SNPMiner Trials by Shray Alag


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Report for Mutation S1255P

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 17 clinical trials

Clinical Trials


1 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

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 ---

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

2 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

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 --- --- G551D --- --- G178R --- --- G551S --- --- S549N --- --- S549R --- --- G970R --- --- G1244E --- --- S1251N --- --- S1255P ---

"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 --- --- G551D --- --- G178R --- --- G551S --- --- S549N --- --- S549R --- --- G970R --- --- G1244E --- --- S1251N --- --- S1255P ---

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])

3 A Phase 3, Two-Part, Randomized, Double-Blind, Placebo-Controlled, Crossover Study With an Open-Label Period to Evaluate the Efficacy and Safety of Ivacaftor in Subjects With Cystic Fibrosis Who Have a Non-G551D CFTR Gating Mutation

The purpose of this study is to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis (CF) who have a non-G551D cystic fibrosis transmembrane regulator (CFTR) gating mutation (any one of the following CFTR mutations: G178R, G551S, S549N, S549R, G970R, G1244E, S1251N, S1255P, or G1349D).

NCT01614470 Cystic Fibrosis Drug: Ivacaftor Drug: Placebo
MeSH: Cystic Fibrosis Fibrosis

Study of Ivacaftor in Subjects With Cystic Fibrosis (CF) Who Have a Non-G551D CF Transmembrane Conductance Regulator (CFTR) Gating Mutation The purpose of this study is to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis (CF) who have a non-G551D cystic fibrosis transmembrane regulator (CFTR) gating mutation (any one of the following CFTR mutations: G178R, G551S, S549N, S549R, G970R, G1244E, S1251N, S1255P, or G1349D). --- G551D --- --- G551D --- --- G178R --- --- G551S --- --- S549N --- --- S549R --- --- G970R --- --- G1244E --- --- S1251N --- --- S1255P ---

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 - At least 1 allele of the following CFTR gating mutations: G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, G1349D - Percent predicted forced expiratory volume in 1 second (FEV1) greater than or equal to (>=) 40 percent (%) 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: - G551D-CFTR mutation on at least 1 allele - 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 - 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 - Use of inhaled hypertonic saline treatment - Use of any inhibitors or inducers of cytochrome (CYP) P450 3A - Evidence of cataract or lens opacity at screening Inclusion Criteria: - Male or female with confirmed diagnosis of CF - At least 1 allele of the following CFTR gating mutations: G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, G1349D - Percent predicted forced expiratory volume in 1 second (FEV1) greater than or equal to (>=) 40 percent (%) 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: - G551D-CFTR mutation on at least 1 allele - 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 - 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 - Use of inhaled hypertonic saline treatment - Use of any inhibitors or inducers of cytochrome (CYP) P450 3A - Evidence of cataract or lens opacity at screening Cystic Fibrosis Cystic Fibrosis Fibrosis Ivacaftor is the first CFTR modulator to show an improvement in CFTR function and clinical benefit in subjects with CF. Results from Phase 3 studies (VX08-770-102 [Study 102] [NCT00909532] and VX08-770-103 [Study 103] [NCT00909727]) showed that ivacaftor is effective in the treatment of subjects with CF who have the G551D-CFTR mutation, as evidenced by sustained improvements in CFTR channel function (measured by reduction in sweat chloride concentration) and corresponding substantial, durable improvements in lung function, pulmonary exacerbations, respiratory symptoms, and weight gain. --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G970R --- --- G1244E --- --- S1251N --- --- S1255P ---

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 - At least 1 allele of the following CFTR gating mutations: G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, G1349D - Percent predicted forced expiratory volume in 1 second (FEV1) greater than or equal to (>=) 40 percent (%) 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: - G551D-CFTR mutation on at least 1 allele - 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 - 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 - Use of inhaled hypertonic saline treatment - Use of any inhibitors or inducers of cytochrome (CYP) P450 3A - Evidence of cataract or lens opacity at screening Inclusion Criteria: - Male or female with confirmed diagnosis of CF - At least 1 allele of the following CFTR gating mutations: G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, G1349D - Percent predicted forced expiratory volume in 1 second (FEV1) greater than or equal to (>=) 40 percent (%) 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: - G551D-CFTR mutation on at least 1 allele - 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 - 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 - Use of inhaled hypertonic saline treatment - Use of any inhibitors or inducers of cytochrome (CYP) P450 3A - Evidence of cataract or lens opacity at screening Cystic Fibrosis Cystic Fibrosis Fibrosis Ivacaftor is the first CFTR modulator to show an improvement in CFTR function and clinical benefit in subjects with CF. Results from Phase 3 studies (VX08-770-102 [Study 102] [NCT00909532] and VX08-770-103 [Study 103] [NCT00909727]) showed that ivacaftor is effective in the treatment of subjects with CF who have the G551D-CFTR mutation, as evidenced by sustained improvements in CFTR channel function (measured by reduction in sweat chloride concentration) and corresponding substantial, durable improvements in lung function, pulmonary exacerbations, respiratory symptoms, and weight gain. --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G970R --- --- G1244E --- --- S1251N --- --- S1255P --- --- G1349D --- --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G970R --- --- G1244E --- --- S1251N --- --- S1255P ---

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. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during study Part 1.

