|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Medical condition in easily understood language
|Diseases [C] - Respiratory Tract Diseases [C08]
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|To evaluate the efficacy of lumacaftor in combination with ivacaftor in subjects aged 6 Through 11 years with cystic fibrosis (CF) who are homozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene
|Secondary objectives of the trial
|- To evaluate the safety of lumacaftor in combination with ivacaftor
- To investigate the pharmacokinetics (PK) of lumacaftor and its metabolite (M28-lumacaftor) and ivacaftor and its metabolites (M1-ivacaftor and M6-ivacaftor)
|Trial contains a sub-study
|Principal inclusion criteria
|- Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.
- Subjects (males and females), will be between the ages of 6 and 11 years, inclusive, on the date of informed consent (and assent, if applicable).
- Subjects who weigh ≥15 kg without shoes at the Screening Visit.
- Subjects with confirmed diagnosis of CF at the Screening Visit. CF is defined as:
• 2 CF causing mutations (all as documented in the subject's medical record) AND
• chronic sinopulmonary disease OR gastrointestinal/nutritional abnormalities
- Subjects who are homozygous for the F508del CFTR mutation (genotype to be confirmed at the Screening Visit).
- Subjects with percent predicted FEV1 of ≥70 through ≤105 percentage points adjusted for age, sex, and height using the Wang equation at the Screening Visit.
- Subjects with a screening LCI 2.5 result greater than or equal to 7.5
- Subjects with stable CF disease as deemed by the investigator at the Screening Visit.
- Subjects who are willing to remain on a stable CF medication regimen through Week 24 or, if applicable, through the Safety Follow up Visit.
- Subjects who are able to swallow tablets.
|Principal exclusion criteria
|- History of any comorbidity reviewed at the Screening Visit 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.
- 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).
- Any of the following abnormal laboratory values at the Screening Visit:
• Hemoglobin <10 g/dL
• Abnormal liver function defined as any 3 or more of the following:
• ≥3 × upper limit of normal (ULN) aspartate aminotransferase (AST)
• ≥3 × ULN alanine aminotransferase (ALT)
• ≥3 × ULN gamma glutamyl transpeptidase
• ≥3 × ULN alkaline phosphatase
• ALT or AST >5 × ULN
• Total bilirubin >2 × ULN
• Abnormal renal function defined as glomerular filtration rate ≤45 mL/min/1.73 m2 (calculated by the Counahan-Barratt equation)
- 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).
- A standard 12 lead ECG demonstrating QTc >450 msec at the Screening Visit. If QTc exceeds 450 msec at the Screening Visit, the ECG should be repeated 2 more times during the Screening Period, and the average of the 3 QTc values should be used to determine the subject's eligibility.
- History of solid organ or hematological transplantation at the Screening Visit.
- Ongoing or prior participation in an investigational drug study (including studies investigating lumacaftor and/or ivacaftor) within 30 days of the Screening Visit.
- Use of restricted medication or food within specified duration before the first dose of study drug
- History of cataract/lens opacity or evidence of cataract/lens opacity, as determined by the ophthalmologic examination at the Screening Visit. The Screening Visit ophthalmologic examination does not need to be repeated if there is documentation of an examination meeting protocol criteria that was conducted within 3 months before the Screening Visit. All subjects will have an eye exam performed by an ophthalmologist at the Screening Visit and at the Week 24 Visit OR the Week 28 Safety Follow up Visit
|E.5 End points
|Primary end point(s)
|Absolute change in lung clearance index 2.5 (LCI2.5)
|Timepoint(s) of evaluation of this end point
|From baseline through Week 24
|Secondary end point(s)
|- Average absolute change in sweat chloride from baseline at Day 15 and at Week 4
- Absolute change in body mass index (BMI) from baseline at Week 24
- Absolute change in Cystic Fibrosis Questionnaire Revised (CFQ R) respiratory domain score from baseline through Week 24
- Absolute change in LCI5.0 from baseline through Week 24
- Absolute change in sweat chloride from baseline at Week 24
- Absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from baseline through Week 24
- Relative change in ppFEV1 from baseline through Week 24
- Absolute change in BMI for age z score from baseline at Week 24
- Absolute change in weight from baseline at Week 24
- Absolute change in weight for age z score from baseline at Week 24
|Timepoint(s) of evaluation of this end point
|Baseline through Week 24 or Baseline at week 24
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days