A Study to Evaluate Efficacy and Safety of TEZ/IVA in Subjects Aged 6 through 11 Years With Cystic Fibrosis

Phase 1

Conditions: Cystic Fibrosis
MedDRA version: 20.0 Level: PT Classification code 10011762 Term: Cystic fibrosis System Organ Class: 10010331 - Congenital, familial and genetic disorders
Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

Registration Number: EUCTR2016-004479-35-BE

Lead Sponsor: Vertex Pharmaceuticals Incorporated

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: Not specified

Target Recruitment: 69

Inclusion Criteria

1. Subject’s legally appointed and authorized representative will sign and date an informed consent form (ICF) and the subject will sign and date an assent form (if applicable).
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) will be between the ages of 6 and 11 years, inclusive, on the date(s) of informed consent (and assent, if applicable).
4. Subjects who weigh =15 kg without shoes at the Screening Visit.
5. Genotypes as presented in Appendix 1 of the Protocol. Genotype is to be confirmed during screening. If the CFTR screening genotype result is not received before enrollment, a previous CFTR genotype lab report may be used to establish eligibility. Subjects who have been enrolled and whose screening genotype does not confirm study eligibility must be discontinued from the study as described in Section 10.7 of the Protocol. Note: Additional mutations may be evaluated and updates to approved mutations will be communicated to investigative sites through a memorandum.
6. A confirmed diagnosis of CF4 as determined by the following criteria:
a. For subjects who are F508del homozygous: confirmed diagnosis of CF defined as a sweat chloride value =60 mmol/L by quantitative pilocarpine iontophoresis (as documented in the subject’s medical record OR from the sweat chloride test result obtained at the Screening Visit).
b. For subjects who are F508del heterozygous:
• Confirmed diagnosis of CF defined as a sweat chloride value =60 mmol/L by quantitative pilocarpine iontophoresis (as documented in the subject’s medical record [this value may be obtained from a record collected prior to use of Kalydeco] OR from the sweat chloride test result obtained at the Screening Visit); OR
• If the sweat chloride value is <60 mmol/L, there must be documented evidence of chronic sinopulmonary disease4 and/or gastrointestinal disease consistent with a diagnosis of CF as judged by the principal investigator, manifest by at least 1 of the following:
o Persistent colonization/infection, defined as =2 positive respiratory cultures within a 6 month period, with 1 or more typical CF pathogens (e.g., Staphylococcus aureus, Haemophilus influenzae, mucoid and nonmucoid Pseudomonas aeruginosa)
o Chronic cough and sputum production
o Persistent chest radiograph abnormalities consistent with CF pulmonary disease (e.g., bronchiectasis, atelectasis, infiltrates, hyperinflation)
o Nasal polyps, chronic sinusitis as manifest by radiographic or computed tomographic abnormalities of the paranasal sinuses
o Evidence of gastrointestinal disease consistent with the diagnosis of CF
o Significant delays in growth and/or weight gain consistent with the diagnosis of CF
9. Subjects with ppFEV1 of =70 percentage points adjusted for age, sex, height, and ethnicity using the Global Lung Function Initiative (GLI) equation5 at the Screening Visit (Section 11.4.2 of the Protocol).
10. Subjects with a screening LCI2.5 result =7.5.
11. Subjects with stable CF disease as deemed by the investigator at the Screening Visit.

Exclusion Criteria

1. 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.
For example, history of cirrhosis with portal hypertension and/or history of risk factors for Torsades de Pointes (e.g., familial long QT syndrome, hypokalemia, heart failure, left ventricular hypertrophy, bradycardia, myocardial infarction, cardiomyopathy, history of arrhythmia [ventricular and atrial fibrillation], obesity, acute neurologic events [subarachnoid hemorrhage, intracranial hemorrhage, cerebrovascular accident, intracranial trauma], and autonomic neuropathy).
2. 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).
3. Any of the following abnormal laboratory values at the Screening Visit:
• Hemoglobin <10 g/dL
• Abnormal liver function defined as any 2 or more of the following:
o =3 × upper limit of normal (ULN) aspartate aminotransferase (AST)
o =3 × ULN alanine aminotransferase (ALT)
o =3 × ULN gamma-glutamyl transpeptidase (GGT)
o =3 × ULN alkaline phosphatase (ALP)
o =2 × ULN total bilirubin
• Abnormal liver function defined as any increase of =5 × ULN ALT or AST
• Abnormal renal function defined as glomerular filtration rate =45 mL/min/1.73 m2 (calculated by the Counahan-Barratt equation)6
4. 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).
5. Colonization with organisms associated with a more rapid decline in pulmonary status (e.g., Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus) at the Screening Visit. The investigator could be guided by the following suggested criteria for a subject to be considered free of colonization:
• The subject should have had at least 2 respiratory tract cultures negative for these organisms within the past 12 months, with no subsequent positive cultures.
• These 2 respiratory tract cultures should have been separated by at least 3 months.
• One of these 2 respiratory tract cultures should have been obtained within the past 6 months.
6. 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.
7. History of solid organ or hematological transplantation at the Screening Visit.
8. Ongoing or prior participation in an investigational drug study or use of commercially available CFTR modulator that does not align with the following requirements:
• A washout period of 30 days or 5 terminal half-lives of the previous investigational study drug, whichever is longer, must elapse before screening.
o The duration of the elapsed time may be longer if required by local regulations.

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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