Measure: Part 1: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8

Time: Part 1: Baseline (pre-dose Day 1), Week 8

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. Absolute change in percent predicted FEV1 over 24 weeks of ivacaftor treatment (from Week 12 [Part 1: Treatment Period 2] through Week 36 [Part 2]) was reported for subjects who received ivacaftor in Part 1: Treatment Period 2, as per planned analysis. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during Part 1: Treatment Period 2.

Measure: Part 2: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through 24 Weeks of Treatment (Week 36 Visit)

Time: Baseline (pre-dose Week 12), Week 36

Secondary Outcomes

Description: BMI was defined as weight in kilogram (kg) divided by height in meters^2 (m^2). Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during study Part 1.

Measure: Part 1: Change From Baseline in Body Mass Index (BMI) at Week 8

Time: Part 1: Baseline (pre-dose Day 1), Week 8

Description: BMI was defined as weight in kg divided by height in m^2. Change in BMI over 24 weeks of ivacaftor treatment (from Week 12 [Part 1: Treatment Period 2] through Week 36 [Part 2]) was reported for subjects who received ivacaftor in Part 1: Treatment Period 2 as per planned analysis. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during Part 1: Treatment Period 2.

Measure: Part 2: Change From Baseline in Body Mass Index (BMI) at 24 Weeks of Treatment (Week 36 Visit)

Time: Baseline (pre-dose Week 12), Week 36

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 during study Part 1.

Measure: Part 1: Change From Baseline in Sweat Chloride Through Week 8

Time: Part 1: Baseline (pre-dose Day 1), Week 8

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. Change in sweat chloride over 24 weeks of ivacaftor treatment (from Week 12 [Part 1: Treatment Period 2] through Week 36 [Part 2]) was reported for subjects who received ivacaftor in Part 1: Treatment Period 2 as per planned analysis. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during Part 1: Treatment Period 2.

Measure: Part 2: Change From Baseline in Sweat Chloride Through 24 Weeks of Treatment (Week 36 Visit)

Time: Baseline (pre-dose Week 12), Week 36

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 during study Part 1.

Measure: Part 1: Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 8

Time: Part 1: Baseline (pre-dose Day 1), Week 8

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. Change in CFQ-R respiratory domain score over 24 weeks of ivacaftor treatment (from Week 12 [Part 1: Treatment Period 2] through Week 36 [Part 2]) was reported for subjects who received ivacaftor in Part 1: Treatment Period 2 as per planned analysis. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during Part 1: Treatment Period 2.

Measure: Part 2: Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through 24 Weeks of Treatment (Week 36 Visit)

Time: Baseline (pre-dose Week 12), Week 36

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.

Measure: Part 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time: Part 1: From signing of informed consent up to Week 20

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.

Measure: Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time: Part 2: Week 20 up to Week 40

4 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 ---

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 ---

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)

5 Observational Study of Outcomes in Cystic Fibrosis Patients With Selected Gating Mutations on a CFTR Allele (The VOCAL Study)

To describe the effectiveness of Kalydeco® treatment in patients with cystic fibrosis (CF) who have 1 of 8 non G551D gating CFTR mutations (G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D).

NCT02445053 Cystic Fibrosis Drug: ivacaftor
MeSH: Cystic Fibrosis Fibrosis

Observational Study of Outcomes in Cystic Fibrosis Patients With Selected Gating Mutations on a CFTR Allele (The VOCAL Study) To describe the effectiveness of Kalydeco® treatment in patients with cystic fibrosis (CF) who have 1 of 8 non G551D gating CFTR mutations (G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D). --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G1244E --- --- S1251N --- --- S1255P ---

Inclusion Criteria: - Male or female with confirmed diagnosis of CF16 - At least 1 allele with 1 of the following CFTR mutations: G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D - Six years of age or older on the date of signed (Informed Consent Form) ICF, and where appropriate, date of assent - Signed ICFs and, where appropriate, signed Assent Form - Able to understand the study requirements and comply with study data collection procedures Exclusion Criteria: - Previously exposed to Kalydeco, except currently treated patients who started Kalydeco treatment within 6 months of enrollment - Currently enrolled in a Kalydeco interventional study or other interventional therapeutic clinical study directed at CFTR modulation - History of organ transplantation Inclusion Criteria: - Male or female with confirmed diagnosis of CF16 - At least 1 allele with 1 of the following CFTR mutations: G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D - Six years of age or older on the date of signed (Informed Consent Form) ICF, and where appropriate, date of assent - Signed ICFs and, where appropriate, signed Assent Form - Able to understand the study requirements and comply with study data collection procedures Exclusion Criteria: - Previously exposed to Kalydeco, except currently treated patients who started Kalydeco treatment within 6 months of enrollment - Currently enrolled in a Kalydeco interventional study or other interventional therapeutic clinical study directed at CFTR modulation - History of organ transplantation Cystic Fibrosis Cystic Fibrosis Fibrosis null --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G1244E --- --- S1251N --- --- S1255P ---

