Cystic Fibrosis
Conditions
Brief summary
This study was evaluate the effect of elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) on glucose tolerance in CF participants, 12 years of age and older who are heterozygous for the F508del mutation and a minimal function mutation (F/MF genotypes), with abnormal glucose metabolism.
Interventions
DRUGELX/TEZ/IVA
Fixed dose combination (FDC) tablets for oral administration.
DRUGIVA
Tablets for oral administration.
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Heterozygous for F508del and an MF mutation (F/MF genotypes) * Forced expiratory volume in 1 second (FEV1) value ≥ 30% of predicted mean for age, sex, and height * Abnormal glucose tolerance determined by an OGTT as either: * Impaired glucose tolerance (IGT) defined as 2 hour post OGTT blood glucose level ≥140 to \<200 mg/dL (≥7.77 to \<11.10 mmol/L) and fasting blood glucose level \<126 mg/dL (\<7.00 mmol/L) * CF-related diabetes (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) Key
Exclusion criteria
* Clinically significant liver cirrhosis with or without portal hypertension * Solid organ or hematological transplantation * Lung infection with organisms associated with a more rapid decline in pulmonary status * Type 1 or Type 2 diabetes * Duration of CFRD ≥5 years Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-hour Blood Glucose Levels Following an OGTT to the Average of Week 36 and Week 48 | Baseline, Week 36 and 48 | Baseline 2-hour post-OGTT blood glucose level was defined as the average of valid pre-dose measurements at screening and Day 1. OGTT results were considered valid only when the participant was fasting for at least 8 hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Improvement in Dysglycemia Categorization at Week 48 | Baseline, Week 48 | Baseline dysglycemia category was defined as the most recent non-missing measurement before the first dose of study drug in the treatment period. Improvement in dysglycemia is a change from cystic fibrosis-related diabetes (CFRD) at baseline to impaired glucose tolerance (IGT)/normal glucose tolerance (NGT) at Week 48 OR change from IGT at baseline to NGT at Week 48. CFRD: 2-hour post-OGTT blood glucose level ≥200 mg/dL or fasting blood glucose level ≥126 mg/dL; IGT: 2-hour post-OGTT blood glucose level ≥140 to \<200 mg/dL and fasting blood glucose level \<126 mg/dL; NGT: 2 hour post-OGTT blood glucose level \<140 mg/dL and fasting blood glucose level \<126 mg/dL. |
| Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Day 1 up to Week 52 | — |
Countries
Australia, Belgium, Czechia, France, Italy, Netherlands, Spain
Participant flow
Pre-assignment details
This study was conducted in participants with cystic fibrosis (CF) aged 12 years and older who are heterozygous for the F508del mutation and a minimal function mutation (F/MF genotypes), with abnormal glucose metabolism.
Participants by arm
| Arm | Count |
|---|---|
| ELX/TEZ/IVA Participants received ELX 200 mg /TEZ 100 mg /IVA 150 mg in the morning and IVA 150 mg in the evening. | 69 |
| Total | 69 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrawal of consent (not due to AE) | 2 |
Baseline characteristics
| Characteristic | ELX/TEZ/IVA |
|---|---|
| 2-hour Post-OGTT Blood Glucose Levels | 217.6 milligrams per deciliter (mg/dl) STANDARD_DEVIATION 73.1 |
| Age, Customized Less than (<)18 years | 19 Participants |
| Age, Customized More than or equal to (≥)18 years | 50 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 8 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Not collected per local regulations | 20 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 41 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 48 Participants |
| Sex: Female, Male Female | 31 Participants |
| Sex: Female, Male Male | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 69 |
| other Total, other adverse events | 62 / 69 |
| serious Total, serious adverse events | 6 / 69 |
Outcome results
Primary
Change From Baseline in 2-hour Blood Glucose Levels Following an OGTT to the Average of Week 36 and Week 48
Baseline 2-hour post-OGTT blood glucose level was defined as the average of valid pre-dose measurements at screening and Day 1. OGTT results were considered valid only when the participant was fasting for at least 8 hours.
Time frame: Baseline, Week 36 and 48
Population: The Full Analysis Set (FAS) will include all enrolled participants who carry the intended CFTR allele mutation and have received at least 1 dose of study drug. Here, Overall Number of Participants Analyzed signifies participants who were evaluable for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ELX/TEZ/IVA | Change From Baseline in 2-hour Blood Glucose Levels Following an OGTT to the Average of Week 36 and Week 48 | -35.0 milligrams per deciliter (mg/dl) |
Secondary
Percentage of Participants With Improvement in Dysglycemia Categorization at Week 48
Baseline dysglycemia category was defined as the most recent non-missing measurement before the first dose of study drug in the treatment period. Improvement in dysglycemia is a change from cystic fibrosis-related diabetes (CFRD) at baseline to impaired glucose tolerance (IGT)/normal glucose tolerance (NGT) at Week 48 OR change from IGT at baseline to NGT at Week 48. CFRD: 2-hour post-OGTT blood glucose level ≥200 mg/dL or fasting blood glucose level ≥126 mg/dL; IGT: 2-hour post-OGTT blood glucose level ≥140 to \<200 mg/dL and fasting blood glucose level \<126 mg/dL; NGT: 2 hour post-OGTT blood glucose level \<140 mg/dL and fasting blood glucose level \<126 mg/dL.
Time frame: Baseline, Week 48
Population: FAS. Here, Overall Number of Participants Analyzed signifies the number participants with non-missing dysglycemia categorization at Week 48 among participants with abnormal glucose tolerance at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ELX/TEZ/IVA | Percentage of Participants With Improvement in Dysglycemia Categorization at Week 48 | 37.7 percentage of participants |
Secondary
Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time frame: Day 1 up to Week 52
Population: Safety set included all participants who received at least 1 dose of study drug in the treatment period.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ELX/TEZ/IVA | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with TEAEs | 67 Participants |
| ELX/TEZ/IVA | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 6 Participants |