E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 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 |
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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 effect of elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) on glucose tolerance in CF subjects with impaired glucose tolerance (IGT) or CF-related diabetes (CFRD) |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of ELX/TEZ/IVA |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject (or his or her 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, and other study procedures. 3. Subjects (male and female) 12 years of age or older on the date of informed consent. 4. Subjects heterozygous for F508del and an MF mutation (F/MF genotypes). a. Genotype should be confirmed at the Screening Visit. b. If the screening CFTR genotype result is not received before the first dose of study drug, a previous CFTR genotype laboratory report may be used to establish eligibility. c. Subjects who have been enrolled and whose screening genotype does not confirm study eligibility must be discontinued from the study (Section 9.9). 5. Forced expiratory volume in 1 second (FEV1) value .30% of predicted mean for age, sex, and height (equations of the Global Lung Function Initiative [GLI])9 at the Screening Visit (spirometry measurements must meet American Thoracic Society/European Respiratory Society criteria10 for acceptability and repeatability) and stable CF disease as judged by the investigator. 6. Willing to remain on a stable CF treatment regimen (other than CFTR modulators) through completion of study participation. 7. Abnormal glucose tolerance as determined by an OGTT, classified as either IGT (defined as 2-hour post-OGTT blood glucose level 140 to 199 mg/dL) or CFRD (defined as either fasting hyperglycemia [blood glucose level >126 mg/dL after an 8-hour fast] or 2-hour post-OGTT blood glucose level >200 mg/dL). |
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E.4 | Principal exclusion criteria |
1. History of any illness or any clinical condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug(s) to the subject. This includes, but is not limited to, the following: - 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. Type 1 or Type 2 diabetes, or a first degree relative with Type 2 diabetes. 3. Duration of CFRD .3 years. 4. 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). 5. Any of the following abnormal laboratory values at screening: - Hemoglobin <10 g/dL - Total bilirubin .2 ¡Ñ upper limit of normal (ULN) - Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), or alkaline phosphatase (ALP) .3 ¡Ñ ULN - Abnormal renal function defined as glomerular filtration rate .45.mL/min/1.73.m2 (calculated by the Counahan-Barratt equation)11 6. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study drug). 7. Lung infection with organisms associated with a more rapid decline in pulmonary status (including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium 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. - 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. 8. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of study drug (Day 1). 9. Ongoing or prior participation in an investigational drug study (including studies investigating ELX with or without coadministration of other study drugs) 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. 10. Use of restricted medication (including antidiabetic medication other than insulin, which must be at a dose no greater than 0.3 units/kg/day) within specified duration before the first dose of study drug as defined in Table 9-1. 11. BMI .30 kg/m2 at the Screening Visit. 12. Pregnant and breast-feeding females. All female subjects regardless of childbearing potential status (Section 11.4.6) must have a negative pregnancy test at the Screening Visit and the Day 1 Visit. 13. The subject or a 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in 2-hour blood glucose levels following an oral glucose tolerance test (OGTT) to the average of Week 36 and Week 48 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
„h Proportion of subjects with improvement in dysglycemia categorization (CFRD, IGT, normal glucose tolerance [NGT]) at Week 48 „h Safety and tolerability of ELX/TEZ/IVA based on adverse events (AEs), clinical laboratory values, ECGs, vital signs, and pulse oximetry |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 |
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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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 41 |
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 |
Australia |
Belgium |
Czech Republic |
France |
Italy |
Netherlands |
Spain |
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E.8.7 | Trial has a data monitoring committee | No |
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 scheduled visit (or scheduled contact) of the last subject |
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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 | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |