Cystic Fibrosis, Homozygous for the F508del CFTR Mutation
Conditions
Brief summary
The primary objective of the study was to evaluate the efficacy of lumacaftor in combination with ivacaftor at Week 24 in participants aged 12 years and older with cystic fibrosis (CF) who are homozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene.
Detailed description
This was a Phase 3, randomized, double-blind, placebo-controlled, parallel-group multicenter study of orally administered lumacaftor in combination with ivacaftor in participants aged 12 years and older with CF who are homozygous for the F508del-CFTR mutation. The study included a Screening Period (Day -28 through Day -1), a Treatment Period (Day 1 \[first dose of study drug\] to Week 24 ± 5 days), and a Safety Follow-up Visit (4 weeks ± 7 days after the Week 24 Visit).
Interventions
DRUGPlacebo
Matching placebo tablet
Fixed dose combination tablet
DRUGIvacaftor
Film-coated tablet
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of CF * Homozygous for the F508del CFTR mutation * Forced expiratory volume in 1 second (FEV1) greater than or equal to (\>=) 40 percent (%) and less than or equal to (=\<) 90% of predicted normal for age, sex, and height * Willing to remain on a stable CF medication regimen through Week 24 or, if applicable, the Safety Follow up Visit
Exclusion criteria
* An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before first dose of study drug * 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 Cytochrome P450 3A (CYP3A) within 14 days before Day 1 of dosing
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 24 | Baseline, Week 16 and 24 | Absolute change from baseline at week 24 was assessed as the average treatment effect at Week 16 and at 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, 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change From Baseline in Percent Predicted FEV1 at Week 24 | Baseline, Week 16 and 24 | Assessed as the average treatment effect at Week 16 and at Week 24. FEV1 and percent predicted FEV1 are defined in Outcome Measure (OM) 1. |
| Absolute Change From Baseline in Body Mass Index (BMI) at Week 24 | Baseline, Week 24 | BMI was defined as weight in kilogram (kg) divided by height\*height in square meter (m\^2). |
| Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Week 24 | Baseline, 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. |
| Percentage of Participants With Response Based on Percent Predicted FEV1 | Week 16 and 24 | A participant was considered as a responder if the participant had \>=5% increase from baseline in average percent predicted FEV1 at Week 16 and at Week 24 (relative change). FEV1 and percent predicted FEV1 are defined in OM 1. A participant with a missing average relative change from baseline in percent predicted FEV1 at Week 16 and at Week 24 was considered as a non-responder. |
| Number of Pulmonary Exacerbation Events | through Week 24 | The total number of days on study is equal to the Week 24 date or the last dose date (whichever occurred last) minus the first dose date plus 1. The total number of years (48 weeks) on study is equal to the number of days on study divided by 336. Pulmonary exacerbation events per year (48 weeks) are reported. |
| Absolute Change From Baseline in Weight at Week 24 | Baseline, Week 24 | — |
| Percentage of Participants With At Least 1 Pulmonary Exacerbation Event | through Week 24 | — |
| Time-to-First Pulmonary Exacerbation | through Week 24 | Time to first pulmonary exacerbation was assessed using Cox Regression method. For participants who completed 24 weeks of treatment, participants without a pulmonary exacerbation before treatment completion were considered censored at the time of treatment completion or at the Week 24 Visit (whichever occurred last). For participants who prematurely discontinued study treatment, participants without a pulmonary exacerbation through the Week 24 Visit were considered censored at the time of the Week 24 Visit. |
| Absolute Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) Index Score at Week 24 | Baseline, Week 24 | EQ-5D-3L: participant rated questionnaire to assess health-related quality of life. It consists of EQ-5D descriptive system and EQ-5D Visual Analog Scale (VAS). EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems (1), some problems (2), and extreme problems (3). The 5 dimensional 3-level systems are converted into a single index utility score. Values for theoretically possible health states are calculated using a regression model and weighted according to the social preferences of the Unites States (US) general population. For this population, the possible EQ-5D-3L index scores ranges from -0.11 (that is, 3 for all 5 dimensions) to 1.0 (that is, 1 for all 5 dimensions), where higher scores indicate a better health state. |
| Absolute Change From Baseline in EQ-5D-3L VAS Score at Week 24 | Baseline, Week 24 | The EQ-5D-3L VAS records the participant's self-rated health on a vertical, visual analogue scale where the best state a participant can imagine is marked 100 and the worst state a participant can imagine is marked 0, higher scores indicates a better health state. |
| Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24 | Baseline, Week 24 | The TSQM is a 14-item self-administered questionnaire which measures participants' experiences with their medication on four dimensions: effectiveness, side effects, convenience and global satisfaction. For each dimension, responses are added and transformed to a scale from 0 to 100, where higher scores indicate greater satisfaction. |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs) | up to Week 28 | AE: any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as Non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the 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. Any AE that increased in severity or that was newly developed at or after the initial dosing of study drug to 28 days after the last dose of study drug is considered treatment-emergent. |
| Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | For C3-6h: 3 to 6 hours after morning dose on Day 1 and 15, Week 4 and 8; For C3-6h,avg 3 to 6 hours after morning dose on Day 15, Week 4 and 8; For Ctrough and Ctrough,avg: before morning dose on Week 4, 8, and 16 | Ctrough, Ctrough,avg, C3-6h, and C3-6h,avg for lumacaftor, M28 lumacaftor (lumacaftor metabolite), ivacaftor, M1 ivacaftor (ivacaftor metabolite), and M6 ivacaftor (ivacaftor metabolite) were calculated. C3-6h,avg is average of individual 3 to 6 hours post-dose observed concentrations across Day 15, and Weeks 4 and 8 and Ctrough,avg is average of individual pre-dose observed concentrations across Weeks 4, 8, and 16. This outcome was not planned to be assessed in Placebo arm. |
| Absolute Change From Baseline in BMI-for-age Z-score at Week 24 | Baseline, Week 24 | Z-Score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is with range from -infinity to +infinity; 0: same mean, \>0: a greater mean, and \<0: a lesser mean than the standard. BMI-for-age z-score was calculated by using centers for disease control and prevention (CDC) growth charts for the pediatric population. |
Countries
Australia, Austria, Belgium, Canada, Denmark, France, Germany, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo matched to LUM and IVA tablet q12h, up to Week 24. | 187 |
| LUM 600 mg qd/IVA 250 mg q12h LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24. | 185 |
| LUM 400 mg q12h/ IVA 250 mg q12h LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24. | 187 |
| Total | 559 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 2 |
| Overall Study | Non-Compliance | 0 | 0 | 1 |
| Overall Study | Randomized But Not Treated | 0 | 2 | 2 |
| Overall Study | Undefined | 0 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 2 |
Baseline characteristics
| Characteristic | Placebo | LUM 600 mg qd/IVA 250 mg q12h | LUM 400 mg q12h/ IVA 250 mg q12h | Total |
|---|---|---|---|---|
| Age, Continuous | 25.7 years STANDARD_DEVIATION 10.02 | 24.3 years STANDARD_DEVIATION 8.31 | 25.0 years STANDARD_DEVIATION 9.03 | 25.0 years STANDARD_DEVIATION 9.16 |
| Sex: Female, Male Female | 97 Participants | 96 Participants | 98 Participants | 291 Participants |
| Sex: Female, Male Male | 90 Participants | 89 Participants | 89 Participants | 268 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 181 / 186 | 179 / 186 | 175 / 187 |
| serious Total, serious adverse events | 57 / 186 | 51 / 186 | 31 / 187 |
Outcome results
Primary
Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 24
Absolute change from baseline at week 24 was assessed as the average treatment effect at Week 16 and at 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, 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.
Time frame: Baseline, Week 16 and 24
Population: Full Analysis Set (FAS) included all randomized participants who received any amount of study drug. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 24 | -0.15 percent predicted of FEV1 | Standard Error 0.539 |
| LUM 600 mg qd/IVA 250 mg q12h | Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 24 | 2.46 percent predicted of FEV1 | Standard Error 0.54 |
| LUM 400 mg q12h/ IVA 250 mg q12h | Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 24 | 2.85 percent predicted of FEV1 | Standard Error 0.54 |
Comparison: Analysis was performed using mixed-effects model for repeated measures (MMRM) model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (less than \[\<\] 18 versus greater than equal to \[\>=\]18 years old), and percent predicted FEV1 severity at Screening (\<70 versus \>=70).p-value: 0.000495% CI: [1.18, 4.06]MMRM
Comparison: Analysis was performed using MMRM model, as described in Statistical Analysis 1.p-value: <0.000195% CI: [1.56, 4.44]MMRM
Secondary
Absolute Change From Baseline in BMI-for-age Z-score at Week 24
Z-Score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is with range from -infinity to +infinity; 0: same mean, \>0: a greater mean, and \<0: a lesser mean than the standard. BMI-for-age z-score was calculated by using centers for disease control and prevention (CDC) growth charts for the pediatric population.
