Cystic Fibrosis, Advanced Lung Disease
Conditions
Brief summary
The purpose of this study is to evaluate the safety and tolerability of LUM/IVA combination therapy in subjects 12 years and older with CF and advanced lung disease and who are homozygous for the F508del CFTR mutation
Interventions
DRUGLumacaftor
DRUGIvacaftor
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
* Homozygous for the F508del-CFTR mutation; historical genotype must be documented in the participant's source documents. * Percent predicted FEV1 \<40 of adjusted for age, sex, and height at Screening
Exclusion criteria
* Participant currently receiving invasive mechanical ventilation. * History of any comorbidity 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 participant * Any clinically significant laboratory abnormalities at screening that would interfere with the study assessments or pose an undue risk for the subject * A 12-lead electrocardiograms (ECG) demonstrating QTcF \>450 msec at Screening * History of solid organ or hematological transplantation * History of alcohol or drug abuse in the past year * Ongoing or prior participation in an investigational drug study (including studies investigating lumacaftor and/or ivacaftor) within 30 days of screening. * Use of strong inhibitors, moderate inducers, or strong inducers of CYP3A * Pregnant and nursing females: Females of childbearing potential must have a negative pregnancy test at Screening and Day 1. * Sexually active subjects of reproductive potential who are not willing to follow the contraception requirements * Use of beta blockers or the equivalent at Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | Day 1 up to Week 28 | AE: any untoward medical occurrence in a participant during the study; event does not necessarily have a causal relationship with treatment. This includes any newly occurring event/previous condition that has increased in severity/frequency after informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event, which falls into any of the following categories, regardless of its relationship to study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. TEAEs: AEs that started/ worsened on/after the start of study drug through the Safety Follow up Visit (4 weeks after the last dose of study drug). Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Up to Week 24 | Baseline, Up to Week 24 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification. |
| Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Up to Week 24 | Baseline, Up to Week 24 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate FEV1 (for age, gender, race, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification. |
| Absolute Change From Baseline in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain Score Through Week 24 | Baseline, Through Week 24 | 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 (for example, coughing, congestion, wheezing), the scaled score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification. |
| Number of Hospitalizations | Baseline through Week 24 | Number of hospitalizations (all causes) through Week 24 was summarized. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification. |
| Absolute Change From Baseline in Sweat Chloride at Average of Day 15 and Week 4 | Baseline, Day 15 and Week 4 | Sweat samples were collected using an approved collection device. Baseline was defined as the average of the measurements at screening and on Day 1 pre-dose. The average absolute change from baseline in sweat chloride was derived as: (Average of Day 15 and Week 4 value) minus Baseline value. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification. |
| Duration For Which Participants Received Intravenous (IV) Antibiotics | Baseline through Week 24 | The duration for which participants received IV antibiotics for sinopulmonary signs and symptoms were reported. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification. |
Countries
United States
Participant flow
Pre-assignment details
A total of 46 participants were enrolled and treated in the study.
Participants by arm
| Arm | Count |
|---|---|
| LUM/IVA Participants received LUM 400 mg in combination with IVA 250 mg as FDC tablet orally q12h for 24 weeks. A reduced initial dose of LUM 200 mg in combination with IVA 125 mg FDC tablet orally q12h was permitted. | 46 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 6 |
| Overall Study | Death | 1 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Other | 2 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | LUM/IVA |
|---|---|
| Age, Continuous | 32.1 years STANDARD_DEVIATION 9 |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 46 |
| other Total, other adverse events | 43 / 46 |
| serious Total, serious adverse events | 18 / 46 |
Outcome results
Primary
Number of Participants With Treatment Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
AE: any untoward medical occurrence in a participant during the study; event does not necessarily have a causal relationship with treatment. This includes any newly occurring event/previous condition that has increased in severity/frequency after informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event, which falls into any of the following categories, regardless of its relationship to study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. TEAEs: AEs that started/ worsened on/after the start of study drug through the Safety Follow up Visit (4 weeks after the last dose of study drug). Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.
Time frame: Day 1 up to Week 28
Population: Safety Set included all participants who were exposed to any amount of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LUM/IVA | Number of Participants With Treatment Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | Participants with AEs | 43 Participants |
| LUM/IVA | Number of Participants With Treatment Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | Participants with SAEs | 18 Participants |
Secondary
Absolute Change From Baseline in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain Score Through Week 24
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 (for example, coughing, congestion, wheezing), the scaled score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.
Time frame: Baseline, Through Week 24
Population: FAS included all participants who were enrolled and administered any amount of study drug. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LUM/IVA | Absolute Change From Baseline in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain Score Through Week 24 | 2.5 Units on a scale | Standard Error 1.7 |
Secondary
Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Up to Week 24
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate FEV1 (for age, gender, race, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.
Time frame: Baseline, Up to Week 24
Population: FAS included all participants who were enrolled and administered any amount of study drug. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LUM/IVA | Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Up to Week 24 | -0.02 Liter (L) | Standard Error 0.03 |
Secondary
Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Up to Week 24
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.
Time frame: Baseline, Up to Week 24
Population: Full Analysis Set (FAS) included all participants who were enrolled and administered any amount of study drug. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LUM/IVA | Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Up to Week 24 | -0.4 Percent predicted of FEV1 | Standard Error 0.7 |
Secondary
Absolute Change From Baseline in Sweat Chloride at Average of Day 15 and Week 4
Sweat samples were collected using an approved collection device. Baseline was defined as the average of the measurements at screening and on Day 1 pre-dose. The average absolute change from baseline in sweat chloride was derived as: (Average of Day 15 and Week 4 value) minus Baseline value. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.
Time frame: Baseline, Day 15 and Week 4
Population: FAS included all participants who were enrolled and administered any amount of study drug. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LUM/IVA | Absolute Change From Baseline in Sweat Chloride at Average of Day 15 and Week 4 | -16.4 Millimoles per litre (mmol/L) | Standard Error 1.3 |
Secondary
Duration For Which Participants Received Intravenous (IV) Antibiotics
The duration for which participants received IV antibiotics for sinopulmonary signs and symptoms were reported. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.
Time frame: Baseline through Week 24
Population: FAS included all participants who were enrolled and administered any amount of study drug. Here, Number of Participants Analyzed signifies those participants who received at least one IV antibiotic for sinopulmonary signs and symptoms.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LUM/IVA | Duration For Which Participants Received Intravenous (IV) Antibiotics | 11.38 Days | Standard Deviation 18.15 |
Secondary
Number of Hospitalizations
Number of hospitalizations (all causes) through Week 24 was summarized. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.
Time frame: Baseline through Week 24
Population: FAS included all participants who were enrolled and administered any amount of study drug. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LUM/IVA | Number of Hospitalizations | 23 Hospitalizations |