E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Nonsense Mutation Cystic Fibrosis |
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E.1.1.1 | Medical condition in easily understood language |
Genetic disease characterized by difficult breathing. Other symptoms include dysfunction of the pancreas, liver, bile duct and intestine, as well as reduced fertility. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10011762 |
E.1.2 | Term | Cystic fibrosis |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 ataluren to improve pulmonary function relative to placebo |
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E.2.2 | Secondary objectives of the trial |
To determine the effect of ataluren on: 1. Pulmonary symptoms 2. General well-being 3. Health-related Quality of Life (HRQL)
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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 his parent/legal guardian) has been informed of all pertinent aspects of the trial. 2. Age ≥6 years. 3. Body weight ≥16 kg. 4. Sweat chloride >60 mEq/L. 5. Documentation of the presence of a nonsense mutation in at least 1 allele of the CFTR gene, as determined by genotyping performed at a laboratory certified by the College of American Pathologists (CAP), or under the Clinical Laboratory Improvement Act/Amendment (CLIA), or by an equivalent organization. 6. Verification that a blood sample has been drawn for sequencing of the CFTR gene. 7. Ability to perform a valid, reproducible spirometry test using the study-specific spirometer with demonstration of an FEV1 ≥40% and ≤90% of predicted for age, gender, and height. 8. Demonstration at Visit 2 of a valid %-predicted FEV1 within 15% of the Screening %-predicted FEV1 value. 9. Resting oxygen saturation (as measured by pulse oximetry) ≥92% on room air. 10. Confirmed screening laboratory values within the central laboratory ranges specified in Table 2 of the protocol. 11. In subjects 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. 12. Willingness and ability to comply with all study procedures and assessments, including scheduled visits, drug administration plan, study procedures, laboratory tests, and study restrictions. |
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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. Previous participation in the Phase 3 trial of ataluren (PTC124-GD-009-CF). 3. 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 or any change in acute therapy between screening and randomization. 4. Chronic use of inhaled or systemic tobramycin within 4 weeks to creening. 5. Exposure to another investigational drug within 4 weeks prior to screening. 6. Ongoing participation in any other therapeutic clinical trial. 7. 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. 8. Treatment with intravenous antibiotics within 3 weeks prior to screening. 9. Ongoing immunosuppressive therapy (other than corticosteroids). 10. Ongoing warfarin, phenytoin, or tolbutamide therapy. 11. History of solid organ or hematological transplantation. 12. Major complications of lung disease (including massive hemoptysis, pneumothorax, or pleural effusion) within 8 weeks prior to screening. 13. Known portal hypertension. 14. Positive hepatitis B surface antigen, hepatitis C antibody test, or human immunodeficiency virus (HIV) test. 15. Pregnancy or breast-feeding. 16. Current smoker or a smoking history of ≥10 pack-years (number of cigarette packs/day × number of years smoked). 17. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Absolute change in %-predicted FEV1 at Week 48, defined as the average between the change at Week 40 and that at Week 48 (by spirometry) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Screening, Week 1 to Week 48, 4-Week Post-Treatment follow-up |
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E.5.2 | Secondary end point(s) |
1. Rate of pulmonary exacerbations (expanded Fuchs criteria) 2. Change from baseline in Body Mass Index (BMI) 3. Respiratory HRQL as assessed by the Cystic Fibrosis Questionnaire - Revised (CFQ-R) respiratory domain
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1: Week 1 to Week 48 2: Screening, Week 1 to Week 48, 4-Week Post-Treatment follow-up 3: Screening, Week 1 to Week 48 |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 | No |
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 |
Argentina |
Australia |
Belgium |
Brazil |
Bulgaria |
Canada |
Denmark |
France |
Germany |
Greece |
Israel |
Italy |
Netherlands |
Poland |
Spain |
United Kingdom |
United States |
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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
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Last visit of the last patient excluding the long-term follow-up |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
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 |