SNPMiner Trials by Shray Alag


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Report for Mutation R117H

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 16 clinical trials

Clinical Trials


1 A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study of VX-770 to Evaluate Safety, Pharmacokinetics, and Biomarkers of CFTR Activity in Cystic Fibrosis (CF) Subjects With Genotype G551D

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.

NCT00457821 Cystic Fibrosis Drug: Ivacaftor 25 mg/75 mg Drug: Ivacaftor 75 mg/150 mg Drug: Ivacaftor 150 mg or 250 mg Drug: Placebo
MeSH: Cystic Fibrosis Fibrosis

Ivacaftor is a potent and selective CFTR potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. --- G551D --- --- R117H ---

Primary Outcomes

Description: 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.

Measure: Number of Subjects With Adverse Events (Combined Part 1 and Part 2)

Time: Baseline to Follow-up

Description: 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.

Measure: Number of Adverse Events (Combined Part 1 and Part 2)

Time: Baseline to Follow-up

Secondary Outcomes

Description: 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.

Measure: Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2)

Time: 14 days and 28 days

Description: 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.

Measure: Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2)

Time: 14 days and 28 days

Description: 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).

Measure: Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score)

Time: 14 days and 28 days

Description: 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.

Measure: Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2)

Time: 14 days and 28 days

2 A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of VX-770 in Subjects With Cystic Fibrosis and the G551D Mutation

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.

NCT00909532 Cystic Fibrosis Drug: Ivacaftor Drug: Placebo
MeSH: Cystic Fibrosis Fibrosis

Ivacaftor is a potent and selective CFTR potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. --- G551D --- --- R117H ---

Primary Outcomes

Description: Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.

Measure: Absolute Mean Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24

Time: baseline through 24 weeks

Secondary Outcomes

Description: Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.

Measure: Absolute Mean Change From Baseline in Percent Predicted FEV1 Through Week 48

Time: baseline through 48 weeks

Description: 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).

Measure: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled)

Time: baseline through 24 weeks and 48 weeks

Description: 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.

Measure: Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48

Time: baseline through 24 weeks and 48 weeks

Description: 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.

Measure: Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48

Time: baseline through 24 weeks and 48 weeks

Description: 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.

Measure: Absolute Change From Baseline in Weight at Week 24 and Week 48

Time: baseline to 24 weeks and 48 weeks

3 A Phase 3, 2-Part, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Pharmacokinetics, Efficacy and Safety of VX-770 in Subjects Aged 6 to 11 Years With Cystic Fibrosis and the G551D Mutation

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.

NCT00909727 Cystic Fibrosis Drug: Ivacaftor Drug: Placebo
MeSH: Cystic Fibrosis Fibrosis

Ivacaftor is a potent and selective potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. --- G551D --- --- R117H ---

Primary Outcomes

Description: Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.

Measure: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24

Time: baseline through 24 weeks

Secondary Outcomes

Description: Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.

Measure: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 48

Time: baseline through 48 weeks

Description: 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).

Measure: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Through Week 24 and Week 48 (Respiratory Domain Score, Children)

Time: baseline through 24 weeks and 48 weeks

Description: 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.

Measure: Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48

Time: baseline through 24 weeks and 48 weeks

Description: 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.

Measure: Absolute Change From Baseline in Weight at Week 24 and Week 48

Time: baseline to 24 weeks and 48 weeks

4 A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Safety and Efficacy of VX-770 in Subjects Aged 12 Years and Older With Cystic Fibrosis Who Are Homozygous for the F508del-CFTR Mutation

The purpose of this study was to evaluate the safety and efficacy of ivacaftor in participants with cystic fibrosis (CF) who were aged 12 years or older and were homozygous for the F508del-CF transmembrane conductance regulator (CFTR) mutation. 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 adenosine monophosphate (AMP)-dependent protein kinase A (PKA) activation.

NCT00953706 Cystic Fibrosis Drug: Ivacaftor Drug: Placebo
MeSH: Cystic Fibrosis Fibrosis

Ivacaftor is a potent and selective CFTR potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. --- G551D --- --- R117H ---

Primary Outcomes

Description: Spirometry (as measured by ppFEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. ppFEV1 (predicted for age, gender, and height) was calculated using the Knudson method.

Measure: Part A : Absolute Change From Part A Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 16

Time: Part A baseline through Week 16

Secondary Outcomes

Description: The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; Higher scores indicating fewer symptoms and better health-related quality of life.

Measure: Part A : Absolute Change From Part A Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 16

Time: Part A baseline through Week 16

Description: 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.

Measure: Part A : Absolute Change From Part A Baseline in Sweat Chloride Concentration Through Week 16

Time: Part A baseline through Week 16

Description: As malnutrition is common in participants 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.

Measure: Part A : Rate of Change From Baseline in Weight Through Week 16

Time: Part A baseline through Week 16

Description: ppFEV1 is defined in Outcome Measure 1.

Measure: Part B : Absolute Change From Part A and Part B Baseline in ppFEV1 Through Week 64

Time: Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64

Description: ppFEV1 is defined in Outcome Measure 1.

Measure: Part B : Rate of Change From Part A Baseline in ppFEV1 Through Week 64

Time: Part A baseline through Week 64

Description: ppFEV1 is defined in Outcome Measure 1.

Measure: Part B : Rate of Change From Part B Baseline in ppFEV1 Through Week 64

Time: Part B baseline through Week 64

Description: The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; Higher scores indicating fewer symptoms and better health-related quality of life.

Measure: Part B : Absolute Change From Part A and Part B Baseline in CFQ-R Respiratory Domain Score Through Week 64

Time: Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64

Description: 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.

Measure: Part B : Absolute Change From Part A and Part B Baseline in Sweat Chloride Concentration Through Week 64

Time: Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64

Description: 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.

Measure: Part B : Absolute Change From Part A and Part B Baseline in Weight Through Week 64

Time: Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64

Description: Pulmonary exacerbation was defined as new, or changed, antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of the following signs/symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees Celsius; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent (%); and radiographic changes indicative of pulmonary infection.

Measure: Part B : Number of Participants With Pulmonary Exacerbations

Time: Part B baseline through Week 64

Description: Pulmonary exacerbation was defined as new, or changed, antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of the following signs/symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees Celsius; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent (%); and radiographic changes indicative of pulmonary infection.

Measure: Part B : Number of Pulmonary Exacerbation Events

Time: Part B baseline through Week 64

Description: Pulmonary exacerbation was defined as new, or changed, antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of the following signs/symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees Celsius; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent (%); and radiographic changes indicative of pulmonary infection.