Inclusion Criteria: - Male or female with confirmed diagnosis of CF16 - At least 1 allele with 1 of the following CFTR mutations: G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D - Six years of age or older on the date of signed (Informed Consent Form) ICF, and where appropriate, date of assent - Signed ICFs and, where appropriate, signed Assent Form - Able to understand the study requirements and comply with study data collection procedures Exclusion Criteria: - Previously exposed to Kalydeco, except currently treated patients who started Kalydeco treatment within 6 months of enrollment - Currently enrolled in a Kalydeco interventional study or other interventional therapeutic clinical study directed at CFTR modulation - History of organ transplantation Inclusion Criteria: - Male or female with confirmed diagnosis of CF16 - At least 1 allele with 1 of the following CFTR mutations: G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D - Six years of age or older on the date of signed (Informed Consent Form) ICF, and where appropriate, date of assent - Signed ICFs and, where appropriate, signed Assent Form - Able to understand the study requirements and comply with study data collection procedures Exclusion Criteria: - Previously exposed to Kalydeco, except currently treated patients who started Kalydeco treatment within 6 months of enrollment - Currently enrolled in a Kalydeco interventional study or other interventional therapeutic clinical study directed at CFTR modulation - History of organ transplantation Cystic Fibrosis Cystic Fibrosis Fibrosis null --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G1244E --- --- S1251N --- --- S1255P --- --- G1349D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G1244E --- --- S1251N --- --- S1255P ---

Primary Outcomes

Measure: Pulmonary exacerbations - Number of pulmonary exacerbations and duration of treatment for pulmonary exacerbations during Kalydeco treatment compared to the period before Kalydeco treatment

Time: 48 Months

Measure: Respiratory Microbiology - Percentage of patients with cultures positive for Pseudomonas aeruginosa during Kalydeco treatment compared to the period before Kalydeco treatment

Time: 48 Months

Measure: Respiratory Microbiology - Percentage of patients with cultures positive for bacteria other than Pseudomonas aeruginosa and for fungi during Kalydeco treatment compared to the period before Kalydeco treatment

Time: 48 Months

Measure: FEV1: Absolute change in percent predicted FEV1 during Kalydeco treatment

Time: 48 Months

Measure: Measures of nutritional status: Absolute change in weight, weight-for-age Z score, body mass index (BMI), and BMI-for-age Z-score during Kalydeco treatment

Time: 48 Months

Measure: Comorbidities: Incidence and prevalence of comorbidities during Kalydeco treatment compared to the period before Kalydeco treatment

Time: 48 Months

Measure: Mortality: Incidence and cause of deaths

Time: 48 Months

Measure: Organ transplantation: Incidence and reason for organ transplantations

Time: 48 Months

Other Outcomes

Measure: To explore the effect of Kalydeco treatment on Health-Related Quality of Life (HRQoL) in patients with CF and in caregivers of pediatric patients enrolled in the study.

Time: 48 Months

6 A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of N91115 for Efficacy and Safety in Patients With CF Heterozygous for F508del-CFTR + Gating Mutation Being Treated With Ivacaftor

Cavosonstat (N91115) is being studied as a potential novel therapy for cystic fibrosis (CF), and this study assesses a target population of patients who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R).

NCT02724527 Cystic Fibrosis Drug: Cavosonstat Drug: Placebo
MeSH: Cystic Fibrosis Fibrosis

Study of Cavosonstat (N91115) in CF Patients Who Are Heterozygous for F508del-CFTR and a Gating Mutation and Being Treated With Ivacaftor Cavosonstat (N91115) is being studied as a potential novel therapy for cystic fibrosis (CF), and this study assesses a target population of patients who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P ---

Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Inclusion Criteria: - Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) - Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor - Negative serum pregnancy test - Weight ≥ 40 kg at screening - Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: - Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 - Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus - Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 - Blood hemoglobin < 10 g/dL at screening - Serum albumin < 2.5 g/dL at screening - Abnormal liver or renal function - History of ventricular tachycardia or other clinically significant ventricular arrhythmias - History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval (> 450 msec for men; > 470 msec for women) - History of solid organ or hematological transplantation - History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening - Use of continuous (24 hr/day) or nocturnal supplemental oxygen Cystic Fibrosis Cystic Fibrosis Fibrosis Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P --- --- S549N --- --- S549R --- --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P ---

Primary Outcomes

Description: Forced Expiratory Volume (FEV) absolute measurements comparing baseline to after 4 and 8 weeks of N91115 treatment. 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) is calculated using the Hankinson method.

