Cystic Fibrosis
Conditions
Brief summary
This is an open-label extension study for participants who completed a Phase 3, placebo-controlled study of ataluren in participants with nonsense mutation cystic fibrosis (nmCF) not receiving chronic inhaled aminoglycosides.
Detailed description
The primary objective of this Phase 3 extension study will be to obtain long-term safety data to augment the overall safety database. The secondary objectives will be to augment the efficacy data collected in the double-blind study (PTC124-GD-021-CF; NCT02139306).
Interventions
DRUGAtaluren
Ataluren will be provided as a vanilla-flavored powder to be mixed with water or milk.
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
* Completion of study treatment (placebo or active) in the previous Phase 3, double-blind study protocol (Protocol PTC124-GD-021-CF) * Evidence of signed and dated informed consent/assent document(s) indicating that the participant (and/or the participant's parent/legal guardian) has been informed of all pertinent aspects of the trial.
Exclusion criteria
* Known hypersensitivity to any of the ingredients or excipients of the study drug. * Ongoing participation in any other therapeutic clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Baseline up to Week 100 | TEAE: any untoward medical occurrence or undesirable event that begins or worsens following administration of study drug, whether or not considered related to study drug by Investigator. Serious adverse event (SAE): an adverse event (AE) resulting in any of following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying) or persistent or significant disability/incapacity. Except for cystic fibrosis (CF) pulmonary exacerbations, an event wasn't reported as an SAE, if event was exclusively a relapse or an expected change or progression of baseline CF. AEs included both SAEs and nonserious AEs. AEs classified according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 and coded using Medical Dictionary for Regulatory Activities. A summary of SAEs and all nonserious AEs, regardless of causality, is located in the Reported Adverse Events section. |
| Number of Participants With a Clinically Meaningful Abnormal Clinical Laboratory (Serum Biochemistry, Hematology, and Urinalysis) Parameter | Baseline up to Week 100 | Clinical laboratory results considered clinically meaningful were determined by Investigator. Serum biochemistry parameters: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, magnesium, calcium, phosphorus, uric acid, glucose, total protein, albumin, globulin, bilirubin, creatine kinase, lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, alkaline phosphatase, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, and cystatin C. Hematology parameters: white blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, red cell count with morphology, and platelet count. Urinalysis parameters: pH, specific gravity, glucose, ketones, blood, protein, creatinine, urobilinogen, bilirubin, nitrite, and leukocyte esterase. A summary of all SAEs/nonserious AEs, regardless of causality, is located in the Reported Adverse Events section. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Percent-Predicted Forced Expiratory Volume in 1 Second (FEV1) as Measured by Spirometry at Week 24 | Baseline, Week 24 | Pulmonary function of percent-predicted FEV1 was measured using a spirometer. FEV1 is the volume of air that can forcibly be blown out in 1 second. Each percent-predicted FEV1 was based gender, age, and the height value obtained at the same study visit. The percentage of change in percent-predicted of FEV1 was calculated as follows: (percent-predicted FEV1 - Baseline percent-predicted FEV1/Baseline percent-predicted FEV1)\*100. |
| Change From Baseline in Percent-Predicted of Forced Vital Capacity (FVC) as Measured by Spirometry at Week 24 | Baseline, Week 24 | Pulmonary function of FVC was measured using a spirometer. FVC is the volume of air that can forcibly be blown out. Each percent-predicted FVC was based gender, age, and the height value obtained at the same study visit. The percentage of change in percent-predicted of FVC was calculated as follows: (percent-predicted FVC - Baseline percent-predicted FVC/Baseline percent-predicted FVC)\*100. |
| Change From Baseline in Forced Expiratory Flow Between 25% and 75% of Expiration (FEF25-75) as Measured by Spirometry at Week 24 | Baseline, Week 24 | Pulmonary function of FEF25-75 was measured using a spirometer. FEF25-75 is the forced expiratory flow between 25% and 75% of vital capacity. Each percent-predicted FEF25-75 was based gender, age, and the height value obtained at the same study visit. The percentage of change in percent-predicted of FEF25-75 was calculated as follows: (percent-predicted FEF25-75 - Baseline percent-predicted FEF25-75/Baseline percent-predicted FEF25-75)\*100. |
| Rate of Pulmonary Exacerbations as Defined by Modified Fuch's Criteria Over 48 Weeks | Baseline up to Week 48 | A modified Fuchs' exacerbation was defined as an event requiring treatment with or without intravenous antibiotics for any 4 of the following 12 symptoms: 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. The 48-week rate = (the total number of events/ treatment duration by week)\*48. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, France, Germany, Greece, Israel, Italy, Netherlands, Poland, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
All eligible participants, including those who received placebo in the double-blind study (PTC124-GD-021-CF; NCT02139306), were enrolled to this open-label extension study. To avoid interruption in treatment, when possible, Screening/Baseline for this extension study was to occur on the same day as the End-of-Study visit for the double-blind study.