Measure: Part B : Number of Pulmonary Exacerbation Events Per Participant Per Year

Time: Part B baseline through Week 64

5 A Phase 2, Single-Blind, Placebo-Controlled Study to Evaluate the Effect of VX-770 on Hyperpolarized Helium-3 Magnetic Resonance Imaging in Subjects With Cystic Fibrosis, the G551D Mutation, and FEV1 ≥40% Predicted

Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The encoded protein, CFTR, is an epithelial chloride ion channel responsible for aiding in the regulation of salt and water absorption and secretion in various tissues. Although the disease affects multiple organs, the leading cause of mortality is the progressive loss of lung function. Obstruction of airways with thick mucus, chronic bacterial infection of the airways, and inflammatory response are all thought to play a role in causing lung damage. Through its function as a chloride channel, CFTR is believed to be integral in epithelial ion and water transport and hence, maintaining the normal hydration of lung secretions. VX-770 (ivacaftor) is a potent and selective potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR. Based on in vitro studies and pharmacologic, pharmacokinetic (PK), and safety profiles, VX-770 has been selected for clinical development as a possible treatment for patients with CF. Hyperpolarized noble gas magnetic resonance imaging (HG-MRI) is a promising new means of assessing lung function by direct imaging of certain non-radioactive isotopes of an inert noble gas, such as helium or xenon. Through this technique, high-resolution 3-dimensional images of lung ventilation can be obtained in both pediatric and adult patients during a single short breath-hold following inhalation of the gas. This is a 2-part study to evaluate the effect of VX-770 on hyperpolarized helium-3 magnetic resonance imaging (3He-MRI), and to evaluate the safety and efficacy of VX-770 in subjects aged 12 years and older with CF who have the G551D-CFTR mutation. Part A is a single-blind, placebo-controlled study that includes 4 weeks of VX-770 treatment and 4 weeks of placebo treatment. Part B is an open-label, 48 week study of long-term effect of VX 770 on hyperpolarized 3He-MRI.

NCT01161537 Cystic Fibrosis Drug: VX-770 Drug: Placebo
MeSH: Cystic Fibrosis Fibrosis

VX-770 (ivacaftor) is a potent and selective potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR. --- G551D --- --- R117H ---

Primary Outcomes

Description: Subjects inhaled hyperpolarized helium-3 (3He) gas mixed with nitrogen to make a total volume of approximately one-third forced vital capacity (FVC) to a maximum of 1 liter and hold their breath for 20 seconds or less. Rapid magnetic resonance imaging (MRI) was performed during inhalation/exhalation and/or breath-hold. Areas of decreased ventilation were observed as ventilation defects that are visualized as decreased (and/or absent) 3He intensity in 3He-MRI. The total ventilation defect was defined as the ratio of total ventilation defect volume (L) to total lung volume (L), expressed as a percentage. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in VX-770 treatment phase (Day 15 to 42).

Measure: Part A: Change From Baseline in Total Ventilation Defect Defined by Hyperpolarized Helium 3 Magnetic Resonance Imaging (3He-MRI) at Day 43

Time: Part A: Baseline (pre-dose Day 15), Day 43

Description: Subjects were asked to inhale hyperpolarized 3 He gas mixed with nitrogen to make a total volume of approximately one-third forced vital capacity (FVC) to a maximum of 1 liter and hold their breath for 20 seconds or less. Rapid MRI was performed during inhalation/exhalation and/or breath-hold. Areas of decreased ventilation were observed as ventilation defects that are visualized as decreased (and/or absent) 3He intensity in 3He MRI. The total ventilation defect was defined as the ratio of total ventilation defect volume (L) to total lung volume (L), expressed as a percentage. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in Part B (48 weeks).

Measure: Part B: Change From Baseline in Total Ventilation Defect Defined by Hyperpolarized Helium 3 Magnetic Resonance Imaging (3He-MRI) at Week 48

Time: Part B: Baseline (Day -1), Week 48

Secondary Outcomes

Description: AE: any adverse change from subject's baseline (pre-treatment) condition, including any adverse experience, abnormal recording/clinical laboratory assessment which occurs during course of study, whether it is considered related to study drug or not. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event. Related AEs includes all AEs for which the causality was either related to study drug or possibly related to study drug.

Measure: Part A: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Related AEs

Time: Part A: Day 1 up to Day 57

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Predicted FEV1 (for age, gender, and height) was calculated using the Knudson method. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in VX-770 treatment phase (Day 15 to 42).

Measure: Part A: Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Day 43

Time: Part A: Baseline (pre-dose Day 15), Day 43

Description: Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in VX-770 treatment phase (Day 15 to 42).

Measure: Part A: Absolute Change From Baseline in Sweat Chloride at Day 43

Time: Part A: Baseline (pre-dose Day 15), Day 43

Description: The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in VX-770 treatment phase (Day 15 to 42).

Measure: Part A: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score At Day 43

Time: Baseline (pre-dose Day 15), Day 43

Description: AE: any adverse change from subject's baseline (pre-treatment) condition, including any adverse experience, abnormal recording/clinical laboratory assessment which occurs during course of study, whether it is considered related to study drug or not. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event. Related AEs includes all AEs for which the causality was either related to study drug or possibly related to study drug.

Measure: Part B: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Related AEs

Time: Part B: Day 1 up to Week 48

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Predicted FEV1 (for age, gender, and height) was calculated using the Knudson method. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in Part B (48 weeks).

Measure: Part B: Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 48

Time: Part B: Baseline (Day -1), Week 48

Description: Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in Part B (48 weeks).

Measure: Part B: Absolute Change From Baseline in Sweat Chloride at Week 48

Time: Part B: Baseline (Day -1), Week 48

Description: The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug in Part B (48 weeks).

Measure: Part B: Absolute Change From Baseline in in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score At Week 48

Time: Part B: Baseline (Day -1), Week 48

6 G551D Observational Study (GOAL)-Expanded to Additional Genotypes and Extended for Long Term Follow up (GOAL-e2)

The goal of this research study is to collect blood and urine samples from people who have either the R117H type of CF or the non-G551D gating type of CF to be kept for future research.We will also use some of the collected blood to measure the number of neutrophils.