Measure: The absolute change in ppFEV1 in the N91115 treated group

Time: Baseline, week 4 and 8 assessments

Secondary Outcomes

Description: Forced Expiratory Volume relative measurements comparing baseline to after 4 and 8 weeks of N91115 treatment. 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) is calculated using the Hankinson method.

Measure: The relative change from study baseline within the active treatment group in ppFEV1 values

Time: Baseline, week 4 and 8 assessments

Description: Sweat chloride concentration measured by pilocarpine iontophoresis, a standard clinical laboratory technique. Sweat collection accomplished with the Wescor Macroduct System.

Measure: Absolute change from study baseline within the active treatment group in sweat chloride

Time: Baseline, week 4 and 8 assessments

Description: Patient questionnaires will compare baseline scores on their respiratory symptoms to weeks 4 and 8

Measure: Changes in the respiratory domain of the Cystic Fibrosis Questionnaire - Revised, (CFQ-R)

Time: Baseline, week 4 and 8 assessments

Description: Patient questionnaires will compare baseline global impression of changes in health from baseline to weeks 4 and 8

Measure: Absolute change from baseline within the active treatment group in Patient Global Impression of Change

Time: Baseline, week 4 and 8 assessments

Description: Assessments of clinical laboratory values, electrocardiogram (ECG), pulmonary exacerbations, and vital signs

Measure: Safety as determined by adverse events assessment

Time: Baseline to 8 weeks treatment with a 28-day follow up period

Description: Plasma collection for assessment of N91115 and ivacaftor Cmax

Measure: Pharmacokinetic Assessment of Maximum Plasma Concentration [Cmax] for N91115 & ivacaftor

Time: Weeks 1, 4 and 8

Description: Plasma collection for assessment of N91115 and ivacaftor AUC

Measure: Pharmacokinetic Assessment of area under the plasma concentration verse time curve [AUC] for N91115 & ivacaftor

Time: Weeks 1, 4 and 8

7 A Phase 3, 2 Part, Open-Label Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Ivacaftor in Subjects With Cystic Fibrosis Who Are Less Than 24 Months of Age and Have a CFTR Gating Mutation

The purpose of this study is to evaluate the safety of ivacaftor treatment, and PK of ivacaftor and metabolites in subjects with cystic fibrosis (CF) who are <24 months of age at treatment initiation and have a CF transmembrane conductance regulator (CFTR) gene gating mutation

NCT02725567 Cystic Fibrosis Drug: ivacaftor
MeSH: Cystic Fibrosis Fibrosis

- Must have 1 of the following 9 CFTR mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D. --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G1244E --- --- S1251N --- --- S1255P ---

Primary Outcomes

Measure: Part A: Safety, as determined by number of subjects with adverse events (AEs), clinically relevant abnormal laboratory values (serum chemistry and hematology), standard 12 lead electrocardiograms (ECGs), vital signs, and ophthalmologic examinations

Time: Day 1 up to Day 70

Measure: Part B: Safety, as determined by number of subjects with adverse events (AEs), clinically relevant abnormal laboratory values (serum chemistry and hematology), standard 12 lead electrocardiograms (ECGs), vital signs, and ophthalmologic examinations

Time: Day 1 up to Week 24

Measure: Part A: Peak concentrations (C3-6h) of ivacaftor, M1 ivacaftor, and M6 ivacaftor

Time: after 4 days of ivacaftor treatment

Measure: Part A: Trough concentrations (Ctrough) of ivacaftor, M1 ivacaftor, and M6 ivacaftor

Time: after 4 days of ivacaftor treatment

Secondary Outcomes

Measure: Part B: Peak concentrations (C3-6h) of ivacaftor, M1 ivacaftor, and M6 ivacaftor

Time: through Week 24

Measure: Part B: Trough concentrations (Ctrough) of ivacaftor, M1 ivacaftor, and M6 ivacaftor

Time: through Week 24

Measure: Part B: Absolute change from baseline in sweat chloride using quantitative pilocarpine iontophoresis

Time: through Week 24

8 A Phase 3b, 2-part, Randomized, Double-blind, Placebo-controlled Crossover Study With a Long-term Open-label Period to Investigate Ivacaftor in Subjects With Cystic Fibrosis Aged 3 Through 5 Years Who Have a Specified CFTR Gating Mutation

To evaluate the efficacy of ivacaftor treatment, as measured by lung clearance index (LCI), in subjects with cystic fibrosis (CF) who have a specified CF transmembrane conductance regulator (CFTR) gating mutation

NCT02742519 Cystic Fibrosis Drug: ivacaftor Drug: Placebo
MeSH: Cystic Fibrosis Fibrosis

Inclusion Criteria: - Male or female with confirmed diagnosis of CF. - Must have 1 of the following CFTR gating mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D. --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G1244E --- --- S1251N --- --- S1255P ---