Time frame: Baseline, Week 24
Population: FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Only participants who were \<20 years of age were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in BMI-for-age Z-score at Week 24 | -0.0674 z-score | Standard Error 0.04706 |
| LUM 600 mg qd/IVA 250 mg q12h | Absolute Change From Baseline in BMI-for-age Z-score at Week 24 | 0.1640 z-score | Standard Error 0.04652 |
| LUM 400 mg q12h/ IVA 250 mg q12h | Absolute Change From Baseline in BMI-for-age Z-score at Week 24 | 0.1544 z-score | Standard Error 0.04513 |
Comparison: Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (\<18 versus \>=18 years old), percent predicted FEV1 severity at Screening (\<70 versus \>=70), and baseline BMI z-score.p-value: 0.000595% CI: [0.1037, 0.3589]MMRM
Comparison: Analysis was performed as described in Statistical Analysis 1.p-value: 0.000695% CI: [0.0961, 0.3473]MMRM
Secondary
Absolute Change From Baseline in Body Mass Index (BMI) at Week 24
BMI was defined as weight in kilogram (kg) divided by height\*height in square meter (m\^2).
Time frame: Baseline, Week 24
Population: FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Body Mass Index (BMI) at Week 24 | 0.07 kilogram per square meter (kg/m^2) | Standard Error 0.066 |
| LUM 600 mg qd/IVA 250 mg q12h | Absolute Change From Baseline in Body Mass Index (BMI) at Week 24 | 0.48 kilogram per square meter (kg/m^2) | Standard Error 0.066 |
| LUM 400 mg q12h/ IVA 250 mg q12h | Absolute Change From Baseline in Body Mass Index (BMI) at Week 24 | 0.43 kilogram per square meter (kg/m^2) | Standard Error 0.066 |
Comparison: Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (\<18 versus \>=18 years old), percent predicted FEV1 severity at Screening (\<70 versus \>=70), and baseline BMI.p-value: <0.000195% CI: [0.23, 0.59]MMRM
Comparison: Analysis was performed using MMRM model, as described in Statistical Analysis 1.p-value: 0.000195% CI: [0.17, 0.54]MMRM
Secondary
Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at 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.
Time frame: Baseline, Week 24
Population: FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Week 24 | 2.81 units on a scale | Standard Error 1.153 |
| LUM 600 mg qd/IVA 250 mg q12h | Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Week 24 | 5.02 units on a scale | Standard Error 1.166 |
| LUM 400 mg q12h/ IVA 250 mg q12h | Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Week 24 | 5.66 units on a scale | Standard Error 1.169 |
Comparison: Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (\<18 versus \>=18 years old), percent predicted FEV1 severity at Screening (\<70 versus \>=70), and baseline CFQ-R respiratory domain score.p-value: 0.165195% CI: [-0.91, 5.33]MMRM
Comparison: Analysis was performed using MMRM model, as described in Statistical Analysis 1.p-value: 0.073695% CI: [-0.27, 5.98]MMRM
Secondary
Absolute Change From Baseline in EQ-5D-3L VAS Score at Week 24
The EQ-5D-3L VAS records the participant's self-rated health on a vertical, visual analogue scale where the best state a participant can imagine is marked 100 and the worst state a participant can imagine is marked 0, higher scores indicates a better health state.
Time frame: Baseline, Week 24
Population: FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in EQ-5D-3L VAS Score at Week 24 | 3.3 units on a scale | Standard Error 1.07 |
| LUM 600 mg qd/IVA 250 mg q12h | Absolute Change From Baseline in EQ-5D-3L VAS Score at Week 24 | 5.7 units on a scale | Standard Error 1.08 |
| LUM 400 mg q12h/ IVA 250 mg q12h | Absolute Change From Baseline in EQ-5D-3L VAS Score at Week 24 | 6.6 units on a scale | Standard Error 1.08 |
Comparison: Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (\<18 versus \>=18 years old), percent predicted FEV1 severity at Screening (\<70 versus \>=70), and baseline EQ-5D-3L VAS score.p-value: 0.103495% CI: [-0.5, 5.3]MMRM
Comparison: Analysis was performed as described in Statistical Analysis 1.p-value: 0.026295% CI: [0.4, 6.2]MMRM
Secondary
Absolute Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) Index Score at Week 24
EQ-5D-3L: participant rated questionnaire to assess health-related quality of life. It consists of EQ-5D descriptive system and EQ-5D Visual Analog Scale (VAS). EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems (1), some problems (2), and extreme problems (3). The 5 dimensional 3-level systems are converted into a single index utility score. Values for theoretically possible health states are calculated using a regression model and weighted according to the social preferences of the Unites States (US) general population. For this population, the possible EQ-5D-3L index scores ranges from -0.11 (that is, 3 for all 5 dimensions) to 1.0 (that is, 1 for all 5 dimensions), where higher scores indicate a better health state.