NCT01521338 Cystic Fibrosis
MeSH: Cystic Fibrosis Fibrosis

G551D Observational Study- Expanded to Additional Genotypes and Extended for Long Therm Follow up (GOAL-e2) The goal of this research study is to collect blood and urine samples from people who have either the R117H type of CF or the non-G551D gating type of CF to be kept for future research.We will also use some of the collected blood to measure the number of neutrophils. --- G551D --- --- R117H ---

2. For Cohort 2: R117H on at least 1 allele Any known or unknown mutation on the second allele except G551D 3. --- R117H ---

For Cohort 3: A Non-G551D gating mutation on one allele: (G178R, S549N, S549R, G551S,G970R, G1244E, S1251N, S1255P, G1349D) Any known or unknown mutation on the second allele except G551D OR R117H 3. Enrolled in the Cystic Fibrosis Foundation Patient Registry (with the exception of Canadian sites). --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G970R --- --- G1244E --- --- S1251N --- --- S1255P --- --- G1349D --- --- G551D --- --- R117H ---

Primary Outcomes

Description: Change in FEV1% predicted between Visit 1 and visit 5

Measure: Primary Endpoint for the Core Study

Time: Change in FEV1% predicted between Visit 1 and Visit 5

Secondary Outcomes

Description: Change in sweat chloride between Visit 1 and Visit 5.

Measure: Change in sweat chloride between Visit 1 and Visit 5.

Time: VISIT 1 AND VISIT 5

Description: Change in body weight between Visit 1 and Visit 5.

Measure: Change in body weight between Visit 1 and Visit 5.

Time: VISIT 1 AND VISIT 5

Other Outcomes

Description: The core and sub-studies will be linked so that associations between primary and secondary endpoints from each sub-study and clinical parameters (e.g., spirometry, weight, and sweat chloride) collected as part of the Core Study may be explored.

Measure: ASSOCIATION BETWEEN PRIMARY AND SECONDARY ENDPOINTS

Time: 1 YEAR

7 A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Ivacaftor in Subjects With Cystic Fibrosis Who Have the R117H-CFTR Mutation

The purpose of this study is to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis (CF) who have the R117H-CFTR mutation.

NCT01614457 Cystic Fibrosis Drug: Ivacaftor Drug: Placebo
MeSH: Cystic Fibrosis Fibrosis

A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Ivacaftor in Subjects With Cystic Fibrosis Who Have the R117H-CFTR Mutation. --- R117H ---

Study of Ivacaftor in Subjects With Cystic Fibrosis (CF) Who Have the R117H-CF Transmembrane Conductance Regulator (CFTR) Mutation (KONDUCT) The purpose of this study is to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis (CF) who have the R117H-CFTR mutation. --- R117H ---

Study of Ivacaftor in Subjects With Cystic Fibrosis (CF) Who Have the R117H-CF Transmembrane Conductance Regulator (CFTR) Mutation (KONDUCT) The purpose of this study is to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis (CF) who have the R117H-CFTR mutation. --- R117H --- --- R117H ---

SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event.. Inclusion Criteria: - Male or female with confirmed diagnosis of CF - Must have at least 1 allele of the R117H CFTR mutation - Percent predicted forced expiratory volume in 1 second (FEV1) 40 percent (%) to 90% (for subjects aged 12 years or older) or 40% to 105% (for subjects aged 6 to 11 years) predicted normal for age, sex, and height - 6 years of age or older - Minimum weight of 15 kilogram (kg) at screening - Females of childbearing potential must not be pregnant - Willing to comply with contraception requirements Exclusion Criteria: - CFTR gene mutation leading to CFTR channel with gating defect (that is, any 1 of the following mutations: G551D, G178R, G551S, S549N, S549R, G970R, G1244E, S1251N, S1255P, or G1349D) - History of any illness or condition that might confound the results of the study or pose an additional risk in administering ivacaftor to the subject - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before the first dose of study drug - Abnormal liver function, at screening, defined as greater than or equal to (>=) 3 time 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), total bilirubin - Colonization with organisms associated with a more rapid decline in pulmonary status (for example, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus) at screening - History of solid organ or hematological transplantation - History of alcohol, medication or illicit drug abuse within 1 year before the first dose of study drug - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days before screening - Any "non-CF-related" illness within 2 weeks before Day 1 (first dose of study drug). --- R117H ---

"Illness" was defined as an acute (serious or non-serious) condition (for example, gastroenteritis) - Use of any inhibitors or inducers of cytochrome (CYP) P450 3A Inclusion Criteria: - Male or female with confirmed diagnosis of CF - Must have at least 1 allele of the R117H CFTR mutation - Percent predicted forced expiratory volume in 1 second (FEV1) 40 percent (%) to 90% (for subjects aged 12 years or older) or 40% to 105% (for subjects aged 6 to 11 years) predicted normal for age, sex, and height - 6 years of age or older - Minimum weight of 15 kilogram (kg) at screening - Females of childbearing potential must not be pregnant - Willing to comply with contraception requirements Exclusion Criteria: - CFTR gene mutation leading to CFTR channel with gating defect (that is, any 1 of the following mutations: G551D, G178R, G551S, S549N, S549R, G970R, G1244E, S1251N, S1255P, or G1349D) - History of any illness or condition that might confound the results of the study or pose an additional risk in administering ivacaftor to the subject - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before the first dose of study drug - Abnormal liver function, at screening, defined as greater than or equal to (>=) 3 time 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), total bilirubin - Colonization with organisms associated with a more rapid decline in pulmonary status (for example, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus) at screening - History of solid organ or hematological transplantation - History of alcohol, medication or illicit drug abuse within 1 year before the first dose of study drug - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days before screening - Any "non-CF-related" illness within 2 weeks before Day 1 (first dose of study drug). --- R117H ---

Primary Outcomes

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male subjects 18 years and older and female subjects 16 years and older. The Wang standard was used for male subjects aged 6 to 17 years and for female subjects aged 6 to 15 years.

Measure: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24

Time: Baseline, Week 24

Secondary Outcomes

Description: BMI was defined as weight in kilogram (kg) divided by height in square meter (m^2).

Measure: Change From Baseline in Body Mass Index (BMI) at Week 24

Time: Baseline, Week 24

Description: Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride.

Measure: Change From Baseline in Sweat Chloride Through Week 24

Time: Baseline, Week 24

Description: The CFQ-R is a validated subject-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life

Measure: Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 24

Time: Baseline, Week 24

Description: Number of events (pulmonary exacerbation) during the pre-specified time intervals were reported. A subject without an exacerbation before withdrawal from the study was considered censored at the time of withdrawal, and a subject without an exacerbation who completes the study period was considered censored at the end of the analysis period.

