Cystic Fibrosis
Conditions
Brief summary
This study will explore the impact of lumacaftor/ivacaftor (LUM/IVA) on disease progression in subjects aged 2 through 5 years with cystic fibrosis (CF), homozygous for F508del (F/F).
Interventions
DRUGLUM/IVA
FDC tablets or granules for oral administration.
DRUGPlacebo
Placebo matched to LUM/IVA for oral administration.
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blinded in Part 1, and Open label in Part 2
Eligibility
Sex/Gender
ALL
Age
2 Years to 5 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Subjects with confirmed diagnosis of CF. * Homozygous for F508del (F/F). * Subjects who weigh ≥8 kg without shoes and wearing light clothing at the Screening Visit. Key
Exclusion criteria
* Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject. * Solid organ or hematological transplantation. * History of any illness or comorbidity reviewed at the Screening Visit that, in the opinion of the investigator, might confound the results of the study. Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Absolute Change From Baseline in MRI Global Chest Score at Week 48 | From Baseline at Week 48 | MRI scans assessed semi-quantitatively via a standardized chest MRI scoring system. Each participant had 6 lobes scored using 7 scoring parameters:1) Bronchiectasis/wall thickening 2) Mucus plugging 3) Abscesses/sacculations 4) Consolidations 5) Special findings 6)Mosaic pattern 7) Perfusion abnormalities. For each of 7 parameter, there were scores of 6 lobes (score of each lobe : 0= normal value, 1 = \<50% of lobe involved and 2 = \>=50% of lobe involved). MRI global score was calculated as sum of parameters 1 to 7. MRI total score is ranged from 0-84. Higher score indicate more lobe involvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Absolute Change in Lung Clearance Index2.5 (LCI2.5) Through Week 48 | From Baseline Through Week 48 | LCI2.5 represents the number of lung turnovers required to reduce the end-tidal inert gas concentration to 1/40th of its starting value. |
| Part 1: Absolute Change in Weight-for-age Z-score at Week 48 | From Baseline at Week 48 | The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard. |
| Part 1: Absolute Change in Stature-for-age Z-score at Week 48 | From Baseline at Week 48 | The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard. |
| Part 1: Absolute Change in Body Mass Index (BMI)-For-age Z-score at Week 48 | From Baseline at Week 48 | BMI was defined as weight in kilogram (kg) divided by squared height in meters (m\^2). The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard. |
Countries
Germany
Participant flow
Recruitment details
This study was planned in 2 parts: Part 1 (Placebo-controlled Period) and Part 2 (Open-label Period). The primary and secondary efficacy analyses were planned for only Part 1.
Pre-assignment details
This study was conducted in participants with cystic fibrosis (CF) aged 2 to 5 years.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Placebo Participants received placebo matched to LUM/IVA in placebo-controlled period for 48 weeks. | 16 |
| Part 1: LUM/IVA Participants weighing \<14 kg at screening received LUM 100 mg/IVA 125 mg FDC every q12h in placebo-controlled period for 48 weeks. Participants weighing \>=14 kg at screening received LUM 150 mg/IVA 188 mg FDC q12h in placebo-controlled period for 48 weeks. | 35 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Open-label Period (48 Weeks) | Withdrawal of Consent (not due to AE) | 0 | 0 | 1 |
| Placebo-controlled Period (48 Weeks) | Adverse Event | 0 | 1 | 0 |
| Placebo-controlled Period (48 Weeks) | Withdrawal of Consent (not due to AE) | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Part 1: Placebo | Part 1: LUM/IVA | Total |
|---|---|---|---|
| Age, Continuous | 4.2 years STANDARD_DEVIATION 1 | 4.2 years STANDARD_DEVIATION 1 | 4.2 years STANDARD_DEVIATION 1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 35 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Magnetic Resonance Imaging (MRI) Global Chest Score | 21.4 score on a scale STANDARD_DEVIATION 9.3 | 17.6 score on a scale STANDARD_DEVIATION 9.7 | 18.8 score on a scale STANDARD_DEVIATION 9.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 35 Participants | 51 Participants |
| Sex: Female, Male Female | 7 Participants | 11 Participants | 18 Participants |
| Sex: Female, Male Male | 9 Participants | 24 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 35 | 0 / 49 |
| other Total, other adverse events | 16 / 16 | 33 / 35 | 41 / 49 |
| serious Total, serious adverse events | 2 / 16 | 7 / 35 | 12 / 49 |
Outcome results
Primary
Part 1: Absolute Change From Baseline in MRI Global Chest Score at Week 48
MRI scans assessed semi-quantitatively via a standardized chest MRI scoring system. Each participant had 6 lobes scored using 7 scoring parameters:1) Bronchiectasis/wall thickening 2) Mucus plugging 3) Abscesses/sacculations 4) Consolidations 5) Special findings 6)Mosaic pattern 7) Perfusion abnormalities. For each of 7 parameter, there were scores of 6 lobes (score of each lobe : 0= normal value, 1 = \<50% of lobe involved and 2 = \>=50% of lobe involved). MRI global score was calculated as sum of parameters 1 to 7. MRI total score is ranged from 0-84. Higher score indicate more lobe involvement.
Time frame: From Baseline at Week 48
Population: Full Analysis Set (FAS) included all randomized participants who carried the intended CF transmembrane conductance regulator gene (CFTR) allele mutation and received at least 1 dose of study drug in Part 1. Here overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Part 1: Absolute Change From Baseline in MRI Global Chest Score at Week 48 | -0.3 score on a scale | Standard Deviation 6.1 |
| Part 1: LUM/IVA | Part 1: Absolute Change From Baseline in MRI Global Chest Score at Week 48 | -1.7 score on a scale | Standard Deviation 6.6 |
95% CI: [-5.5, 2.6]
Secondary
Part 1: Absolute Change in Body Mass Index (BMI)-For-age Z-score at Week 48
BMI was defined as weight in kilogram (kg) divided by squared height in meters (m\^2). The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.
Time frame: From Baseline at Week 48
Population: FAS.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part 1: Placebo | Part 1: Absolute Change in Body Mass Index (BMI)-For-age Z-score at Week 48 | -0.24 z-score |
| Part 1: LUM/IVA | Part 1: Absolute Change in Body Mass Index (BMI)-For-age Z-score at Week 48 | 0.20 z-score |
Secondary
Part 1: Absolute Change in Lung Clearance Index2.5 (LCI2.5) Through Week 48
LCI2.5 represents the number of lung turnovers required to reduce the end-tidal inert gas concentration to 1/40th of its starting value.
Time frame: From Baseline Through Week 48
Population: FAS.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part 1: Placebo | Part 1: Absolute Change in Lung Clearance Index2.5 (LCI2.5) Through Week 48 | 0.32 lung clearance index |
| Part 1: LUM/IVA | Part 1: Absolute Change in Lung Clearance Index2.5 (LCI2.5) Through Week 48 | -0.37 lung clearance index |
Secondary
Part 1: Absolute Change in Stature-for-age Z-score at Week 48
The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.
Time frame: From Baseline at Week 48
Population: FAS.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part 1: Placebo | Part 1: Absolute Change in Stature-for-age Z-score at Week 48 | 0.10 z-score |
| Part 1: LUM/IVA | Part 1: Absolute Change in Stature-for-age Z-score at Week 48 | 0.09 z-score |
Secondary
Part 1: Absolute Change in Weight-for-age Z-score at Week 48
The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.
Time frame: From Baseline at Week 48
Population: FAS.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part 1: Placebo | Part 1: Absolute Change in Weight-for-age Z-score at Week 48 | -0.07 z-score |
| Part 1: LUM/IVA | Part 1: Absolute Change in Weight-for-age Z-score at Week 48 | 0.13 z-score |