Participants by arm
| Arm | Count |
|---|---|
| Ataluren Participants were administered ataluren orally at a dose of 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for up to 96 weeks. | 245 |
| Total | 245 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Abnormal Laboratory Value | 2 |
| Overall Study | Adverse Event | 5 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Required prohibited medications | 5 |
| Overall Study | Study Closure | 207 |
| Overall Study | Withdrawal by Subject | 24 |
Baseline characteristics
| Characteristic | Ataluren |
|---|---|
| Age, Continuous | 23.1 years STANDARD_DEVIATION 10.88 |
| Race/Ethnicity, Customized Asian | 4 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 16 participants |
| Race/Ethnicity, Customized Non-White | 5 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 229 participants |
| Race/Ethnicity, Customized White | 235 participants |
| Race/Ethnicity, Customized White-Arabic/North African Heritage | 1 participants |
| Sex: Female, Male Female | 113 Participants |
| Sex: Female, Male Male | 132 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 245 |
| other Total, other adverse events | 191 / 245 |
| serious Total, serious adverse events | 89 / 245 |
Outcome results
Primary
Number of Participants With a Clinically Meaningful Abnormal Clinical Laboratory (Serum Biochemistry, Hematology, and Urinalysis) Parameter
Clinical laboratory results considered clinically meaningful were determined by Investigator. Serum biochemistry parameters: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, magnesium, calcium, phosphorus, uric acid, glucose, total protein, albumin, globulin, bilirubin, creatine kinase, lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, alkaline phosphatase, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, and cystatin C. Hematology parameters: white blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, red cell count with morphology, and platelet count. Urinalysis parameters: pH, specific gravity, glucose, ketones, blood, protein, creatinine, urobilinogen, bilirubin, nitrite, and leukocyte esterase. A summary of all SAEs/nonserious AEs, regardless of causality, is located in the Reported Adverse Events section.
Time frame: Baseline up to Week 100
Population: Participants who received at least 1 dose of ataluren (As-Treated Population).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ataluren | Number of Participants With a Clinically Meaningful Abnormal Clinical Laboratory (Serum Biochemistry, Hematology, and Urinalysis) Parameter | 0 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
TEAE: any untoward medical occurrence or undesirable event that begins or worsens following administration of study drug, whether or not considered related to study drug by Investigator. Serious adverse event (SAE): an adverse event (AE) resulting in any of following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying) or persistent or significant disability/incapacity. Except for cystic fibrosis (CF) pulmonary exacerbations, an event wasn't reported as an SAE, if event was exclusively a relapse or an expected change or progression of baseline CF. AEs included both SAEs and nonserious AEs. AEs classified according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 and coded using Medical Dictionary for Regulatory Activities. A summary of SAEs and all nonserious AEs, regardless of causality, is located in the Reported Adverse Events section.
Time frame: Baseline up to Week 100
Population: Participants who received at least 1 dose of ataluren (As-Treated Population).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | At least 1 TEAE | 222 Participants |
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Mild TEAE | 28 Participants |
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Moderate TEAE | 147 Participants |
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Severe TEAE | 46 Participants |
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Life-Threatening TEAE | 1 Participants |
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Fatal TEAE | 0 Participants |
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Serious TEAE | 89 Participants |
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE Unrelated to Study Drug | 140 Participants |
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE Unlikely Related to Study Drug | 55 Participants |
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE Possibly Related to Study Drug | 23 Participants |
| Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE Probably Related to Study Drug | 4 Participants |
Secondary
Change From Baseline in Forced Expiratory Flow Between 25% and 75% of Expiration (FEF25-75) as Measured by Spirometry at Week 24
Pulmonary function of FEF25-75 was measured using a spirometer. FEF25-75 is the forced expiratory flow between 25% and 75% of vital capacity. Each percent-predicted FEF25-75 was based gender, age, and the height value obtained at the same study visit. The percentage of change in percent-predicted of FEF25-75 was calculated as follows: (percent-predicted FEF25-75 - Baseline percent-predicted FEF25-75/Baseline percent-predicted FEF25-75)\*100.