Measure: Time to First Pulmonary Exacerbation

Time: Day 0 to 15, Day 16 to 56, Day 57 to 112, Day 113 to 168

Description: AE: any untoward medical occurrence, including clinically significant clinical laboratory assessments which occurs during course of study, whether it is considered related to study drug or not. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event.

Measure: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time: Baseline up to follow-up (3 to 4 weeks after last dose [last dose = Week 24])

8 A Pilot Study Testing the Effect of Ivacaftor on Lung Function in Subjects With Cystic Fibrosis, Residual CFTR Function, and FEV1 ≥40% Predicted

This study is a multiple within participant crossover study to evaluate the effect of ivacaftor on lung function in participants aged 12 years and older with cystic fibrosis (CF) who have phenotypic or molecular evidence of residual CF transmembrane conductance regulator (CFTR) function.

NCT01685801 Cystic Fibrosis Drug: Ivacaftor Drug: Placebo-matched-to-ivacaftor tablet
MeSH: Cystic Fibrosis Fibrosis

Data was to be reported by drug treatment for double-blind crossover period (Cycle 1 up to Washout Period 2) and open-label period.. Inclusion Criteria: - Male or female participants with confirmed diagnosis of CF - Clinical evidence of residual CFTR function based on any 1 of the following: 1) Clinically documented residual exocrine pancreatic function, 2) Sweat chloride value less than equal to (<=) 80 millimole per liter (mmol/L) at screening, or 3) Age of diagnosis greater than equal to (>=) 12 years and at least 1 copy of a CFTR mutation associated with residual CFTR function or defective mRNA splicing - FEV1 >= 40 percent (%) - 12 years of age or older - Willing to agree to meet the contraception requirements - Able to swallow tablets Exclusion Criteria: - A copy of any of the following CFTR mutations: G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, or G1349D - Unable to perform spirometry - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before Day 1 - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening Inclusion Criteria: - Male or female participants with confirmed diagnosis of CF - Clinical evidence of residual CFTR function based on any 1 of the following: 1) Clinically documented residual exocrine pancreatic function, 2) Sweat chloride value less than equal to (<=) 80 millimole per liter (mmol/L) at screening, or 3) Age of diagnosis greater than equal to (>=) 12 years and at least 1 copy of a CFTR mutation associated with residual CFTR function or defective mRNA splicing - FEV1 >= 40 percent (%) - 12 years of age or older - Willing to agree to meet the contraception requirements - Able to swallow tablets Exclusion Criteria: - A copy of any of the following CFTR mutations: G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, or G1349D - Unable to perform spirometry - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before Day 1 - Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within the 30 days prior to screening Cystic Fibrosis Cystic Fibrosis Fibrosis CFTR Mutations associated with residual function or defective messenger ribonucleic acid (mRNA) splicing include the following: R117H, E56K, P67L, D110E, D110H, R117C, R347H, R352Q, A455E, D579G, S945L, L206W, R1070W, F1074L, D1152H, S1235R, D1270N, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G970R --- --- G1244E --- --- S1251N --- --- S1255P --- --- G1349D --- --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G970R --- --- G1244E --- --- S1251N --- --- S1255P --- --- G1349D --- --- R117H ---

Primary Outcomes

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Data was to be reported for each cycle (Cycle 1 and Cycle 2) and as per drug treatment, for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).

Measure: Cycle 1 and Cycle 2: Absolute Change From Cycle Baseline In Percent Predicted Forced Expiratory Volume In 1 Second (FEV1) After 2 Weeks of Treatment

Time: Cycle 1 baseline, Cycle 1 Day 15 (for Cycle 1 reporting arms); Cycle 2 baseline, Cycle 2 Day 15 (for Cycle 2 reporting arms)

Secondary Outcomes

Description: 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 concentration of an inert gas to 1/40th of the starting value. Data was to be reported for each cycle (Cycle 1 and Cycle 2) and as per drug treatment. Data was to be reported for each cycle (Cycle 1 and Cycle 2) and as per drug treatment, for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).

Measure: Cycle 1 and Cycle 2: Absolute Change From Cycle Baseline In Lung Clearance Index (LCI) After 2 Weeks of Treatment

Time: Cycle 1 baseline, Cycle 1 Day 15 (for Cycle 1 reporting arms); Cycle 2 baseline, Cycle 2 Day 15 (for Cycle 2 reporting arms)

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Data was to be reported for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).

Measure: Open-label Period: Absolute Change From Open-label Baseline In Percent Predicted Forced Expiratory Volume In 1 Second (FEV1) at Day 57

Time: Open-label Baseline, Open-label Day 57

Description: 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 concentration of an inert gas to 1/40th of the starting value. Data was to be reported for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).

Measure: Open-label Period: Absolute Change From Open-label Baseline In Lung Clearance Index (LCI) at Day 57

Time: Open-label Baseline, Open-label Day 57

Description: Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride. Data was to be reported for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).

Measure: Open-label Period: Absolute Change From Study Baseline In Sweat Chloride at Day 57

Time: Study Baseline, Open-label Day 57

Description: Data was to be reported for overall participants and as per genotype (residual function mutation and mRNA splice site mutation).

Measure: Open-label Period: Absolute Change From Open-label Baseline In Weight at Day 57

Time: Open-label Baseline, Open-label Day 57

Description: Adverse events (AEs) that started (or increased in severity) from first dose of study drug through completion of Follow-up were considered TEAEs, with exception that if an AE started during a Washout Period and was beyond 14 days from last dose date of preceding cycle, AE was considered as a "Washout Period" AE, and hence not TEAE. A TEAE was attributed to treatment in which it started or to the treatment in second cycling period of previous Crossover Period if it started during a Washout Period. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Data was to be reported by drug treatment for double-blind crossover period (Cycle 1 up to Washout Period 2) and open-label period.

Measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Time: From first dose of study drug through completion of follow-up visit (up to 26 weeks)

9 Effects of Ivacaftor (Kalydeco) Treatment Upon Insulin and Incretin Secretion in Patients With Cystic Fibrosis

This study is aimed at better understanding the impact of ivacaftor upon insulin and incretin secretion and glucose tolerance in patients with Cystic Fibrosis with a glycine (G551D) mutation. Investigators hypothesize that treatment with ivacaftor improves insulin secretion in individuals with CF.