Exclusion Criteria: - An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before Day 1 - Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject (in the opinion of the investigator) - Abnormal liver function, at Screening, defined as ≥3 × 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), and total bilirubin - History of solid organ or hematological transplantation - Any clinically significant "non-CF-related" illness within 2 weeks before Day 1 - Use of any moderate or strong inducers or inhibitors of cytochrome P450 (CYP) 3A within 2 weeks before Day 1 - Participation in a clinical study involving administration of either an investigational or a marketed drug within 30 days or 5 terminal half-lives (whichever is longer or as determined by the local requirements) before Screening Inclusion Criteria: - Male or female with confirmed diagnosis of CF. - Must have 1 of the following CFTR gating mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D. --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G1244E --- --- S1251N --- --- S1255P ---

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: Absolute Change From Baseline in Lung Clearance Index (LCI2.5) Through 8 Weeks of Treatment (Average of Week 4 and Week 8 LCI2.5)

Time: Baseline Through Week 8 for each treatment period, Up to 24 Weeks

Secondary Outcomes

Description: Serum samples were collected for evaluation of change in immunoreactive trypsinogen levels at Week 8.

Measure: Absolute Change From Baseline in Immunoreactive Trypsinogen Levels at Week 8

Time: Baseline and Week 8 of each treatment period, Up to 24 Weeks

Description: Fecal elastase-1 was used clinically to diagnose pancreatic exocrine insufficiency in participants with cystic fibrosis.

Measure: Absolute Change From Baseline in Fecal Elastase-1 Levels at Week 8

Time: Baseline and Week 8 of each treatment period, Up to 24 Weeks

Measure: Absolute Change From Baseline in Weight at Week 8

Time: Baseline and Week 8 of each treatment period, Up to 24 Weeks

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

Measure: Absolute Change From Baseline in Body Mass Index (BMI) at Week 8

Time: Baseline and Week 8 of each treatment period, Up to 24 Weeks

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

Time: Baseline up to Month 15

9 A Phase 2, Randomized, Parallel-Group, Double-Blind, Placebo Controlled Study to Evaluate the Safety and Efficacy of CTP-656 With an Open-Label Active Comparator in Patients With Cystic Fibrosis With CFTR Gating Mutations.

This study will evaluate the efficacy and safety of CTP-656 in patients with cystic fibrosis (CF) who have a cystic fibrosis transmembrane conductance regulator (CFTR) gating mutation.

NCT02971839 Cystic Fibrosis Drug: CTP-656, 20 mg (QD) Drug: CTP-656, 100 mg (QD) Drug: CTP-656, 150 mg (QD) Drug: Placebo (QD) Drug: Kalydeco, 150 mg Tablet (BID; open-label)
MeSH: Cystic Fibrosis Fibrosis

Inclusion Criteria: - 18 years of age or older - Has a confirmed diagnosis of CF with at least one allele of the following CFTR gating mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, and S549R. --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P ---

Exclusion Criteria: - Acute upper respiratory infection or lower respiratory infection, pulmonary exacerbation, or changes in therapy within 4 weeks of study treatment - Uncontrolled type 2 diabetes, or uncontrolled CF-related diabetes - History of hepatitis C or chronic active hepatitis B infection - History of pulmonary tuberculosis, non-tuberculosis mycobacterial infections or allergic bronchopulmonary aspergillosis (ABPA) treated during screening or within 2 years prior to screening - Colonization with B. cenocepacia, B. dolosa, B. multivorans, and/or M. abcessus within 2 years prior to Screening - Abnormal liver function - History of abnormal renal function - History of prolonged QTcF > 450 msec for males or QTcF > 470 msec for females - History of solid organ or hematological transplantation - Using any inhibitor or inducer of cytochrome P450/3A during the study or within 30 days of screening - Women who are pregnant or lactating, or have plans to become pregnant during the study or within 1 month following the last dose Inclusion Criteria: - 18 years of age or older - Has a confirmed diagnosis of CF with at least one allele of the following CFTR gating mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, and S549R. --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P ---

Primary Outcomes

Measure: Change from baseline in sweat chloride at Day 28

Time: 28 days

Secondary Outcomes

Measure: Change from baseline in percent predicted FEV1 at Day 28

Time: 28 days

Measure: Change from baseline in CFQ-R Respiratory Domain at Day 28

Time: 28 days

10 A Phase IIa, Randomized, Double-blind, Placebo-controlled Study to Evaluate GLPG2222 in Ivacaftor-treated Subjects With Cystic Fibrosis Harbouring One F508del CFTR Mutation and a Second Gating (Class III) Mutation

This clinical study is a phase IIa, multi-center, randomized, double-blind, placebo-controlled, parallel group study to evaluate two doses of orally administered GLPG2222 in adult subjects with a confirmed diagnosis of CF harbouring one F508del CFTR mutation and a second gating (class III) mutation and on stable treatment with ivacaftor. Up to 35 evaluable subjects are planned to be included in the study. Eligible subjects must be on stable treatment with physician prescribed ivacaftor (Kalydeco®) for at least 28 days at the baseline visit. They will be randomized in a 2:2:1 ratio to receive one of two active doses of GLPG2222 (150 mg q.d. or 300 mg q.d.) or placebo q.d. administered for 29 days. Subjects will be in the study for a minimum of 6 weeks and a maximum of 10 weeks, from screening until the follow-up visit.

