| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.0 |
| 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 |
|
| 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 efficacy and pharmacodynamics (PD) of ELX/TEZ/IVA |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate safety and tolerability of ELX/TEZ/IVA |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject (or the subject's legally appointed and authorized representative) will sign and date an informed consent form (ICF) and, when appropriate, an assent form.
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines (as applicable), and other study procedures.
. For subjects <18 years of age: as judged by the investigator, parent or legal guardian must be able to understand protocol requirements, restrictions, and instructions and the parent or legal guardian should be able to ensure that the subject will comply with and is likely to complete the study as planned.
3. Subjects (male or female) 6 years of age and older on the date of informed consent.
4. Subjects has an eligible ELX/TEZ/IVA-responsive CFTR mutation listed in Table 15-1 and none of the exclusionary mutations in Table 15-2.
5. Subject has stable CF disease, as deemed by the investigator, before randomization.
6. Forced expiratory volume in 1 second (FEV1) value .40% and .90% of predicted mean for age, sex, and height (equations of the Global Lung Function Initiative [GLI])11 at the Screening Visit (spirometry measurements must meet American Thoracic Society/European Respiratory Society criteria12 for acceptability and repeatability).
7. Subject is able to swallow tablets. |
|
| E.4 | Principal exclusion criteria |
1. History of any illness or any clinical condition that might confound the results of the study or pose an additional risk in administering study drug(s) to the subject. This may include, but is not limited to:
• Clinically significant liver cirrhosis with or without portal hypertension
• Solid organ or hematological transplantation
• Alcohol or drug abuse in the past year, including, but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator
Cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical carcinoma in situ (all 3 with no recurrence for the last 5 years).
2. Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject (as deemed by the investigator).
3. Any of the following abnormal laboratory values at screening:
. Hemoglobin <10 g/dL
. Total bilirubin .2 ~ upper limit of normal (ULN)
. AST, ALT, gamma-glutamyl transferase (GGT), or alkaline phosphatase (ALP) ≥ 3 x ULN
. Abnormal renal function defined as glomerular filtration rate .50 mL/min/1.73 m2 (calculated by the Modification of Diet in Renal Disease Study Equation)13, 14for subjects .18 years of age and .45 mL/min/1.73 m2 (calculated by the Counahan-Barratt equation)15 for subjects <18 years of age.
4. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for sinopulmonary disease within 28 days before Day 1 (first dose of study drug).
5. Lung infection with organisms associated with a more rapid decline in pulmonary status (including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobaterium abscessus). For subjects who have had a history of a positive culture, the investigator will apply the following criteria to establish whether the subject is free of infection with such organisms.
. The subject has not had a respiratory tract culture positive for these organisms within the 12 months before the date of informed consent, and
. The subject has had at least 2 respiratory tract cultures negative for such organisms within the 12 months before the date of informed consent, with the first and last of these separated by at least 3 months, and the most recent one within the 6 months before the date of informed consent.
6. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of study drug (Day 1).
7. Ongoing or prior participation in an investigational drug study within 28 days of the Screening Visit.
. A washout period of 5 terminal half-lives of the previous investigational study drug, or 28 days, whichever is longer, must elapse before the Screening Visit.
. The duration of the elapsed time may be longer if required by local regulations.
8. Pregnant and breast-feeding females. Female subjects of childbearing potential (Section 11.5.6.1) must have a negative pregnancy test at the Screening Visit and the Day 1 Visit.
9. Use of restricted medication within specified duration before the first dose of study drug as defined in Table 9-3.
10. Subject, or close relative of the subject, is the investigator or a subinvestigator, research assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of the study at that site. However, an adult (aged 18 years or older) who is a relative of a study staff member may be enrolled in the study provided that:
• the adult lives independently of and does not reside with the study staff member, and
• the adult participates in the study at a site other than the site at which the family member is employed. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) through Week 24 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From signing of ICF until safety Follow up visit. |
|
| E.5.2 | Secondary end point(s) |
•Absolute change from baseline in SwCl through Week 24
• Absolute change from baseline in Cystic Fibrosis Questionnaire- Revised respiratory domain (CFQ-R RD) score through Week 24
• Absolute change from baseline in body mass index (BMI) at Week 24
• Absolute change from baseline in weight at Week 24
• Number of pulmonary exacerbations (PEx) through Week 24
• Safety and tolerability assessments based on AE, clinical laboratory values, ECGs, vital signs, and pulse oximetry |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From signing of ICF until safety Follow up visit. |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| 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 | 23 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 87 |
| 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 |
| Austria |
| Belgium |
| Germany |
| Italy |
| Netherlands |
| Portugal |
| Spain |
| Switzerland |
| France |
|
| 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
|
| last scheduled visit (or scheduled contact) of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 8 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 8 |
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