Time frame: Baseline, Week 24
Population: Participants who received at least 1 dose of ataluren and have at least 1 postbaseline efficacy assessment (ITT Population) and had evaluable FEF25-75 data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in Forced Expiratory Flow Between 25% and 75% of Expiration (FEF25-75) as Measured by Spirometry at Week 24 | Baseline | 38.099 percentage of FEF25-75 | Standard Deviation 22.098 |
| Ataluren | Change From Baseline in Forced Expiratory Flow Between 25% and 75% of Expiration (FEF25-75) as Measured by Spirometry at Week 24 | Change from Baseline at Week 24 | 0.698 percentage of FEF25-75 | Standard Deviation 13.1241 |
Secondary
Change From Baseline in Percent-Predicted Forced Expiratory Volume in 1 Second (FEV1) as Measured by Spirometry at Week 24
Pulmonary function of percent-predicted FEV1 was measured using a spirometer. FEV1 is the volume of air that can forcibly be blown out in 1 second. Each percent-predicted FEV1 was based gender, age, and the height value obtained at the same study visit. The percentage of change in percent-predicted of FEV1 was calculated as follows: (percent-predicted FEV1 - Baseline percent-predicted FEV1/Baseline percent-predicted FEV1)\*100.
Time frame: Baseline, Week 24
Population: Participants who received at least 1 dose of ataluren and have at least 1 postbaseline efficacy assessment (ITT Population) and had evaluable FEV1 data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in Percent-Predicted Forced Expiratory Volume in 1 Second (FEV1) as Measured by Spirometry at Week 24 | Baseline | 60.219 percentage of predicted FEV1 | Standard Deviation 17.6163 |
| Ataluren | Change From Baseline in Percent-Predicted Forced Expiratory Volume in 1 Second (FEV1) as Measured by Spirometry at Week 24 | Change from Baseline at Week 24 | 0.015 percentage of predicted FEV1 | Standard Deviation 6.718 |
Secondary
Change From Baseline in Percent-Predicted of Forced Vital Capacity (FVC) as Measured by Spirometry at Week 24
Pulmonary function of FVC was measured using a spirometer. FVC is the volume of air that can forcibly be blown out. Each percent-predicted FVC was based gender, age, and the height value obtained at the same study visit. The percentage of change in percent-predicted of FVC was calculated as follows: (percent-predicted FVC - Baseline percent-predicted FVC/Baseline percent-predicted FVC)\*100.
Time frame: Baseline, Week 24
Population: Participants who received at least 1 dose of ataluren and have at least 1 postbaseline efficacy assessment (ITT Population) and had evaluable FVC data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in Percent-Predicted of Forced Vital Capacity (FVC) as Measured by Spirometry at Week 24 | Baseline | 75.249 percentage of predicted FVC | Standard Deviation 15.8508 |
| Ataluren | Change From Baseline in Percent-Predicted of Forced Vital Capacity (FVC) as Measured by Spirometry at Week 24 | Change from Baseline at Week 24 | 0.166 percentage of predicted FVC | Standard Deviation 6.5276 |
Secondary
Rate of Pulmonary Exacerbations as Defined by Modified Fuch's Criteria Over 48 Weeks
A modified Fuchs' exacerbation was defined as an event requiring treatment with or without intravenous antibiotics for any 4 of the following 12 symptoms: 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. The 48-week rate = (the total number of events/ treatment duration by week)\*48.
Time frame: Baseline up to Week 48
Population: Participants who received at least 1 dose of ataluren and have at least 1 postbaseline efficacy assessment (ITT Population).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ataluren | Rate of Pulmonary Exacerbations as Defined by Modified Fuch's Criteria Over 48 Weeks | 1.051 exacerbations | Standard Deviation 2.1654 |