Cystic Fibrosis
Conditions
Keywords
Cystic fibrosis, Nonsense mutation, Premature stop codon, PTC124, Ataluren
Brief summary
The primary objective of this study is to determine the long-term safety and tolerability of ataluren in participants with nonsense mutation cystic fibrosis (nmCF) who completed participation in the double-blind study PTC124-GD-009-CF (NCT00803205), as assessed by adverse events and laboratory abnormalities. The secondary objective of this study includes the assessment of the efficacy of ataluren, as measured by forced expiratory volume in 1 second (FEV1) and pulmonary exacerbation rate, and other safety parameters (for example, 12-lead electrocardiogram \[ECG\] measurements, vital signs).
Interventions
DRUGAtaluren
Ataluren will be administered per dose and schedule specified in the arm.
Sponsors
PTC Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Ability to provide written informed consent (parental/guardian consent and participant assent if less than \[\<\] 18 years of age). * Evidence of completed participation in the double-blind study, PTC124-GD-009-CF (Study 009). * Body weight greater than or equal to (≥) 16 kilograms (kg). * Performance of a valid, reproducible spirometry test using the study-specific spirometer during the screening period. * Confirmed laboratory values within the central laboratory ranges at screening. * In male and female participants who are sexually active, willingness to abstain from sexual intercourse or employ a barrier or medical method of contraception during the study drug administration and 60-day follow-up period. * Willingness and ability to comply with all study procedures and assessments, including scheduled visits, drug administration plan, laboratory tests, and study restrictions. Key
Exclusion criteria
* Chronic use of systemic tobramycin within 4 weeks prior to screening. * Evidence of pulmonary exacerbation or acute upper or lower respiratory tract infection (including viral illnesses) within 3 weeks prior to screening or between screening and randomization. * Any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation, or re-initiation) in a chronic treatment/prophylaxis regimen for CF or for CF-related conditions within 4 weeks prior to screening and randomization. * Known hypersensitivity to any of the ingredients or excipients of the study drug. * Exposure to another investigational drug within 4 weeks prior to screening. * Treatment with intravenous antibiotics within 3 weeks prior to screening. * History of solid organ or hematological transplantation. * Ongoing immunosuppressive therapy (other than corticosteroids). * Positive hepatitis B surface antigen, hepatitis C antibody test or human immunodeficiency virus (HIV) test. * Known portal hypertension. * Pregnancy or breast-feeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Baseline (Day 1) up to end of study (Week 196) | AE: any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severity of an AE was classified as: mild (does not interfere with usual function), moderate (interferes to some extent with usual function), severe (interferes significantly with usual function), life threatening (results in potential threat to life), and fatal AEs. Drug-related AEs: AEs with a possible or probable relationship to study drug. Serious AEs: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention. TEAE: AE that occurred or worsened from first dose of study drug to 4 weeks after last dose of study drug. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. |
| Number of Participants With Clinically Significant Laboratory Abnormalities | Baseline (Day 1) up to end of study (Week 196) | Laboratory parameters tests included hematology, biochemistry assay (hepatic, renal, and serum electrolyte values), adrenal assays, and urinalysis. Clinical significance was defined as per investigator's judgement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Pulmonary Exacerbation, As Assessed by Modified Fuchs Criteria | Baseline up to Week 192 | The modified Fuchs' criteria defined exacerbation as the presence of at least 4 of the following 12 Fuchs' signs and symptoms without the requirement for treatment with antibiotics: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; fatigue; temperature greater than (\>) 38 degrees celsius (°C); anorexia; sinus pain; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent or more from a previously recorded value; or radiographic changes indicative of pulmonary function. |
| Percentage of Participants With Pulmonary Exacerbation, As Assessed by Expanded Fuchs' Criteria | Baseline up to Week 192 | The expanded Fuchs' criteria defined exacerbation as the presence of at least 4 of the following 12 Fuchs' signs and symptoms requiring any form of antibiotic treatment (inhaled, oral, or intravenous): change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; fatigue; temperature \>38°C; anorexia; sinus pain; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent or more from a previously recorded value; or radiographic changes indicative of pulmonary function. |
| Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters at Final Visit (Week 196) | Baseline, Week 196 | ECG parameters included RR duration, PR duration, QRS duration, QT duration, QTCB (Bazett's correction formula) duration, QTCF (Fridericia's correction formula) duration. |
| Change From Baseline in Heart Rate at Final Visit (Week 196), as Assessed by 12-Lead ECG | Baseline, Week 196 | Heart rate was measured using 12-lead ECG. |
| Change From Baseline in Vital Signs at Final Visit (Week 196) | Baseline, Week 196 | Vital Signs included systolic blood pressure (SBP) and diastolic blood pressure (DBP). |
