| 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 respiratory safety of TEZ/IVA in subjects with CF homozygous for F508del and who discontinued treatment with Orkambi due to respiratory symptoms considered related to treatment |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of tezacaftor in combination with ivacaftor (TEZ/IVA) in subjects with CF homozygous for F508del and who discontinued treatment with Orkambi due to respiratory symptoms considered related to treatment.
• To evaluate patient-reported outcomes after treatment with TEZ/IVA in subjects with CF homozygous for F508del who discontinued with Orkambi due to respiratory symptoms considered related to treatment.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject (or subject’s legally appointed and authorized representative) will sign and date an informed consent form (ICF) and, where 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. Males or females, aged 12 years or older on the date of informed consent or, where appropriate, date of assent.
4. Prior discontinuation of Orkambi, with at least 1 respiratory sign or symptom considered related to therapy, including but not limited to the following:
• Chest discomfort
• Dyspnea (shortness of breath)
• Respiration abnormal (chest tightness)
• Asthma
• Bronchial hyperreactivity
• Bronchospasm
• Wheezing
• Asymptomatic reduction in relative change in ppFEV1 of >12% within 2 weeks after Orkambi initiation
Discontinuation from Orkambi should primarily be due to a respiratory event. However, concomitant non-respiratory events will not exclude subjects from participation. Documentation of specific qualifying signs or symptoms is not required. Investigator attestation will be accepted if information is not present in source materials.
5. Resolution or stabilization of qualifying event(s) >28 days prior to Screening.
6. Discontinuation of Orkambi therapy must have occurred within approximately 12 weeks from the first dose of Orkambi. In the event that the subject reinitiated Orkambi, discontinuation of Orkambi therapy must have occurred within approximately 12 weeks from the time of the most recent initiation. Investigator attestation will be accepted if information is not present in source materials.
7. Homozygous for F508del as documented in the subject’s medical record. If genotype documentation is not available in the medical record, genotyping will be performed during screening. If the screening genotype result is not received by the end of the Screening Period and all other eligibility criteria have been met, the subject may be randomized. Note: Subjects who have been randomized and whose screening genotype does not confirm study eligibility must be discontinued from the study as described in Section 9.9.
8. FEV1 ≥25% and ≤90% of predicted normal for age, sex, and height (equations of Wang et al. or Hankinson et al. 12, 13) at Screening Visit (Section 11.3.1). Spirometry measurements must meet American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria for acceptability and repeatability (Section 11.3.1).
9. Stable CF disease as judged by the investigator.
10. Willing to remain on a stable CF medication regimen from screening through the Safety Follow-up Contact.
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| E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria will not be eligible for this study:
1. History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject
Examples of such comorbidities may include, but are not limited to:
• Respiratory:
o Massive hemoptysis within the last 12 months
o Any of the following within the past 12 months and not associated with an acute, resolved event:
- Six-minute walk test distance <400 m
- Resting arterial blood gas on room air showing PaCO2 >50 mm Hg or PaO2 <55 mm Hg
- Systolic pulmonary arterial pressure (PAP) >35 mm Hg on echocardiography or a mean PAP >25 mm Hg measured by right heart catheterization, in the absence of a hypoxemic exacerbation or with an alternate etiology to explain the findings
• Non-respiratory: history of cirrhosis with portal hypertension, history of and/or risk factors for ventricular arrhythmia (e.g., long QT syndrome, hypokalemia, heart failure, left ventricular hypertrophy, bradycardia, myocardial infarction, cardiomyopathy, morbid obesity, acute neurologic events [subarachnoid hemorrhage, intracranial hemorrhage, cerebrovascular accident, and intracranial trauma], autonomic neuropathy, and significant anemia)
2. Recent rapid or progressive deterioration in respiratory status
3. Receiving continuous oxygen at >2L/min or on face-mask ventilation
4. Any of the following abnormal laboratory values at Screening:
• Abnormal liver function defined as any 2 or more of the following: ≥3 × upper limit of normal (ULN) aspartate transferase (AST), ≥3 × ULN alanine transferase (ALT), ≥3 × ULN gamma-glutamyl transpeptidase, ≥3 × ULN alkaline phosphatase (ALP), or ≥2 × ULN total bilirubin.
• Abnormal liver function defined as any increase of ≥5 × ULN AST or ALT.
• 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) for subjects ≥18 years of age and ≤45 mL/min/1.73 m2 (calculated by the Counahan-Barratt equation) for subjects aged 12 to 17 years (inclusive).
5. Child-Pugh Class B or C hepatic impairment
6. An acute upper or lower respiratory infection, pulmonary exacerbation, or change in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study drug)
7. Documentation of colonization with organisms associated with a more rapid decline in pulmonary status (e.g. Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus)
8. History of lung transplantation since most recent initiation of Orkambi
9. History of alcohol or drug abuse in the past year as deemed by the investigator, including but not limited to cannabis, cocaine, and opiates
10. Participation in an investigational drug study or use of a CFTR modulator (including Orkambi) within 28 days or 5 terminal half-lives before screening of the previous investigational study drug or CFTR modulator, whichever is longer
• Ongoing participation in a noninterventional study (including observational studies and studies requiring assessments without administration of study drug) is permitted.
11. Use of restricted medications or foods within the specified window before the first dose of study drug, or an anticipated need or use of restricted medication or foods after the first dose of study drug, as defined in Table 9-1
12. Pregnant or nursing females: Females of child-bearing potential must have a negative pregnancy test at Screening and Day 1
13. The subject or a close relative of the subject is the investigator or a sub-investigator, research assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of the study. An adult (aged 18 years or older) who is a relative of a study staff member may be randomized in the study provided that
• the adult lives independently of and does not reside with the study staff member, or
• 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) |
| • Incidence of respiratory AEs |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Monitored throughout the study |
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| E.5.2 | Secondary end point(s) |
Key Secondary end point:
1. Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from baseline to the average of the Day 28 and Day 56 measurements.
Secondary end points:
2. Relative change in ppFEV1 from baseline to the average of the Day 28 and Day 56 measurements.
3. Absolute change in Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory domain score from baseline to the average of the Day 28 and Day 56 measurements.
4. Tolerability based on discontinuation of TEZ/IVA through Day 56
5. Safety assessments based on AEs, clinical laboratory values (hematology, serum chemistry, coagulation studies, and urinalysis), vital signs, pulse oximetry, and postdose spirometry
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. from baseline to the average of the Day 28 and Day 56 measurements
2. from baseline to the average of the Day 28 and Day 56 measurements
3. from baseline to the average of the Day 28 and Day 56 measurements
4. Monitored throughout the study
5. Screening visit, Days 1, 15, 28, 56, ETT
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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 | 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 | 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 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| France |
| Germany |
| 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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| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 16 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 8 |
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