Time frame: Baseline, Week 24
Population: FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) Index Score at Week 24 | 0.0117 units on a scale | Standard Error 0.00673 |
| LUM 600 mg qd/IVA 250 mg q12h | Absolute Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) Index Score at Week 24 | 0.0090 units on a scale | Standard Error 0.00682 |
| LUM 400 mg q12h/ IVA 250 mg q12h | Absolute Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) Index Score at Week 24 | 0.0108 units on a scale | Standard Error 0.00683 |
Comparison: Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (\<18 versus \>=18 years old), percent predicted FEV1 severity at Screening (\<70 versus \>=70), and baseline EQ-5D-3L index score.p-value: 0.767995% CI: [-0.0211, 0.0156]MMRM
Comparison: Analysis was performed as described in Statistical Analysis 1.p-value: 0.921495% CI: [-0.0192, 0.0174]MMRM
Secondary
Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24
The TSQM is a 14-item self-administered questionnaire which measures participants' experiences with their medication on four dimensions: effectiveness, side effects, convenience and global satisfaction. For each dimension, responses are added and transformed to a scale from 0 to 100, where higher scores indicate greater satisfaction.
Time frame: Baseline, Week 24
Population: FAS. Here, n signifies participants who were evaluable for specified category for each arm, respectively.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24 | Effectiveness (n = 159, 161, 161) | -8.49 units on a scale | Standard Error 1.814 |
| Placebo | Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24 | Global Satisfaction (n= 158, 160, 161) | -9.62 units on a scale | Standard Error 1.841 |
| Placebo | Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24 | Convenience (n = 158, 160, 161) | 4.57 units on a scale | Standard Error 1.525 |
| Placebo | Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24 | Side Effects (n = 157, 159, 161) | 2.03 units on a scale | Standard Error 1.144 |
| LUM 600 mg qd/IVA 250 mg q12h | Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24 | Convenience (n = 158, 160, 161) | 4.57 units on a scale | Standard Error 1.523 |
| LUM 600 mg qd/IVA 250 mg q12h | Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24 | Side Effects (n = 157, 159, 161) | -1.14 units on a scale | Standard Error 1.137 |
| LUM 600 mg qd/IVA 250 mg q12h | Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24 | Global Satisfaction (n= 158, 160, 161) | -4.98 units on a scale | Standard Error 1.845 |
| LUM 600 mg qd/IVA 250 mg q12h | Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24 | Effectiveness (n = 159, 161, 161) | 0.15 units on a scale | Standard Error 1.807 |
| LUM 400 mg q12h/ IVA 250 mg q12h | Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24 | Global Satisfaction (n= 158, 160, 161) | -2.46 units on a scale | Standard Error 1.814 |
| LUM 400 mg q12h/ IVA 250 mg q12h | Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24 | Effectiveness (n = 159, 161, 161) | 3.12 units on a scale | Standard Error 1.793 |
| LUM 400 mg q12h/ IVA 250 mg q12h | Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24 | Side Effects (n = 157, 159, 161) | -2.26 units on a scale | Standard Error 1.121 |
| LUM 400 mg q12h/ IVA 250 mg q12h | Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24 | Convenience (n = 158, 160, 161) | 4.88 units on a scale | Standard Error 1.501 |
Comparison: Effectiveness: analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (\<18 versus \>=18 years old), percent predicted FEV1 severity at Screening (\<70 versus \>=70), and baseline TSQM effectiveness score.p-value: 0.000595% CI: [3.77, 13.51]MMRM
Comparison: Effectiveness: analysis was performed as described in Statistical Analysis 1.p-value: <0.000195% CI: [6.75, 16.48]MMRM
Comparison: Side Effects: analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (\<18 versus \>=18 years old), percent predicted FEV1 severity at Screening (\<70 versus \>=70), and baseline TSQM side effects score.p-value: 0.040395% CI: [-6.21, -0.14]MMRM
Comparison: Side Effects: analysis was performed as described in Statistical Analysis 1.p-value: 0.005495% CI: [-7.31, -1.28]MMRM
Comparison: Convenience: analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (\<18 versus \>=18 years old), percent predicted FEV1 severity at Screening (\<70 versus \>=70), and baseline TSQM convenience score.p-value: 195% CI: [-4.07, 4.07]MMRM
Comparison: Convenience: analysis was performed as described in Statistical Analysis 1.p-value: 0.877795% CI: [-3.74, 4.37]MMRM
