Study of Lumacaftor Monotherapy, and Lumacaftor and Ivacaftor Combination Therapy in Cystic Fibrosis (CF) Patients Homozygous or Heterozygous for the F508del-CFTR Mutatio

Conditions: Cystic Fibrosis
MedDRA version: 17.0Level: PTClassification code 10011762Term: Cystic fibrosisSystem Organ Class: 10010331 - Congenital, familial and genetic disorders
Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Registration Number: EUCTR2010-020413-90-IE

Lead Sponsor: Vertex Pharmaceuticals Incorporated

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 120

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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 120
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

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 adu

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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