| Percentage of Participants With Pulmonary Exacerbation, As Assessed by Classic Fuchs' Criteria | Baseline up to Week 192 | The Classic Fuchs' criteria defined exacerbation as the presence of at least 4 of the following 12 Fuchs' signs and symptoms requiring treatment with parenteral antibiotics: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; fatigue; temperature \>38°C; anorexia; sinus pain; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent or more from a previously recorded value; or radiographic changes indicative of pulmonary function. |
| Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at the End of Treatment (Week 192), as Assessed by Spirometry | Baseline, Week 192 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Percent of predicted FEV1 = (observed value)/(predicted value) \* 100%. Change from baseline in percent predicted FEV1 at the end of treatment was reported. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at the End of Treatment (Week 192), as Assessed by Spirometry | Baseline, Week 192 | FVC is the volume of air that can forcibly be blown out after full inspiration in the upright position. Percent of predicted FVC = (observed value)/(predicted value) \* 100%. Change from baseline in percent predicted FVC at the end of treatment was reported. |
| Change From Baseline in Percent Predicted Forced Expiratory Flow Between 25% and 75% of Expiration (FEF25-75) at the End of Treatment (Week 192), as Assessed by Spirometry | Baseline, Week 192 | FEF25-75 is the forced expiratory flow between 25 and 75% of vital capacity. |
Countries
Belgium, France, Israel, Italy, Spain, Sweden, United States
Participant flow
Recruitment details
Participants with nonsense mutation cystic fibrosis (nmCF) who had completed the double-blind study PTC124-GD-009-CF (NCT00803205) were enrolled and treated in this open-label extension study.
Pre-assignment details
On 2 March 2017, it was announced that the Phase 3 double-blind study PTC124-GD-021-CF (NCT02139306) did not achieve its primary or secondary endpoints. Based on these results, clinical development of ataluren in cystic fibrosis was discontinued and this ongoing open-label extension study was closed.
Participants by arm
| Arm | Count |
|---|---|
| Ataluren Participants received ataluren suspension orally TID, 10 mg/kg at morning, 10 mg/kg at midday, and 20 mg/kg at evening (total daily dose 40 mg/kg) for 192 weeks. | 61 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Other than specified | 3 |
| Overall Study | Study closure | 41 |
| Overall Study | Withdrawal by Subject | 14 |
Baseline characteristics
| Characteristic | Ataluren |
|---|---|
| Age, Continuous | 27.5 years STANDARD_DEVIATION 10.73 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 60 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized White-White/Caucasian | 61 Participants |
| Sex: Female, Male Female | 34 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 61 |
| other Total, other adverse events | 61 / 61 |
| serious Total, serious adverse events | 36 / 61 |
Outcome results
Primary
Number of Participants With Clinically Significant Laboratory Abnormalities
Laboratory parameters tests included hematology, biochemistry assay (hepatic, renal, and serum electrolyte values), adrenal assays, and urinalysis. Clinical significance was defined as per investigator's judgement.
Time frame: Baseline (Day 1) up to end of study (Week 196)
Population: As-treated population included all participants who received at least 1 dose of ataluren.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ataluren | Number of Participants With Clinically Significant Laboratory Abnormalities | 0 Participants |
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
AE: any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severity of an AE was classified as: mild (does not interfere with usual function), moderate (interferes to some extent with usual function), severe (interferes significantly with usual function), life threatening (results in potential threat to life), and fatal AEs. Drug-related AEs: AEs with a possible or probable relationship to study drug. Serious AEs: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention. TEAE: AE that occurred or worsened from first dose of study drug to 4 weeks after last dose of study drug. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time frame: Baseline (Day 1) up to end of study (Week 196)
Population: As-treated population included all participants who received at least 1 dose of ataluren.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ataluren | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAEs | 61 Participants |
| Ataluren | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Mild AEs | 4 Participants |
| Ataluren | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Moderate AEs | 26 Participants |
| Ataluren | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Severe AEs | 30 Participants |
| Ataluren | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Life-threatening AEs | 0 Participants |
| Ataluren | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Fatal AEs | 1 Participants |
| Ataluren | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | AEs unrelated to ataluren | 35 Participants |
| Ataluren | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | AEs unlikely related to ataluren | 12 Participants |
| Ataluren | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | AEs possible related to ataluren | 13 Participants |
| Ataluren | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | AEs probable related to ataluren | 1 Participants |
| Ataluren | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAEs | 36 Participants |
Secondary
Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters at Final Visit (Week 196)
ECG parameters included RR duration, PR duration, QRS duration, QT duration, QTCB (Bazett's correction formula) duration, QTCF (Fridericia's correction formula) duration.
