| 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] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| 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 |
Cohorts 1, 2 and 3 :
- To evaluate the safety and tolerability when lumacaftor (VX-809) is administered alone or in combination with ivacaftor (VX-770)
- To evaluate the effect of lumacaftor administered alone or in combination with ivacaftor on sweat chloride
Cohort 4 :
-To evaluate the safety and tolerability of lumacaftor in combination with ivacaftor
-To evaluate the efficacy of lumacaftor in combination with ivacaftor
|
|
| E.2.2 | Secondary objectives of the trial |
Cohort 1 :
- To evaluate the effect of lumacaftor administered alone or in combination with ivacaftor on pulmonary function
- To evaluate the effect of lumacaftor administered alone on sweat chloride
- To assess the PK of lumacaftor and its major metabolite, M28-lumacaftor, alone and in combination with ivacaftor (including the M1-ivacaftor and M6-ivacaftor)
Cohorts 2 and 3:
-To evaluate the effect of lumacaftor administered alone or in combination with ivacaftor on pulmonary function
-To evaluate the effect of increasing doses of lumacaftor administered alone on sweat Chloride
-To assess the PK of lumacaftor and M28-lumacaftor alone and in combination with ivacaftor (including M1-ivacaftor and M6-ivacaftor)
-To evaluate the effect of lumacaftor administered alone or in combination with ivacaftor on CFQ-R score
Cohort 4 :
To assess the PK of lumacaftor, M28-lumacaftor, ivacaftor, M1-ivacaftor, and M6-ivacaftor |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Cohorts 1, 2 and 3
1. Male or female subjects with confirmed diagnosis of CF
2. Homozygous subjects must have the F508del-CFTR mutation in both alleles (Cohort 1, 2 and 3). Heterozygous subjects (Cohort 2 only) must have the F508del-CFTR mutation on 1 allele, as appropriate for the cohort. For the heterozygous subjects, the second CFTR allele must encode a mutation predicted to either result in the lack of CFTR production or in the production of a CFTR that is not responsive to ivacaftor.
3. Age 18 years or older on the date of informed consent.
4. FEV1 >=40% of predicted normal for age, gender, and height (Knudson standards) pre bronchodilator value at Screening
5. Hematology and serum chemistry of blood and urine results with no clinically significant abnormalities that would interfere with the study assessments (as judged by the investigator).
6. Able to understand and comply with protocol requirements, restrictions, and instructions, and likely to complete the study as planned.
7. If sexually active, male subjects who are able to father a child and female subjects of childbearing potential must meet the contraception requirements
8. Willing and able to remain on a stable medication regimen for the duration of study participation.
9. Signed informed consent form (ICF).
10. If the subject received prior treatment in a previous clinical study with either lumacaftor or ivacaftor, the last dose of that study drug must have been administered at least 3 months prior to Day 1 of the current study. Subjects who participated in Cohort 1 of this study are not eligible for participation in Cohort 2 or Cohort 3. Subjects who participated in Cohort 2 of this study are not eligible for participation in Cohort 3.
Cohort 4:
1. Signed ICF.
2. Male and females, age 18 years or older on the date of informed consent.
3. Male or female subjects with confirmed diagnosis of CF35 defined as:
- A sweat chloride value not less than 60 mmol/L by quantitative pilocarpine iontophoresis OR CF-causing mutations (all as documented in the subject’s medical record) AND
- chronic sinopulmonary disease OR gastrointestinal/nutritional abnormalities
4. Subjects must have the F508del-CFTR mutation on 1 allele, as appropriate for the cohort.
The second CFTR allele must encode a mutation predicted to either result in the lack of CFTR production or in the production of a CFTR that is not responsive to ivacaftor.The CFTR mutations must be confirmed before randomization.
5. FEV1 40% to 90% of predicted normal for age, gender, and height (Hankinson standards)
6. Stable CF disease as judged by the investigator.
7. Hematology and clinical chemistry of blood and urine results with no clinically significant abnormalities that would interfere with the study assessments (as judged by the investigator).
8. Able to understand and comply with protocol requirements, restrictions, and instructions, and likely to complete the study as planned.
9. Willing and able to remain on a stable medication regimen for the duration of study participation. |
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| E.4 | Principal exclusion criteria |
Cohort 1, 2 and 3:
- History of any illness or condition 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 (e.g., cirrhosis with portal hypertension).
- An acute illness including acute upper or lower respiratory infection, pulmonary exacerbation or changes in therapy (including antibiotics) for pulmonary disease within 14 days before receiving the first dose of study drug.
- History of solid organ or hematological transplantation.
- Pregnant or nursing females; females of childbearing potential who are unwilling or unable to use an acceptable method of nonhormonal contraception, as outlined in this protocol
Cohort 4:
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.
