Cystic Fibrosis
Conditions
Brief summary
This study will evaluate the efficacy of tezacaftor in combination with ivacaftor (TEZ/IVA) in participants with cystic fibrosis (CF) aged 6 through 11 years, who are homozygous for the F508del mutation (F/F) or heterozygous for F508del with an eligible residual function mutation (F/RF).
Interventions
DRUGTEZ/IVA
Participants weighing \<40 kg received TEZ 50 mg/IVA 75 mg FDC tablet and those weighing ≥40 kg received TEZ 100 mg/IVA 150 mg FDC tablet.
DRUGIVA
Participants weighing \<40 kg IVA 75 mg tablet and those weighing ≥40 kg received IVA 150 mg tablet.
DRUGPlacebo
Placebo matched to TEZ/IVA FDC
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Homozygous for F508del or heterozygous for F508del and an RF mutation (as defined in the protocol). * Participants with ppFEV1 of ≥70 percentage points adjusted for age, sex, height. * Participants with a screening LCI2.5 result ≥7.5. * Participants who are able to swallow tablets. Key
Exclusion criteria
* Clinically significant cirrhosis with or without portal hypertension. * Colonization with organisms associated with a more rapid decline in pulmonary status. * Solid organ or hematological transplantation. Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Lung Clearance Index 2.5 (LCI2.5) Through Week 8 | From baseline through Week 8 | LCI2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Sweat Chloride At Week 8 | From baseline at Week 8 | Sweat samples were collected using an approved collection device. |
| Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 8 | From baseline through Week 8 | The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. |
| Safety and Tolerability as Assessed Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) up to Safety Follow-up Visit | From first dose of study drug up to safety follow-up visit (up to Week 12) | — |
Countries
Australia, Belgium, Denmark, France, Germany, Ireland, Poland, Switzerland, United Kingdom
Participant flow
Pre-assignment details
A total of 69 participants were randomized, out of which 67 participants received study drug and were included in participant flow and baseline characteristics section.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants with genotype F/F received placebo matched to TEZ/IVA fixed dose combination (FDC) in the morning and placebo matched to IVA in the evening for 8 weeks. | 10 |
| TEZ/IVA Participants with genotype F/F received TEZ/IVA FDC in the morning and IVA in the evening for 8 weeks. Participants with genotype F/RF received TEZ/IVA FDC and placebo matched to IVA in the morning and IVA in the evening for 8 weeks. | 54 |
| Ivacaftor Participants with genotype F/RF received placebo matched to TEZ/IVA FDC in the morning and IVA in morning and evening for 8 weeks. | 3 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Other | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | TEZ/IVA | Ivacaftor | Total |
|---|---|---|---|---|
| Age, Continuous | 9.0 years STANDARD_DEVIATION 1.7 | 8.5 years STANDARD_DEVIATION 1.7 | 9.0 years STANDARD_DEVIATION 1.7 | 8.6 years STANDARD_DEVIATION 1.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 46 Participants | 3 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 7 Participants | 0 Participants | 7 Participants |
| Lung Clearance Index 2.5 (LCI2.5) | 9.67 lung clearance index STANDARD_DEVIATION 1.65 | 9.56 lung clearance index STANDARD_DEVIATION 2.06 | 8.60 lung clearance index STANDARD_DEVIATION 1.4 | 9.54 lung clearance index STANDARD_DEVIATION 1.97 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 10 Participants | 51 Participants | 3 Participants | 64 Participants |
| Sex: Female, Male Female | 6 Participants | 29 Participants | 2 Participants | 37 Participants |
| Sex: Female, Male Male | 4 Participants | 25 Participants | 1 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 54 | 0 / 3 |
| other Total, other adverse events | 8 / 10 | 31 / 54 | 2 / 3 |
| serious Total, serious adverse events | 0 / 10 | 0 / 54 | 0 / 3 |
Outcome results
Primary
Absolute Change in Lung Clearance Index 2.5 (LCI2.5) Through Week 8
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 8
Population: Full Analysis Set: all participants who were randomized, received at least 1 dose of study drug and had an eligible genotype. As per the pre-specified analysis, efficacy was only planned to be assessed for TEZ/IVA group. Placebo or IVA groups were used for blinding purposes only and were not applicable for the purpose of primary efficacy analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TEZ/IVA | Absolute Change in Lung Clearance Index 2.5 (LCI2.5) Through Week 8 | -0.51 lung clearance index | Standard Error 0.11 |
p-value: <0.0001Mixed-effects model for repeated measure
Secondary
Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 8
The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
Time frame: From baseline through Week 8
Population: FAS. As per the pre-specified analysis, efficacy was only planned to be assessed for TEZ/IVA group. Placebo or IVA groups were used for blinding purposes only and were not applicable for the purpose of secondary efficacy analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TEZ/IVA | Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 8 | 2.3 units on a scale | Standard Error 1.2 |
p-value: 0.0546Mixed-effects model for repeated measure
Secondary
Absolute Change in Sweat Chloride At Week 8
Sweat samples were collected using an approved collection device.
Time frame: From baseline at Week 8
Population: FAS. As per the pre-specified analysis, efficacy was only planned to be assessed for TEZ/IVA group. Placebo or IVA groups were used for blinding purposes only and were not applicable for the purpose of secondary efficacy analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TEZ/IVA | Absolute Change in Sweat Chloride At Week 8 | -12.3 millimole per liter (mmol/L) | Standard Error 1.5 |
p-value: <0.0001Mixed-effects model for repeated measure
Secondary
Safety and Tolerability as Assessed Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) up to Safety Follow-up Visit
Time frame: From first dose of study drug up to safety follow-up visit (up to Week 12)
Population: Safety set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TEZ/IVA | Safety and Tolerability as Assessed Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) up to Safety Follow-up Visit | Participants with AEs | 8 Participants |
| TEZ/IVA | Safety and Tolerability as Assessed Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) up to Safety Follow-up Visit | Participants with SAEs | 0 Participants |
| TEZ/IVA | Safety and Tolerability as Assessed Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) up to Safety Follow-up Visit | Participants with AEs | 41 Participants |
| TEZ/IVA | Safety and Tolerability as Assessed Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) up to Safety Follow-up Visit | Participants with SAEs | 0 Participants |
| Ivacaftor | Safety and Tolerability as Assessed Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) up to Safety Follow-up Visit | Participants with AEs | 2 Participants |
| Ivacaftor | Safety and Tolerability as Assessed Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) up to Safety Follow-up Visit | Participants with SAEs | 0 Participants |