Time frame: Baseline, Week 196
Population: As-treated population included all participants who received at least 1 dose of ataluren. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure. 'Number analyzed' signifies participants evaluable for specified categories.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters at Final Visit (Week 196) | Baseline: RR duration | 828.17 miiliseconds | Standard Deviation 132.15 |
| Ataluren | Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters at Final Visit (Week 196) | Change at Week 196: RR duration | -14.27 miiliseconds | Standard Deviation 115.62 |
| Ataluren | Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters at Final Visit (Week 196) | Baseline: PR duration | 145.02 miiliseconds | Standard Deviation 19.29 |
| Ataluren | Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters at Final Visit (Week 196) | Change at Week 196: PR duration | -2.69 miiliseconds | Standard Deviation 12.25 |
| Ataluren | Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters at Final Visit (Week 196) | Baseline: QRS duration | 83.90 miiliseconds | Standard Deviation 8 |
| Ataluren | Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters at Final Visit (Week 196) | Change at Week 196: QRS duration | 0.33 miiliseconds | Standard Deviation 6.12 |
| Ataluren | Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters at Final Visit (Week 196) | Baseline: QT duration | 370.71 miiliseconds | Standard Deviation 28.11 |
| Ataluren | Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters at Final Visit (Week 196) | Change at Week 196: QT duration | -4.38 miiliseconds | Standard Deviation 25.63 |
| Ataluren | Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters at Final Visit (Week 196) | Baseline: QTCB duration | 408.92 miiliseconds | Standard Deviation 22.05 |
| Ataluren | Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters at Final Visit (Week 196) | Change at Week 196: QTCB duration | -0.71 miiliseconds | Standard Deviation 17.96 |
| Ataluren | Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters at Final Visit (Week 196) | Baseline: QTCF duration | 395.47 miiliseconds | Standard Deviation 19.23 |
| Ataluren | Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters at Final Visit (Week 196) | Change at Week 196: QTCF duration | -2.27 miiliseconds | Standard Deviation 17.13 |
Secondary
Change From Baseline in Heart Rate at Final Visit (Week 196), as Assessed by 12-Lead ECG
Heart rate was measured using 12-lead ECG.
Time frame: Baseline, Week 196
Population: As-treated population included all participants who received at least 1 dose of ataluren. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure. 'Number analyzed' signifies participants evaluable for specified categories.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in Heart Rate at Final Visit (Week 196), as Assessed by 12-Lead ECG | Baseline | 74.31 beats/minute | Standard Deviation 12.06 |
| Ataluren | Change From Baseline in Heart Rate at Final Visit (Week 196), as Assessed by 12-Lead ECG | Change at Week 196 | 2.04 beats/minute | Standard Deviation 10.11 |
Secondary
Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at the End of Treatment (Week 192), as Assessed by Spirometry
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Percent of predicted FEV1 = (observed value)/(predicted value) \* 100%. Change from baseline in percent predicted FEV1 at the end of treatment was reported.
Time frame: Baseline, Week 192
Population: ITT population included all participants who had at least 1 post-baseline efficacy assessment. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure. 'Number analyzed' signifies participants evaluable at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at the End of Treatment (Week 192), as Assessed by Spirometry | Baseline | 56.203 percentage of predicted FEV1 | Standard Deviation 17.2964 |
| Ataluren | Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at the End of Treatment (Week 192), as Assessed by Spirometry | Change at Week 192 | -1.214 percentage of predicted FEV1 | Standard Deviation 3.6384 |
Secondary
Change From Baseline in Vital Signs at Final Visit (Week 196)
Vital Signs included systolic blood pressure (SBP) and diastolic blood pressure (DBP).