NCT02039986 Cystic Fibrosis Related Diabetes Cystic Fibrosis
MeSH: Cystic Fibrosis Fibrosis

To explore the composite relationships of insulin secretion, maximal insulin secretory capacity, and incretin secretion with secreted frizzled protein-4 levels and interleukin 1β levels.. Inclusion Criteria: - 6 yrs or older with cystic fibrosis - at least one G551D CFTR mutation or other non-G551D gating mutation, or residual function CFTR mutation such as, but not limited to, R117H mutation, for which ivacaftor is to be initiated. --- G551D --- --- G551D --- --- R117H ---

Inclusion Criteria: - 6 yrs or older with cystic fibrosis - at least one G551D CFTR mutation or other non-G551D gating mutation, or residual function CFTR mutation such as, but not limited to, R117H mutation, for which ivacaftor is to be initiated. --- G551D --- --- G551D --- --- R117H ---

Primary Outcomes

Description: To compare insulin secretion and maximal insulin secretory capacity prior to initiation of ivacaftor and after 16 weeks of ivacaftor treatment in subjects with CF and at least one G551D CFTR mutation, or other CFTR gating mutation, and to explore the impact of ivacaftor upon incretin secretion, incretin regulation of insulin secretion, and glucose excursion during a mixed meal tolerance test in CF.

Measure: Change from baseline in insulin secretion capacity at 16 weeks

Time: baseline and 16 weeks

Secondary Outcomes

Description: To explore the composite relationships of insulin secretion, maximal insulin secretory capacity, and incretin secretion with secreted frizzled protein-4 levels and interleukin 1β levels.

Measure: Composite change from baseline in relationships of insulin secretion and protein and interleukin levels at 16 weeks

Time: baseline and 16 weeks

10 A Study in US Cystic Fibrosis Patients With the R117H-CFTR Mutation to Confirm the Long-term Safety and Effectiveness of Kalydeco, Including Patients <18 Years of Age, Combining Data Captured in the Cystic Fibrosis Foundation Registry From an Interventional Cohort and a Non-Interventional Cohort

The purpose of this study is to confirm the long-term safety and effectiveness of Kalydeco® (ivacaftor) in US CF patients with the R117H-CFTR mutation <18 years of age and to describe the long-term safety and effectiveness of Kalydeco in CF patients with the R117H-CFTR mutation overall and in patients ≥18 years. The long-term safety and effectiveness of Kalydeco will be examined in totality through the evaluation of the primary outcome measures.

NCT02722057 Cystic Fibrosis
MeSH: Cystic Fibrosis Fibrosis

A Study in US Cystic Fibrosis Patients With the R117H-CFTR Mutation to Confirm the Long-term Safety and Effectiveness of Kalydeco, Including Patients <18 Years of Age, Combining Data Captured in the Cystic Fibrosis Foundation Registry From an Interventional Cohort and a Non-Interventional Cohort. --- R117H ---

A Study to Confirm the Long-term Safety and Effectiveness of Kalydeco in Patients With Cystic Fibrosis Who Have an R117H-CFTR Mutation, Including Pediatric Patients The purpose of this study is to confirm the long-term safety and effectiveness of Kalydeco® (ivacaftor) in US CF patients with the R117H-CFTR mutation <18 years of age and to describe the long-term safety and effectiveness of Kalydeco in CF patients with the R117H-CFTR mutation overall and in patients ≥18 years. --- R117H ---

A Study to Confirm the Long-term Safety and Effectiveness of Kalydeco in Patients With Cystic Fibrosis Who Have an R117H-CFTR Mutation, Including Pediatric Patients The purpose of this study is to confirm the long-term safety and effectiveness of Kalydeco® (ivacaftor) in US CF patients with the R117H-CFTR mutation <18 years of age and to describe the long-term safety and effectiveness of Kalydeco in CF patients with the R117H-CFTR mutation overall and in patients ≥18 years. --- R117H --- --- R117H ---

A Study to Confirm the Long-term Safety and Effectiveness of Kalydeco in Patients With Cystic Fibrosis Who Have an R117H-CFTR Mutation, Including Pediatric Patients The purpose of this study is to confirm the long-term safety and effectiveness of Kalydeco® (ivacaftor) in US CF patients with the R117H-CFTR mutation <18 years of age and to describe the long-term safety and effectiveness of Kalydeco in CF patients with the R117H-CFTR mutation overall and in patients ≥18 years. --- R117H --- --- R117H --- --- R117H ---

Inclusion Criteria: Non Interventional Cohort - Male or female with confirmed diagnosis of CF - Must have at least 1 allele of the R117H-CFTR mutation - Enrolled in the US CFF Patient Registry - With a record of Kalydeco treatment initiation from 01 January 2015 through 31 December 2016 Historical Cohort - Patients with CF in the CFF Patient Registry as of 01 January 2009 - Must have at least 1 allele of the R117H-CFTR mutation - Patients with no evidence of any prior Kalydeco exposure Inclusion Criteria: Non Interventional Cohort - Male or female with confirmed diagnosis of CF - Must have at least 1 allele of the R117H-CFTR mutation - Enrolled in the US CFF Patient Registry - With a record of Kalydeco treatment initiation from 01 January 2015 through 31 December 2016 Historical Cohort - Patients with CF in the CFF Patient Registry as of 01 January 2009 - Must have at least 1 allele of the R117H-CFTR mutation - Patients with no evidence of any prior Kalydeco exposure Cystic Fibrosis Cystic Fibrosis Fibrosis Patient follow-up (i.e., collection of outcomes data after treatment initiation) in the Non-Interventional Cohort will be at least 36 months. --- R117H ---

Inclusion Criteria: Non Interventional Cohort - Male or female with confirmed diagnosis of CF - Must have at least 1 allele of the R117H-CFTR mutation - Enrolled in the US CFF Patient Registry - With a record of Kalydeco treatment initiation from 01 January 2015 through 31 December 2016 Historical Cohort - Patients with CF in the CFF Patient Registry as of 01 January 2009 - Must have at least 1 allele of the R117H-CFTR mutation - Patients with no evidence of any prior Kalydeco exposure Inclusion Criteria: Non Interventional Cohort - Male or female with confirmed diagnosis of CF - Must have at least 1 allele of the R117H-CFTR mutation - Enrolled in the US CFF Patient Registry - With a record of Kalydeco treatment initiation from 01 January 2015 through 31 December 2016 Historical Cohort - Patients with CF in the CFF Patient Registry as of 01 January 2009 - Must have at least 1 allele of the R117H-CFTR mutation - Patients with no evidence of any prior Kalydeco exposure Cystic Fibrosis Cystic Fibrosis Fibrosis Patient follow-up (i.e., collection of outcomes data after treatment initiation) in the Non-Interventional Cohort will be at least 36 months. --- R117H --- --- R117H ---