NCT03045523 Cystic Fibrosis Drug: GLPG2222 150 mg q.d. Drug: GLPG2222 300 mg q.d. Drug: Placebo
MeSH: Cystic Fibrosis Fibrosis

2. A confirmed clinical diagnosis of CF. 3. One F508del mutation on one allele in the CFTR gene, a gating (class III) mutation (one of the following: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) on the 2nd allele in the CFTR gene (documented in the subject's medical record or CF registry). --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P ---

Primary Outcomes

Description: To evaluate the safety and tolerability of GLPG2222 as compared to placebo in terms of adverse events

Measure: Changes in adverse events

Time: at screening and at each study visit up to day 43 which is the final FU visit

Description: To evaluate the safety and tolerability of GLPG2222 as compared to placebo in terms of laboratory

Measure: Changes in abnormal laboratory

Time: at screening and at each study visit up to day 43 which is the final FU visit

Description: To evaluate the safety and tolerability of GLPG2222 as compared to placebo in terms of vital signs, ECG or physical examination

Measure: Changes in abnormal vital signs, ECG or physical examination

Time: at screening and at each study visit up to day 43 which is the final FU visit

Secondary Outcomes

Measure: Change from baseline of Sweat chloride concentration

Time: at screening and at each study visit up to day 43 which is the final FU visit

Measure: Change from baseline of FEV1 (L) and percent predicted FEV1 for age, gender and height as assessed by spirometry

Time: at screening and at each study visit up to day 43 which is the final FU visit

Measure: Change from baseline on the respiratory domain of Revised Cystic Fibrosis Questionnaire (CFQ-R)

Time: at screening and at each study visit up to day 43 which is the final FU visit

11 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 ---

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

12 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 ---

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

13 Lum-Iva-biota: Exploring the Respiratory Mycobiota and Microbiota Profile in French CF Patients Taking Lumacaftor-Ivacaftor

n2015, VERTEX company - producing already KALYDECO (IVACAFTOR, VX-770) potentiator molecule that is recommended for the treatment of CF patients aged ≥ 6 y, with CFTR mutation altering the channel regulation (class III mutations) as G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549Nou S549R) -was allowed by the Federal Drug Administration (FDA) and European Medicines Agency (EMEA) for producing and using ivacaftor combination (such as lumacaftor/ ivacaftor initially, and more recently tezacaftor/ivacaftor, tezacaftor/ivacaftor/VX-659, tezacaftor/ivacaftor/VX-445 and tezacaftor/ivacaftor/VX-152) in clinical trials for patient with cystic fibrosis, according to age and mutation eligibility criteria. Since 2016, the French patients homozygous for the p.Phe508del mutation and older than 12 years are able to be treated with the association LUMACAFTOR-IVACAFTOR and this French authorization is being extended for 6-11 years old children (while the European Commission has already granted an extension of the Marketing Authorization for lumacaftor/ivacaftor to include 6-11 years old children with cystic fibrosis since January 2018). Patients treated by lumacaftor/ivacaftor (or other ivacaftor new combinations) are closely monitored according to criteria established by the working group "New Therapeutic Approaches" of the French Society Cystic fibrosis. This study is a phase IV observational trial for a period of 1 year. In this context, the team aims at initiating a comprehensive monitoring of the lung and gut mycobiota and microbiota evolution under LUMACAFTOR-IVACAFTOR (or other ivacaftor combinations) treatment. This project is directly linked to the monitoring of cystic fibrosis patients who begin treatment with LUMACAFTOR-IVACAFTOR (or other ivacaftor combinations) in France. The pro- and eukaryotic microbiota analysis is based on the secondary use of sputum and stool samples associated with several clinical data of CF patients under ivacaftor combinations and follow-up during the 1st year of therapy. According to the French law, Lum-Iva-Biota project is a non-interventional study. It aims at demonstrating that changes in the hydration of secretions at the pulmonary and intestinal levels related to LUMACAFTOR-IVACAFTOR therapy (or other new generation of ivacaftor combinations) promote a change in the lung and gut mycobiota and microbiota profiles which may achieve the characteristics of the "healthy type" (in terms of composition, richness and diversity).