2-Any clinically significant laboratory abnormalities at screening that would interfere with the study assessments or pose an undue risk for the subject (as judged by the investigator).
3- Any of the following abnormal values at screening:
- Hemoglobin <10 g/dL
- Abnormal liver function
- Creatinine clearance <50 mL/min/m2 using the Modification of Diet in Renal Disease calculation equation
4. An acute illness including acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before receiving the first dose of study drug.
5. Colonization with organisms associated with a more rapid decline in pulmonary status (e.g., Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus).
6. A 12-lead ECG demonstrating QTcF >450 at the Screening Visit. If QTcF exceeds 450 msec for the screening ECG, the ECG should be repeated 2 more times during the Screening Period, and the average of the 3 QTcF values should be used to determine the subject's eligibility.
7. History of solid organ or hematological transplantation.
8. History of alcohol abuse or drug addiction in the past year, including cannabis, cocaine, and opiates, as deemed by the investigator.
9. Ongoing or prior participation in an investigational drug study (including studies investigating lumacaftor and/or ivacaftor) within 30 days of the Screening Visit. A washout period of 5 terminal half-lives of the previous investigational study drug, or 30 days, whichever is longer, must elapse before the Screening Visit. The duration of the elapsed time may be longer if required by local regulations. Heterozygous subjects who participated in Cohort 2 and meet the eligibility criteria for Cohort 4 may participate in Cohort 4.
10. Use of moderate to strong inducers of CYP3A AND use of strong inhibitors, including consumption of certain herbal medications (e.g., St. John's Wort) and certain fruit and fruit juices within 14 days before Day 1
11. Pregnant and nursing females: Females of childbearing potential must have a negative pregnancy test at the Screening Visit.
12. Sexually active subjects of reproductive potential who are not willing to follow the contraception requirements
13. Evidence of lens opacity or cataract as determined by the ophthalmologic examination at the Screening Visit.
14. 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. An adult (18 years of age or older) who is a relative of a study staff member may be enrolled in the study provided that the adult otherwise qualifies to be enrolled, lives independent of and does not reside with the study staff member, and receives medical care and participates in the study at a site other than the study staff member’s site. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Cohorts 1, 2 and 3
- Safety and tolerability assessments based on adverse events, hematology, serum chemistry, coagulation, urinalysis, standard 12-lead electrocardiograms (ECGs), and vital signs
- Change in sweat chloride
Cohort 4:
- Safety and tolerability assessments based on AEs, hematology, serum chemistry, coagulation studies, urinalysis, standard 12-lead ECGs, vital signs, and pulse oximetry
- Absolute change in percent predicted FEV1 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Safety will be evaluated through follow-up visit
- Change in sweat chloride with be evaluated from Day 14 to Day 21 in Cohort 1 and Day 28 to Day 56 in Cohort 2 and 3
- Absolute change in percent predicted FEV1 from baseline at Day 56 (cohort 4) |
|
| E.5.2 | Secondary end point(s) |
Cohorts 1, 2 and 3:
- Change in percent predicted forced expiratory volume in 1 second (FEV1)
- Change in sweat chloride
- PK parameters of VX-809 and metabolite in presence and absence of VX-770
- PK parameters of VX-770 and metabolite in presence and absence of VX-809
- Cystic Fibrosis Questionnaire (CFQ-R) Score
Cohort 4 :
- Relative change in percent predicted FEV1
- Absolute change in body mass index (BMI)
- Absolute change in CFQ-R score
- Absolute change in body weight
- Absolute change in sweat chloride from baseline
- PK parameters of lumacaftor, M28-lumacaftor, ivacaftor, M1-ivacaftor, and M6-ivacaftor |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Change in percent predicted FEV1 evaluated through D21 in Cohort 1
and through D56 in Cohort 2, 3
-Relative change in percent predicted FEV1, baseline at D56 in cohort 4
-Change in sweat chloride from baseline through D14 in Cohort 1 and from baseline through D28 in Cohort 2. Change in sweat chloride from baseline to D14 of lumacaftor administered alone in Cohort 3. Change in sweat chloride evaluated from baseline at D56 in cohort 4.
-PK of lumacaftor evaluated through D21 in Cohort 1 and through D56 in Cohort 2 and 3
-PK of ivacaftor evaluated through D21 in Cohort 1 and through D56 in Cohort 2 and 3
-CFQ-R evaluated through D56 in Cohort 2, 3 and 4
Cohort 4 only:
-BMI from baseline at D56; body weight from baseline at D56
-PK of lumacaftor, ivacaftor + metabolites through D56 |
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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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 12 |
| 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 | 6 |
| 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 |
| New Zealand |
| United States |
|
| 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
|
| End of the trial is defined as database lock. |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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