Time frame: Baseline, Week 196
Population: As-treated population included all participants who received at least 1 dose of ataluren. Here, 'Number analyzed' signifies participants evaluable for specified categories.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in Vital Signs at Final Visit (Week 196) | Baseline: SBP | 114.8 millimeters of mercury (mmHg) | Standard Deviation 9.1 |
| Ataluren | Change From Baseline in Vital Signs at Final Visit (Week 196) | Change at Week 196: SBP | 0.6 millimeters of mercury (mmHg) | Standard Deviation 12.62 |
| Ataluren | Change From Baseline in Vital Signs at Final Visit (Week 196) | Baseline: DBP | 71.2 millimeters of mercury (mmHg) | Standard Deviation 8.93 |
| Ataluren | Change From Baseline in Vital Signs at Final Visit (Week 196) | Change at Week 196: DBP | -0.3 millimeters of mercury (mmHg) | Standard Deviation 9.93 |
Secondary
Percentage of Participants With Pulmonary Exacerbation, As Assessed by Classic Fuchs' Criteria
The Classic Fuchs' criteria defined exacerbation as the presence of at least 4 of the following 12 Fuchs' signs and symptoms requiring treatment with parenteral antibiotics: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; fatigue; temperature \>38°C; anorexia; sinus pain; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent or more from a previously recorded value; or radiographic changes indicative of pulmonary function.
Time frame: Baseline up to Week 192
Population: ITT population included all participants who had at least 1 post-baseline efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ataluren | Percentage of Participants With Pulmonary Exacerbation, As Assessed by Classic Fuchs' Criteria | 58.3 percentage of participants |
Secondary
Percentage of Participants With Pulmonary Exacerbation, As Assessed by Expanded Fuchs' Criteria
The expanded Fuchs' criteria defined exacerbation as the presence of at least 4 of the following 12 Fuchs' signs and symptoms requiring any form of antibiotic treatment (inhaled, oral, or intravenous): change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; fatigue; temperature \>38°C; anorexia; sinus pain; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent or more from a previously recorded value; or radiographic changes indicative of pulmonary function.
Time frame: Baseline up to Week 192
Population: ITT population included all participants who had at least 1 post-baseline efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ataluren | Percentage of Participants With Pulmonary Exacerbation, As Assessed by Expanded Fuchs' Criteria | 68.3 percentage of participants |
Secondary
Percentage of Participants With Pulmonary Exacerbation, As Assessed by Modified Fuchs Criteria
The modified Fuchs' criteria defined exacerbation as the presence of at least 4 of the following 12 Fuchs' signs and symptoms without the requirement for treatment with antibiotics: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; fatigue; temperature greater than (\>) 38 degrees celsius (°C); anorexia; sinus pain; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent or more from a previously recorded value; or radiographic changes indicative of pulmonary function.
Time frame: Baseline up to Week 192
Population: ITT population included all participants who had at least 1 post-baseline efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ataluren | Percentage of Participants With Pulmonary Exacerbation, As Assessed by Modified Fuchs Criteria | 68.3 percentage of participants |
Other Pre-specified
Change From Baseline in Percent Predicted Forced Expiratory Flow Between 25% and 75% of Expiration (FEF25-75) at the End of Treatment (Week 192), as Assessed by Spirometry
FEF25-75 is the forced expiratory flow between 25 and 75% of vital capacity.
Time frame: Baseline, Week 192
Population: Due to change in planned analysis FEV25-75 was not calculated and summarized.
Other Pre-specified
Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at the End of Treatment (Week 192), as Assessed by Spirometry
FVC is the volume of air that can forcibly be blown out after full inspiration in the upright position. Percent of predicted FVC = (observed value)/(predicted value) \* 100%. Change from baseline in percent predicted FVC at the end of treatment was reported.
Time frame: Baseline, Week 192
Population: ITT population included all participants who had at least 1 post-baseline efficacy assessment. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure. 'Number analyzed' signifies participants evaluable at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at the End of Treatment (Week 192), as Assessed by Spirometry | Baseline | 73.576 percentage of predicted FVC | Standard Deviation 14.6552 |
| Ataluren | Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at the End of Treatment (Week 192), as Assessed by Spirometry | Change at Week 192 | -2.286 percentage of predicted FVC | Standard Deviation 4.5722 |