NCT03565692 Cystic Fibrosis Biological: the lung mycobiota and microbiota profile Biological: the gut mycobiota and microbiota profile
MeSH: Cystic Fibrosis Fibrosis

Lum-Iva-biota: Exploring the Respiratory Mycobiota and Microbiota Profile in French CF Patients Taking Lumacaftor-Ivacaftor. Lum-Iva-biota: Exploring the Respiratory Mycobiota and Microbiota Profile in French CF Patients Taking Lumacaftor-Ivacaftor n2015, VERTEX company - producing already KALYDECO (IVACAFTOR, VX-770) potentiator molecule that is recommended for the treatment of CF patients aged ≥ 6 y, with CFTR mutation altering the channel regulation (class III mutations) as G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549Nou S549R) -was allowed by the Federal Drug Administration (FDA) and European Medicines Agency (EMEA) for producing and using ivacaftor combination (such as lumacaftor/ ivacaftor initially, and more recently tezacaftor/ivacaftor, tezacaftor/ivacaftor/VX-659, tezacaftor/ivacaftor/VX-445 and tezacaftor/ivacaftor/VX-152) in clinical trials for patient with cystic fibrosis, according to age and mutation eligibility criteria. --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P ---

In 2015, the American company VERTEX - producing already KALYDECO (IVACAFTOR, VX-770) potentiator molecule that is recommended for the treatment of CF patients aged ≥ 6 y, with mutation altering the channel regulation (class III mutations) as G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549Nou S549R) - was allowed by the Federal Drug Administration (FDA) and European Medicines Agency (EMA) for producing and using LUMACAFTOR-IVACAFTOR in clinical trials to manage CF patients over 12 years and having two p.Phe508del mutations. --- G551D --- --- G1244E --- --- G1349D --- --- G178R --- --- G551S --- --- S1251N --- --- S1255P ---

Primary Outcomes

Description: Measure by conventional methods (history of microbial culture and GM assay) and particularly by metagenomic analysis of pulmonary pro- and eukaryotic microbiota.

Measure: Change of specific bacterial and/or fungal pathogens

Time: 18 months

Secondary Outcomes

Description: Difference between the amount of air exhaled may be measured during the first second

Measure: Forced expiratory volume in 1 second (FEV1)

Time: Day 1

Description: Difference between the amount of air exhaled may be measured during the first second

Measure: Forced expiratory volume (FEV1)

Time: 6 Months

Description: Difference between the amount of air exhaled may be measured during the first second

Measure: Forced expiratory volume (FEV1)

Time: 12 Months

Description: Measure by conventional methods (history of microbial culture and GM assay) and particularly by metagenomic analysis of lung pro- and eukaryotic microbiota.

Measure: Change of specific bacterial and/or fungal pathogens

Time: 12 months

Description: Measure by metagenomic analysis of gut pro- and eukaryotic microbiota.

Measure: Change of specific bacterial and/or fungal pathogens

Time: 12 months

14 Impact of the Introduction of ORKAMBI on Anxiety, Depression, Quality of Life and Adherence of Adolescents and Young Adults

The aim of this project is to evaluate the psychological reshuffle induced by ORKAMBI. The particular focus of this study is the consequence of its introduction on anxiety, depression, quality of life and adherence to all cystic fibrosis (CF) treatment. To answer this question investigators will monitor the psychological function of CF adolescents and young adults treated with ORKAMBI and compare them to CF adolescents and young adults not treated with ORKAMBI.

NCT03659214 Cystic Fibrosis Behavioral: Questionnaires
MeSH: Cystic Fibrosis Fibrosis Depression

Inclusion Criteria: - Treated group: Patients with proven CF (sweat-test > 60 mEq, 2 DF508 CF causing mutations, 12 to 20 years, and treated with ORKAMBI - Control group: Patients not carrying 2 DF508 CF causing mutations, not treated with ORKAMBI, and not carrying the G551D, G178R, S549N, S549R, G551S, G1244E,S1251N, S1255P or G1349D mutation or treated with Kalydeco Exclusion Criteria: - Transplanted patients - Patients younger than 12 years - Patients older than 20 years Inclusion Criteria: - Treated group: Patients with proven CF (sweat-test > 60 mEq, 2 DF508 CF causing mutations, 12 to 20 years, and treated with ORKAMBI - Control group: Patients not carrying 2 DF508 CF causing mutations, not treated with ORKAMBI, and not carrying the G551D, G178R, S549N, S549R, G551S, G1244E,S1251N, S1255P or G1349D mutation or treated with Kalydeco Exclusion Criteria: - Transplanted patients - Patients younger than 12 years - Patients older than 20 years Cystic Fibrosis Cystic Fibrosis Fibrosis Depression Introduction of KALYDECO then ORKAMBI, as a personalized medicine in the therapeutic strategy of Cystic Fibrosis (CF) may deeply modify the prognosis of patients with CF. --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G1244E --- --- S1255P ---

Inclusion Criteria: - Treated group: Patients with proven CF (sweat-test > 60 mEq, 2 DF508 CF causing mutations, 12 to 20 years, and treated with ORKAMBI - Control group: Patients not carrying 2 DF508 CF causing mutations, not treated with ORKAMBI, and not carrying the G551D, G178R, S549N, S549R, G551S, G1244E,S1251N, S1255P or G1349D mutation or treated with Kalydeco Exclusion Criteria: - Transplanted patients - Patients younger than 12 years - Patients older than 20 years Inclusion Criteria: - Treated group: Patients with proven CF (sweat-test > 60 mEq, 2 DF508 CF causing mutations, 12 to 20 years, and treated with ORKAMBI - Control group: Patients not carrying 2 DF508 CF causing mutations, not treated with ORKAMBI, and not carrying the G551D, G178R, S549N, S549R, G551S, G1244E,S1251N, S1255P or G1349D mutation or treated with Kalydeco Exclusion Criteria: - Transplanted patients - Patients younger than 12 years - Patients older than 20 years Cystic Fibrosis Cystic Fibrosis Fibrosis Depression Introduction of KALYDECO then ORKAMBI, as a personalized medicine in the therapeutic strategy of Cystic Fibrosis (CF) may deeply modify the prognosis of patients with CF. --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G1244E --- --- S1255P --- --- G1349D --- --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G1244E --- --- S1255P ---

