| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Nonsense-Mutation-Mediated Cystic Fibrosis |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10011762 |
| E.1.2 | Term | Cystic fibrosis |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the ability of PTC124 to improve pulmonary function as assessed by FEV1. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the trial are to confirm and extend perspectives on complications of CF through evaluation of pulmonary symptoms and exacerbations, cough, and subject or parent/caregiver perception of respiratory functioning |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Evidence of signed and dated informed consent assent document(s) indicating that the subject (and or parent legal guardian) has been informed of all pertinent aspects of the study. Note: If the study candidate is considered a child under local regulation, a parent or legal guardian must provide written consent prior to initiation of study screening procedures and the study candidate may be required to provide written assent. The rules of the responsible Institutional Review Board Institutional Ethics Committee (IRB IEC) regarding whether one or both parents must provide consent and the appropriate ages for obtaining consent and assent from the subject should be followed. 2. Age >= 6 years. 3. Body weight >=16kg. 4. Abnormal nasal TEPD total chloride conductance (a less electrically negative value than -5 mV for total chloride conductance [Δchloride-free+isoproterenol]). Note: Even if a subject has past documentation of an abnormal TEPD, a TEPD must be performed as part of the screening procedures, must show an adequate tracing in at least 1 nostril, and must be abnormal (taken as a mean of both nostrils if values for both nostrils are available). 5. Sweat chloride >40 mEq/L. Note: A patient does not need to have a repeat sweat test solely for enrollment into this study if documentation of a sweat chloride value>40 mEq/L is already available. 6. Documentation of the simultaneous presence of a nonsense mutation in at least 1 allele of the CFTR gene and a CF-causing mutation in the other CFTR allele, as determined by gene sequencing from a laboratory certified by the College of American Pathologists (CAP), or under the Clinical Laboratory Improvement Act/Amendment (CLIA), or by an equivalent organization. 7. Verification that a blood sample has been drawn for confirmation of the presence of a nonsense mutation in the CFTR gene. Note: A subject who has written documentation of a nonsense mutation as the cause of CF need not wait for confirmatory results to start study drug as long as the confirmatory genotyping blood sample has been drawn. 8. Ability to perform a valid, reproducible spirometry test using the study-specific spirometer with demonstration of an FEV1 >=40 per cento and >=90 per cento of predicted for age, gender, and height [Wang 1993, Hankinson 1999]. 9. Resting oxygen saturation (as measured by pulse oximetry) >=92 per cento on room air. 10. Documentation by VivoMetrics that the subject has satisfactorily completed a 24-hour LifeShirt cough frequency assessment. 11. Confirmed screening laboratory values within the central laboratory ranges specified in protocol Table 2 below. Note: Confirmation should be performed for out-of-range values to determine if the abnormality is real or artifactual. Values used to establish eligibility should be obtained within the 4-week screening period, and should generally be the most recent measurement obtained. |
|
| E.4 | Principal exclusion criteria |
| 1. Known hypersensitivity to any of the ingredients or excipients of the study drug (polydextrose, polyethylene glycol 3350, poloxamer 407, mannitol 25C, crospovidone XL10, hydroxyethyl cellulose, vanilla, colloidal silica, or magnesium stearate). 2. Any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation, or reinitiation) in a chronic treatment/prophylaxis regimen for CF or for CF-related conditions within 4 weeks prior to start of study treatment. Note: A subject can be enrolled who is using inhaled medications such as aztreonam, tobramycin, dornase-alfa, hypertonic saline, corticosteroids, or β2 agonists; or systemic drugs such as azithromycin or ibuprofen. Expected cycling of inhaled aztreonam or inhaled tobramycin (or similar inhaled aminoglycoside) is permitted. Other than for treatment of CF pulmonary exacerbations, subjects should remain on a stable medical regimen of treatment/prophylaxis for CF-related conditions to avoid confounding interpretation of study results. 3. Exposure to another investigational drug within 4 weeks prior to start of study treatment. 4. Treatment with systemic aminoglycoside antibiotics at the time of the baseline TEPD assessment. 5. Treatment with intravenous antibiotics within 3 weeks prior to start of study treatment. 6. History of solid organ or hematological transplantation. 7. Ongoing immunosuppressive therapy (other than corticosteroids). 8. Ongoing participation in any other therapeutic clinical trial. 9. Major complications of lung disease (including massive hemoptysis, pneumothorax, or pleural effusion) within 8 weeks prior to start of study treatment. 10. Evidence of pulmonary exacerbation or acute upper or lower respiratory tract infection (including viral illnesses) within 3 weeks prior to randomization. 11. Known portal hypertension. 12. Positive hepatitis B surface antigen, hepatitis C antibody test, or human immunodeficiency virus (HIV) test. 13. Pregnancy or breast-feeding. 14. Current smoker or a smoking history of ≥10 pack-years (number of cigarette packs/day �number of years smoked). 15. Prior or ongoing medical condition (eg, concomitant illness, alcoholism, drug abuse, psychiatric condition), medical history, physical findings, ECG findings, or laboratory abnormality that, in the investigator�s opinion, could adversely affect the safety of the subject, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the relative change in %-predicted FEV1 measured by spirometry from Baseline to Week 48. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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