Inclusion Criteria: Non Interventional Cohort - Male or female with confirmed diagnosis of CF - Must have at least 1 allele of the R117H-CFTR mutation - Enrolled in the US CFF Patient Registry - With a record of Kalydeco treatment initiation from 01 January 2015 through 31 December 2016 Historical Cohort - Patients with CF in the CFF Patient Registry as of 01 January 2009 - Must have at least 1 allele of the R117H-CFTR mutation - Patients with no evidence of any prior Kalydeco exposure Inclusion Criteria: Non Interventional Cohort - Male or female with confirmed diagnosis of CF - Must have at least 1 allele of the R117H-CFTR mutation - Enrolled in the US CFF Patient Registry - With a record of Kalydeco treatment initiation from 01 January 2015 through 31 December 2016 Historical Cohort - Patients with CF in the CFF Patient Registry as of 01 January 2009 - Must have at least 1 allele of the R117H-CFTR mutation - Patients with no evidence of any prior Kalydeco exposure Cystic Fibrosis Cystic Fibrosis Fibrosis Patient follow-up (i.e., collection of outcomes data after treatment initiation) in the Non-Interventional Cohort will be at least 36 months. --- R117H --- --- R117H --- --- R117H ---

Inclusion Criteria: Non Interventional Cohort - Male or female with confirmed diagnosis of CF - Must have at least 1 allele of the R117H-CFTR mutation - Enrolled in the US CFF Patient Registry - With a record of Kalydeco treatment initiation from 01 January 2015 through 31 December 2016 Historical Cohort - Patients with CF in the CFF Patient Registry as of 01 January 2009 - Must have at least 1 allele of the R117H-CFTR mutation - Patients with no evidence of any prior Kalydeco exposure Inclusion Criteria: Non Interventional Cohort - Male or female with confirmed diagnosis of CF - Must have at least 1 allele of the R117H-CFTR mutation - Enrolled in the US CFF Patient Registry - With a record of Kalydeco treatment initiation from 01 January 2015 through 31 December 2016 Historical Cohort - Patients with CF in the CFF Patient Registry as of 01 January 2009 - Must have at least 1 allele of the R117H-CFTR mutation - Patients with no evidence of any prior Kalydeco exposure Cystic Fibrosis Cystic Fibrosis Fibrosis Patient follow-up (i.e., collection of outcomes data after treatment initiation) in the Non-Interventional Cohort will be at least 36 months. --- R117H --- --- R117H --- --- R117H --- --- R117H ---

Primary Outcomes

Description: Spirometry will be performed according to the standard procedure at each site, and FEV1 values as recorded in the registry will be evaluated. All descriptive and summary data collected for FEV1 will be repeated for FVC

Measure: Lung function measurements (percent predicted forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC])

Time: 36 Months

Description: Pulmonary exacerbation data will be collected as recorded in the registry.

Measure: Pulmonary exacerbations, use of IV antibiotics

Time: 36 Months

Description: Height and weight measurements as recorded in the registry will be evaluated. BMI, BMI-for-age z-score, and weight-for-age z-score will be derived

Measure: Nutritional parameters (body mass index [BMI], BMI-for-age z-score, weight, and weight-for-age z-score)

Time: 36 Months

Description: Death will be collected from the registry database.

Measure: Death or transplantation

Time: 36 months

Description: Hospitalizations will be collected from the registry database.

Measure: Hospitalizations

Time: 36 Months

Description: Information for the above shown CF-related complications as recorded in the registry will be evaluated

Measure: Selected Complications (Symptomatic sinus disease, Pulmonary complications, CF-related diabetes (CFRD) and distal intestinal obstruction syndrome (DIOS), Hepatobiliary complications, Pancreatitis)

Time: 36 Months

Description: Data on microorganisms as recorded in the registry will be evaluated

Measure: Select pulmonary microorganisms (e.g., P. aeruginosa, S. aureus)

Time: 36 Months

11 Prospective Study of the Phenotypic Expression of Cystic Fibrosis (CF) Screened Positive Newborns With an Atypical Form of CF (DPAM)

The strategy of neonatal screening for Cystic Fibrosis in France relies on Immuno Reactive Trypsinogen (IRT) at day 3/DNA analysis with a CF Elucigen 30 mutations kit/ IRT safety-net at day 21. This strategy has significantly improved the performance of CF neonatal screening (NNS) in terms of positive predictive value and sensitivity but revealed new difficulties. Up to 85-90% of CF patients detected through the NNS program has a classical CF form with a positive sweat test and 2, 1 or no CF causing mutations but the remainder has either 2 CFTR mutations with at least one non-CF causing mutation and a sweat test <60mmol/L or 1, 0 CFTR mutation and an intermediate sweat test value ≥ 30 et < 60mmol/L raising a diagnosis and prognosis dilemma. Meanwhile the vast majority of these cohorts will remain asymptomatic over time, some will develop symptoms prompting clinicians to maintain a rigorous surveillance for the entire atypical cohort, whose modalities vary a lot among centers and countries. This prospective multicenter study with a standardized assessment of a matched cohort with "atypical" CF versus "classical" CF from 6 years of age (60-65 cases in each cohort) is aimed at evaluating pulmonary and nutritional status to, better define the best monitoring follow-up, therapeutic management and familial genetic counseling.