Primary Outcomes

Description: to assess the impact on Anxiety

Measure: Score of Generalized Anxiety Disorder-7 questionnaire (GAD-7)

Time: 24 months

Secondary Outcomes

Description: To assess the impact on Depression

Measure: Score of Patient Health Questionnaire-9 (PHQ-9 )

Time: 24 months

Description: Disease-specific instrument designed to measure impact on overall health, daily life, perceived well-being and symptoms (Quality of Life)

Measure: Scores of Cystic Fibrosis Questionnaire 14+ (CFQ 14+)

Time: 24 months

Description: The 6 items are assessed using a YES/NO answer .The scale was validated in patients with chronic disease to assess medication adherence

Measure: GIRERD Scale

Time: 24 months

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 ---

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 ---

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 A Phase 2, Randomized, Double-blind Study to Evaluate the Efficacy and Safety of VX-561 in Subjects Aged 18 Years and Older With Cystic Fibrosis

The purpose of this study is to evaluate the efficacy, safety, pharmacodynamic (PD) and pharmacokinetic (PK) effect of VX-561.

NCT03911713 Cystic Fibrosis Drug: VX-561 Drug: IVA Drug: Placebo Drug: Placebo
MeSH: Cystic Fibrosis Fibrosis

Key Inclusion Criteria: - Must have 1 of the following 9 CFTR mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D - On ivacaftor therapy - FEV1 value ≥40% and ≤100% of predicted mean for age, sex, and height Key Exclusion Criteria: - History of clinically significant cirrhosis with or without portal hypertension - History of solid organ or hematological transplantation - Lung infection with organisms associated with a more rapid decline in pulmonary status Other protocol defined Inclusion/Exclusion criteria may apply Key Inclusion Criteria: - Must have 1 of the following 9 CFTR mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D - On ivacaftor therapy - FEV1 value ≥40% and ≤100% of predicted mean for age, sex, and height Key Exclusion Criteria: - History of clinically significant cirrhosis with or without portal hypertension - History of solid organ or hematological transplantation - Lung infection with organisms associated with a more rapid decline in pulmonary status Other protocol defined Inclusion/Exclusion criteria may apply Cystic Fibrosis Cystic Fibrosis Fibrosis null --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G1244E --- --- S1251N --- --- S1255P ---

Key Inclusion Criteria: - Must have 1 of the following 9 CFTR mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D - On ivacaftor therapy - FEV1 value ≥40% and ≤100% of predicted mean for age, sex, and height Key Exclusion Criteria: - History of clinically significant cirrhosis with or without portal hypertension - History of solid organ or hematological transplantation - Lung infection with organisms associated with a more rapid decline in pulmonary status Other protocol defined Inclusion/Exclusion criteria may apply Key Inclusion Criteria: - Must have 1 of the following 9 CFTR mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D - On ivacaftor therapy - FEV1 value ≥40% and ≤100% of predicted mean for age, sex, and height Key Exclusion Criteria: - History of clinically significant cirrhosis with or without portal hypertension - History of solid organ or hematological transplantation - Lung infection with organisms associated with a more rapid decline in pulmonary status Other protocol defined Inclusion/Exclusion criteria may apply Cystic Fibrosis Cystic Fibrosis Fibrosis null --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G1244E --- --- S1251N --- --- S1255P --- --- G1349D --- --- G551D --- --- G178R --- --- S549N --- --- S549R --- --- G551S --- --- G1244E --- --- S1251N --- --- S1255P ---

Primary Outcomes

Measure: Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1)

Time: From Baseline at Week 12

Secondary Outcomes

Measure: Absolute change in sweat chloride concentrations

Time: From Baseline at Week 12

Measure: Maximum observed concentration (Cmax) of VX-561, IVA, and relevant metabolites

Time: From Baseline up to Week 16

Measure: Area under the concentration versus time curve during a dosing interval (AUCtau) of VX-561, IVA, and relevant metabolites

Time: From Baseline up to Week 16

Measure: Observed pre-dose concentration (Ctrough) of VX-561, IVA, and relevant metabolites

Time: From Baseline up to Week 16

Measure: Safety and tolerability as assessed by number of subjects with adverse events (AEs) and serious adverse events (SAEs)

Time: From baseline up to Week 16

17 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 ---

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


HPO Nodes