7 percentage STANDARD_DEVIATION 20.37 | 84.7 percentage STANDARD_DEVIATION 15.83 | 84.2 percentage STANDARD_DEVIATION 18.07 |
| Race/Ethnicity, Customized Hispanic or Latino | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Not Allowed to Ask Per Local Regulations | 2 participants | 2 participants | 4 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 24 participants | 23 participants | 47 participants |
| Race/Ethnicity, Customized Other | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized White | 23 participants | 22 participants | 45 participants |
| Region of Enrollment Australia | 6 participants | 8 participants | 14 participants |
| Region of Enrollment Europe | 5 participants | 6 participants | 11 participants |
| Region of Enrollment North America | 15 participants | 12 participants | 27 participants |
| Sex: Female, Male Female | 10 Participants | 17 Participants | 27 Participants |
| Sex: Female, Male Male | 16 Participants | 9 Participants | 25 Participants |
| Sweat Chloride | 104.8 millimoles per liter STANDARD_DEVIATION 8.87 | 104.3 millimoles per liter STANDARD_DEVIATION 14.54 | 104.6 millimoles per liter STANDARD_DEVIATION 11.92 |
| Weight | 30.0 kilograms STANDARD_DEVIATION 7.16 | 31.8 kilograms STANDARD_DEVIATION 9.95 | 30.9 kilograms STANDARD_DEVIATION 8.63 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 25 / 26 | 26 / 26 |
| serious Total, serious adverse events | 6 / 26 | 5 / 26 |
Outcome results
Primary
Absolute 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 Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24 | 0.1 percent of predicted volume (L) | Standard Error 2.1 |
| 150 mg Ivacaftor q12h | Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24 | 12.6 percent of predicted volume (L) | Standard Error 2.1 |
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 value of percent predicted FEV1.p-value: <0.000195% CI: [6.6, 18.3]Mixed Models Analysis
Secondary
Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Through Week 24 and Week 48 (Respiratory Domain Score, Children)
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) Through Week 24 and Week 48 (Respiratory Domain Score, Children) | Change from Baseline Through Week 24 | 0.3 score on a scale | Standard Error 2.6 |
| Placebo | Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Through Week 24 and Week 48 (Respiratory Domain Score, Children) | Change from Baseline Through Week 48 | 1.0 score on a scale | Standard Error 2.3 |
| 150 mg Ivacaftor q12h | Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Through Week 24 and Week 48 (Respiratory Domain Score, Children) | Change from Baseline Through Week 24 | 6.3 score on a scale | Standard Error 2.5 |
| 150 mg Ivacaftor q12h | Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Through Week 24 and Week 48 (Respiratory Domain Score, Children) | Change from Baseline Through Week 48 | 6.1 score on a scale | Standard Error 2.2 |
Comparison: Through Week 24: Analysis for this variable was similar to that of the primary analysis of the primary efficacy endpoint, a Mixed-Effects Model for Repeated Measures (MMRM), with the addition of the baseline domain score as a covariate.p-value: 0.109295% CI: [-1.4, 13.5]Mixed Models Analysis
Comparison: Through Week 48: Analysis for this variable was similar to that of the primary analysis of the primary efficacy endpoint, a Mixed-Effects Model for Repeated Measures (MMRM), with the addition of the baseline domain score as a covariate.p-value: 0.135495% CI: [-1.6, 11.8]Mixed Models Analysis
Secondary
Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (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 Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 48 | 0.7 percent of predicted volume (L) | Standard Error 2 |
| 150 mg Ivacaftor q12h | Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 48 | 10.7 percent of predicted volume (L) | Standard Error 1.9 |
Comparison: Analysis for this variable was similar to that of the primary analysis of the primary efficacy endpoint, a Mixed-Effects Model for Repeated Measures (MMRM). Estimates were obtained from MMRM with dependent variable absolute change from baseline, fixed effects for categorical visit \& treatment group, \& adjustment for the continuous baseline value of percent predicted FEV1, using unstructured covariance matrix.p-value: 0.000695% CI: [4.5, 15.5]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 | -1.2 millimoles per liter | Standard Error 2.6 |
| Placebo | Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48 | Change from Baseline Through Week 48 | -2.6 millimoles per liter | Standard Error 2.6 |
| 150 mg Ivacaftor q12h | Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48 | Change from Baseline Through Week 24 | -55.5 millimoles per liter | Standard Error 2.6 |
| 150 mg Ivacaftor q12h | Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48 | Change from Baseline Through Week 48 | -56.0 millimoles per liter | Standard Error 2.5 |
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 sweat chloride and percent predicted forced expiratory volume in 1 second (FEV1), using unstructured covariance matrix.p-value: <0.000195% CI: [-61.8, -46.8]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 sweat chloride and percent predicted forced expiratory volume in 1 second (FEV1), using unstructured covariance matrix.p-value: <0.000195% CI: [-60.9, -46]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 | 1.8 kilograms | Standard Error 0.4 |
| Placebo | Absolute Change From Baseline in Weight at Week 24 and Week 48 | At Week 48 | 3.1 kilograms | Standard Error 0.5 |
| 150 mg Ivacaftor q12h | Absolute Change From Baseline in Weight at Week 24 and Week 48 | At Week 24 | 3.7 kilograms | Standard Error 0.4 |
| 150 mg Ivacaftor q12h | Absolute Change From Baseline in Weight at Week 24 and Week 48 | At Week 48 | 5.9 kilograms | Standard Error 0.5 |
Comparison: At Week 24: Analysis for this variable was based on a Linear Mixed Effect (LME) model with dependent variable weight; treatment as a fixed effect; and intercept, visit, and treatment by visit interaction as random effects, with adjustment for baseline percent predicted forced expiratory volume in 1 second (FEV1) severity.p-value: 0.000495% CI: [0.9, 2.9]Mixed Models Analysis
Comparison: At Week 48: Analysis for this variable was based on a Linear Mixed Effect (LME) model with random intercept and random slope, treatment as a fixed effect, and visit (days on study) and treatment by visit interaction as random effects, with adjustment for categorical baseline percent predicted forced expiratory volume in 1 second (FEV1) severity.p-value: 0.000295% CI: [1.3, 4.2]Mixed Models Analysis