NCT02869932 Cystic Fibrosis Radiation: Lung CT scan
MeSH: Cystic Fibrosis Fibrosis

Inclusion Criteria: - Atypical CF cohort: children identified trough newborn screening on a hypertrypsinemia, who are older than 6 years of age at the time of inclusion and who carry a) 2 CFTR gene mutations of the CF30 kit with at least one R117H whatever the value of the sweat test or b) 2 CFTR gene mutations of the CF30 kit with a sweat test chloride < 60mmol/L or c) 1 or 0 mutation in the CF30 kit with a sweat test ≥ 30 and <60mmol/L and identification of additional mutations by comprehensive screening of the gene - Classical CF cohort: children identified by newborn screening on a hypertrypsinemia, who are matched with an Atypical CF by age and sex if possible and who were diagnosed with a classical CF based on a sweat test > 60 mmol/ L with 0, 1 or 2 CF causing gene mutations. --- R117H ---

Primary Outcomes

Description: Score Brody 2 (0 to 270) mesured by Lung CT scan without injection

Measure: Comparison of Score Brody 2 (0 to 270) between the atypical and classical CF cohorts

Time: 1 day

Secondary Outcomes

Description: Wisconsin and Brasfield scores will be mesured by Chest X-ray

Measure: Comparison of Wisconsin and Brasfield scores between the atypical and classical CF cohorts

Time: 1 day

12 A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Efficacy of Lumacaftor/Ivacaftor Combination Therapy in Subjects With Cystic Fibrosis Who Have an A455E-CFTR Mutation

This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter, crossover study that will evaluate the efficacy of LUM/IVA in subjects with CF 12 years of age and older who have at least one A455E mutation.

NCT03061331 Cystic Fibrosis Drug: LUM/IVA Drug: Placebo
MeSH: Cystic Fibrosis Fibrosis

- A G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H mutation on at least one CFTR allele. --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- R117H ---

Primary Outcomes

Description: FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

Measure: Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 8

Time: Study Baseline, Through Week 8

13 A Randomized, Double-blind, Placebo-controlled, Crossover Study to Evaluate the Efficacy of Ivacaftor in Subjects With Cystic Fibrosis Who Are 6 Years of Age and Older and Have Either a 3849 + 10KB C→T or D1152H-CFTR Mutation

This study will evaluate the efficacy of ivacaftor treatment in subjects with CF 6 years of age and older who have a 3849 + 10KB C→T or D1152H CFTR mutation.

NCT03068312 Cystic Fibrosis Drug: Ivacaftor Drug: Placebo
MeSH: Cystic Fibrosis Fibrosis

Exclusion Criteria: - A G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H mutation. --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- R117H ---

Primary Outcomes

Description: LCI2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value.

Measure: Change in Lung Clearance Index 2.5 (LCI2.5)

Time: From baseline through 8 weeks

14 Evaluation of the Primary Human Nasal Epithelial Cell Culture Model in the Context of Personalized Therapy in Cystic Fibrosis

characterization of CFTR function and expression in nasal primary cells collected from patients with cystic fibrosis in comparison to their parents, healthy heterozygotes and healthy controls

NCT03652090 Cystic Fibrosis Procedure: cell sampling
MeSH: Cystic Fibrosis Fibrosis

Apical CFTR staining was assessed semi quantitatively as the percentage of cells displaying apical staining multiplied by the average corrected apical fluorescence 32.. Inclusion Criteria: - patients with Cystic Fibrosis with 2 mutations in CFTR - healthy heterozygotes with 1 mutation in CFTR - healthy subjects with no familial history of Cystic Fibrosis and no symptoms suggesting Cystic Fibrosis Exclusion Criteria: - smoking Inclusion Criteria: - patients with Cystic Fibrosis with 2 mutations in CFTR - healthy heterozygotes with 1 mutation in CFTR - healthy subjects with no familial history of Cystic Fibrosis and no symptoms suggesting Cystic Fibrosis Exclusion Criteria: - smoking Cystic Fibrosis Cystic Fibrosis Fibrosis 3 groups of subjects are enrolled CF subjects according to their genotypes (aiming to enroll patients carrying 2 CF causing mutations with no CFTR expression/function, and patients carrying at least 1 mutation with residual function, such R117H) Parents or siblings of the CF subjects, as healthy hétérozygotes healthy controls All these subjects experience nasal brushings. --- R117H ---

Primary Outcomes

Description: The short-circuit-current (Isc) was measured under voltage clamp conditions. Inhibitors and activators were added after stabilization of baseline Isc. The sum of the change after Forskolin (Forskolin)/IBMx and VX-770 (∆IscFsk/IBMx+VX-770) served as an index of CFTR function.

Measure: variation in the short-circuit-current (Isc) after Forskolin (Forskolin)/IBMx and VX-770 (∆IscFsk/IBMx+VX-770)

Time: 1 day

Secondary Outcomes

Description: CFTR immuno-detection was performed as previously described 31. Apical CFTR staining was assessed semi quantitatively as the percentage of cells displaying apical staining multiplied by the average corrected apical fluorescence 32.

Measure: percentage of cells displaying apical staining

Time: 1 day

15 Nutritional Impact of Ivacaftor Treatment in 6 Month to 2 Year Old Children With CF Gating Mutations

The purpose of this research study is to determine the effects of clinically prescribed ivacaftor treatment on 6-24 month old children with CF and gating mutations on sleeping energy expenditure, growth status and gut health and function.

NCT03783286 Cystic Fibrosis Drug: Ivacaftor
MeSH: Cystic Fibrosis

Each value will be used to calculate the growth velocity percentile of the subjects over the course of 12 weeks on ivacaftor treatment compared to baseline.. Inclusion Criteria: - Cystic fibrosis with at least one CFTR gating mutation (E56K, G178R, S549R, S977F, F1074L, 2789+5G→A,P67L, E193K, G551D, F1052V, D1152H, 3272-26A→G, R74W, L206W, G551S, K1060T, G1244E, 3849+10kbC→T, D110E, R347H, D579G, A1067T, S1251N, D110H, R352Q, 711+3A→G, G1069R, S1255P, R117C, A455E, E831X, R1070Q, D1270N, R117H, S549N, S945L, R1070W, G1349D) approved for treatment - Age: 6-24 months of age - In their usual state of good health - A clinical decision has been made for subject to begin ivacaftor treatment - Family committed to the 4 to 6 month study protocol with visits to CHOP that will last 2 or 3 days for the baseline visit (Visit 1) prior to ivacaftor and the 12 week visit (Visit 3) after clinically prescribed ivacaftor treatment has begun, and will last 2 days for the 6 week visit (Visit 2) after ivacaftor treatment has begun. --- E56K --- --- G178R --- --- S549R --- --- S977F --- --- F1074L --- --- P67L --- --- E193K --- --- G551D --- --- F1052V --- --- D1152H --- --- R74W --- --- L206W --- --- G551S --- --- K1060T --- --- G1244E --- --- D110E --- --- R347H --- --- D579G --- --- A1067T --- --- S1251N --- --- D110H --- --- R352Q --- --- G1069R --- --- S1255P --- --- R117C --- --- A455E --- --- R1070Q --- --- D1270N --- --- R117H ---

