A study Evaluating the effect of Elexacaftor/Tezacaftor/Ivacaftor on Glucose Tolerance in Cystic Fibrosis Subjects with Abnormal Glucose Metabolism

Phase 1

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

Registration Number: EUCTR2020-003170-44-CZ

Lead Sponsor: Vertex Pharmaceuticals Incorporated

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 60

Inclusion Criteria

1. Subject (or his or her legally appointed and authorized
representative) will sign and date an informed consent form (ICF), and,
when 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. Subjects (male and female) 12 years of age or older on the date of
informed consent.
4. Subjects heterozygous for F508del and an MF mutation (F/MF
genotypes).
a. Genotype should be confirmed at the Screening Visit.
b. If the screening CFTR genotype result is not received before the first
dose of study drug, a previous CFTR genotype laboratory report may be
used to establish eligibility.
c. Subjects who have been enrolled and whose screening genotype does
not confirm study eligibility must be discontinued from the study
(Section 9.9).
5. Forced expiratory volume in 1 second (FEV1) value .30% of predicted
mean for age, sex, and height (equations of the Global Lung Function
Initiative [GLI])9 at the Screening Visit (spirometry measurements must
meet American Thoracic Society/European Respiratory Society criteria10
for acceptability and repeatability) and stable CF disease as judged by the investigator.
6. Willing to remain on a stable CF treatment regimen (other than CFTR
modulators) through completion of study participation.
7. Abnormal glucose tolerance as determined by an OGTT, classified as
either IGT (defined as 2-hour post-OGTT blood glucose level =140 to
<200 mg/dL [=7.77 to <11.10 mmol/L]) or
CFRD (defined as either fasting hyperglycemia [blood glucose level =126
mg/dL
(=7.00 mmol/L) after an 8-hour fast] or 2-hour post-OGTT blood glucose
level =200 mg/dL
[=11.10 mmol/L]).
Are the trial subjects under 18? yes
Number of subjects for this age range: 60
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 20
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 20

Exclusion Criteria

1. History of any illness or any clinical condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug(s) to the subject. This includes, but is not limited to, the following:
- Clinically significant liver cirrhosis with or without portal hypertension
- Solid organ or hematological transplantation
- Alcohol or drug abuse in the past year, including, but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator
- Cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical carcinoma in situ (all 3 with no recurrence for the last 5 years)
2. Type 1 or Type 2 diabetes, or a first degree relative with Type 2 diabetes.
3. Duration of CFRD .3 years.
4. 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).
5. Any of the following abnormal laboratory values at screening:
- Hemoglobin <10 g/dL
- Total bilirubin .2 ¡Ñ upper limit of normal (ULN)
- Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), or alkaline phosphatase (ALP) .3 ¡Ñ ULN
- Abnormal renal function defined as glomerular filtration rate .45.mL/min/1.73.m2 (calculated by the Counahan-Barratt equation)11
6. 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).
7. Lung infection with organisms associated with a more rapid decline in pulmonary status (including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus). For subjects who have had a history of a positive culture, the investigator will apply the following criteria to establish whether the subject is free of infection with such organisms:
- The subject has not had a respiratory tract culture positive for these organisms within the 12 months before the date of informed consent.
- The subject has had at least 2 respiratory tract cultures negative for such organisms within the 12 months before the date of informed consent, with the first and last of these separated by at least 3 months, and the most recent one within the 6 months before the date of informed consent.
8. An acute illness not related to CF (e.g., gastroenteritis) within 14 days before the first dose of study drug (Day 1).
9. Ongoing or prior participation in an investigational drug study (including studies investigating ELX with or without coadministration of other study drugs) within 28 days of the Screening Visit.
- A washout period of 5 terminal half-lives of the previous investigational study drug, or 28 days, whichever is longer, must elapse before the Screening Visit.
- The duration of the elapsed time may be longer if required by local regulations.
10. Use of restricted medication (including antidiabetic medication other than insulin, which must be at a dose no greater than 0.3 units/kg/day) within specified duration before the first dose of study drug as defined in Table 9-1.
11. BMI .30 kg/m2 at the Screening Visit.
12. Pregnant and breast-feeding females. All female subjects regardless of childbearing potential status (Section 11.4.6) must have a negative pregnancy test at the Screening Visit and the Day 1 Visit.
13. The subject or a close relative of the subject is

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the effect of elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) on glucose tolerance in CF subjects with impaired glucose tolerance (IGT) or CF-related diabetes (CFRD);Secondary Objective: To evaluate the safety and tolerability of ELX/TEZ/IVA;Primary end point(s): Change from baseline in 2-hour blood glucose levels following an oral glucose tolerance test<br>(OGTT) to the average of Week 36 and Week 48;Timepoint(s) of evaluation of this end point: Week 36 and Week 48

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): „h Proportion of subjects with improvement in dysglycemia categorization (CFRD, IGT,<br>normal glucose tolerance [NGT]) at Week 48<br>„h Safety and tolerability of ELX/TEZ/IVA based on adverse events (AEs), clinical laboratory<br>values, ECGs, vital signs, and pulse oximetry;Timepoint(s) of evaluation of this end point: Week 48

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