Exclusion Criteria: - On parenteral nutrition - Use of any medications which are as inhibitors or inducers of cytochrome P450 (CYP) 3A - Liver function tests elevated above 3x the reference range for age and sex - Other illness affecting growth or nutritional status - Other contraindications described for ivacaftor therapy Inclusion Criteria: - Cystic fibrosis with at least one CFTR gating mutation (E56K, G178R, S549R, S977F, F1074L, 2789+5G→A,P67L, E193K, G551D, F1052V, D1152H, 3272-26A→G, R74W, L206W, G551S, K1060T, G1244E, 3849+10kbC→T, D110E, R347H, D579G, A1067T, S1251N, D110H, R352Q, 711+3A→G, G1069R, S1255P, R117C, A455E, E831X, R1070Q, D1270N, R117H, S549N, S945L, R1070W, G1349D) approved for treatment - Age: 6-24 months of age - In their usual state of good health - A clinical decision has been made for subject to begin ivacaftor treatment - Family committed to the 4 to 6 month study protocol with visits to CHOP that will last 2 or 3 days for the baseline visit (Visit 1) prior to ivacaftor and the 12 week visit (Visit 3) after clinically prescribed ivacaftor treatment has begun, and will last 2 days for the 6 week visit (Visit 2) after ivacaftor treatment has begun. --- E56K --- --- G178R --- --- S549R --- --- S977F --- --- F1074L --- --- P67L --- --- E193K --- --- G551D --- --- F1052V --- --- D1152H --- --- R74W --- --- L206W --- --- G551S --- --- K1060T --- --- G1244E --- --- D110E --- --- R347H --- --- D579G --- --- A1067T --- --- S1251N --- --- D110H --- --- R352Q --- --- G1069R --- --- S1255P --- --- R117C --- --- A455E --- --- R1070Q --- --- D1270N --- --- R117H ---

Primary Outcomes

Description: Investigators will examine the effects of 12 weeks of Ivacaftor treatment on subject's SEE. Using indirect calorimetry, SEE will be assessed using a computerized metabolic cart Vmax ENCORE at each protocol visit while the child is asleep. SEE will be assessed in the morning if possible and careful note of previous feeding of the child, including the time of day, amount of food, and feeding interval prior to test

Measure: Sleeping Energy Expenditure

Time: 12 Weeks

Description: Investigators will examine the effects of 12 weeks of Ivacaftor treatment on subject's BMI. Investigators will compare the results to BMI Z scores over 12 weeks compared to baseline.

Measure: Anthropometric Assessment

Time: 12 Weeks

Secondary Outcomes

Description: Investigators will examine the effects of 12 weeks of Ivacaftor treatment on subject's pancreatic function. Pancreatic function will be assessed at two visits by obtaining spot stool samples with fecal elastase 1. The concentration of fecal elastase I is indicative of pancreatic function.

Measure: Fecal Elastase I/Pancreatic Function

Time: 12 Weeks

Description: Investigators will examine the effects of 12 weeks of Ivacaftor treatment on subject's gut health and function. Spot stool samples will be obtained to determine fecal calprotectin, a marker for gut inflammation.

Measure: Fecal Calprotectin/Gut Inflammation

Time: 12 Weeks

Description: Investigators will examine the effects of 12 weeks of Ivacaftor treatment on subject's dietary fat absorption. A total plasma fatty acid panel will be assessed to measure the change in status of 22 fatty acids, the concentration of plasma fatty acids is indicative of dietary fat absorption.

Measure: Plasma Total Fatty Acids:

Time: 4 to 6 months

Other Outcomes

Description: Three day weighed food record will be obtained and to determine changes in dietary caloric intake and micro and macronutrient intake over the course of 12 weeks on ivacaftor treatment. The weighed food in grams will be used to determine the calories consumed, as well as calories from fat. The caloric intake will be used to determine micro and macro nutrient intake.

Measure: Dietary Intake

Time: 12 Weeks

Description: Investigators will examine the changes in serum vitamin A, E, D and K concentrations after 12 weeks of Ivacaftor treatment. Additionally, investigators will examine the changes in total serum bile acids concentration and 14 bile acid species. Additionally, serum calprotectin will be obtained as a marker of lung and gut inflammation.

Measure: Serum fat soluble vitamins A, D, E and K, bile acids, and serum calprotectin

Time: 12 Weeks

Description: Investigators will measure body composition to determine muscle and fat store changes over the course of 12 weeks on ivacaftor treatment compared to baseline.

Measure: Muscle/Fat Stores

Time: 12 Weeks

Description: Investigators will observe the changes in growth status/growth velocity. This will be assessed amongst three different measurements- length (cm), weight (kg) and head circumference (cm). Each value will be used to calculate the growth velocity percentile of the subjects over the course of 12 weeks on ivacaftor treatment compared to baseline.

Measure: Growth Status/Growth Velocity

Time: 12 Weeks

16 Response to CFTR-modulators in Intestinal Organoids of Patients With CF Having at Least One R334W Mutation

In contrary to what is seen in FRT cells, rectal organoids of patients with a R334W mutation do respond to CFTR modulators ivacaftor and lumacaftor. The present study will investigate the response to modulators in organoids of 30 patients with CF and a R334W mutation, to allow further stratificaton for a future clinical trial assessing the clinical effect of ivacaftor/tezacaftor in patients with CF and a R334W mutation.

NCT04254705 Cystic Fibrosis Procedure: Rectal Biopsy
MeSH: Cystic Fibrosis

Exclusion Criteria: - A potential subject who meets any of the following criteria will be excluded from participation: 1. Subject has one of the following CFTR-mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, R117H, P67L, R117C, L206W, R352Q, A455E, D579G, 711+3A>G, S945L, S977F, R1070W, D1152H, 2789+5G>A, 3272 26A>G, 3849+10kbC>T 2. A history of hemorrhoids and recent rectal bleeding 3. FEV1 above 90% predicted or below 30% predicted during stable disease 4. History of lung transplantation. --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- R117H ---

Primary Outcomes

Description: Response to tezacaftor+ivacaftor in the Forskolin Induced Swelling (FIS) assay in rectal organoids

Measure: Response to CFTR-modulator in Intestinal Organoids: Increase in Forskolin induced swelling by addition of tezacaftor+ivacaftor after stimulation with Forskolin (0.8 µmol/L)

Time: At study completion (when rectal biopsy is performed or when organoids are retrieved from the biobank and FIS has been performed), an average of 2 months


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