Comparison: Global Satisfaction: analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (\<18 versus \>=18 years old), percent predicted FEV1 severity at Screening (\<70 versus \>=70), and baseline TSQM global satisfaction score.p-value: 0.066895% CI: [-0.32, 9.61]MMRM
Comparison: Global Satisfaction: analysis was performed as described in Statistical Analysis 1.p-value: 0.004595% CI: [2.23, 12.08]MMRM
Secondary
Absolute Change From Baseline in Weight at Week 24
Time frame: Baseline, Week 24
Population: FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Weight at Week 24 | 0.44 kilograms (kg) | Standard Error 0.187 |
| LUM 600 mg qd/IVA 250 mg q12h | Absolute Change From Baseline in Weight at Week 24 | 1.57 kilograms (kg) | Standard Error 0.188 |
| LUM 400 mg q12h/ IVA 250 mg q12h | Absolute Change From Baseline in Weight at Week 24 | 1.38 kilograms (kg) | Standard Error 0.187 |
Comparison: Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (\<18 versus \>=18 years old), percent predicted FEV1 severity at Screening (\<70 versus \>=70), and baseline weight.p-value: <0.000195% CI: [0.62, 1.64]MMRM
Comparison: Analysis was performed as described in Statistical Analysis 1.p-value: 0.000395% CI: [0.43, 1.46]MMRM
Secondary
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs)
AE: any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as Non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the 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. Any AE that increased in severity or that was newly developed at or after the initial dosing of study drug to 28 days after the last dose of study drug is considered treatment-emergent.
Time frame: up to Week 28
Population: Safety Set (SS) included all randomized participants who received any amount of study drug. Participants were analyzed as per actual treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs) | Participants With Treatment-Emergent AEs | 181 participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs) | Participants With Treatment-Emergent SAEs | 57 participants |
| LUM 600 mg qd/IVA 250 mg q12h | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs) | Participants With Treatment-Emergent AEs | 181 participants |
| LUM 600 mg qd/IVA 250 mg q12h | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs) | Participants With Treatment-Emergent SAEs | 51 participants |
| LUM 400 mg q12h/ IVA 250 mg q12h | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs) | Participants With Treatment-Emergent AEs | 177 participants |
| LUM 400 mg q12h/ IVA 250 mg q12h | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs) | Participants With Treatment-Emergent SAEs | 31 participants |
Secondary
Number of Pulmonary Exacerbation Events
The total number of days on study is equal to the Week 24 date or the last dose date (whichever occurred last) minus the first dose date plus 1. The total number of years (48 weeks) on study is equal to the number of days on study divided by 336. Pulmonary exacerbation events per year (48 weeks) are reported.
Time frame: through Week 24
Population: FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Pulmonary Exacerbation Events | 1.18 pulmonary exacerbation events per year |
| LUM 600 mg qd/IVA 250 mg q12h | Number of Pulmonary Exacerbation Events | 0.82 pulmonary exacerbation events per year |
| LUM 400 mg q12h/ IVA 250 mg q12h | Number of Pulmonary Exacerbation Events | 0.67 pulmonary exacerbation events per year |
Comparison: Analysis was performed using regression analysis for a negative binomial distribution with sex (male versus female), age group at baseline (\<18 versus \>=18 years old), and percent predicted FEV1 severity at Screening (\<70 versus \>=70) as covariates with the logarithm of time on study as the offset.p-value: 0.011695% CI: [0.5187, 0.9209]Negative Binomial Regression
Comparison: Analysis was performed as described in Statistical Analysis 1.p-value: 0.000295% CI: [0.4191, 0.7641]Negative Binomial Regression
Secondary
Percentage of Participants With At Least 1 Pulmonary Exacerbation Event
Time frame: through Week 24
Population: FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With At Least 1 Pulmonary Exacerbation Event | 47.1 percentage of participants |
| LUM 600 mg qd/IVA 250 mg q12h | Percentage of Participants With At Least 1 Pulmonary Exacerbation Event | 36.8 percentage of participants |
| LUM 400 mg q12h/ IVA 250 mg q12h | Percentage of Participants With At Least 1 Pulmonary Exacerbation Event | 28.9 percentage of participants |
Comparison: OR and 95% confidence intervals (CIs) are Mantel-Haenszel estimates. P values are from a Cochran-Mantel-Haenszel test stratified by sex (male versus female), age group at baseline (\<18 versus \>=18 years old), and percent predicted FEV1 severity at Screening (\<70 versus \>=70).p-value: 0.039395% CI: [0.416, 0.9764]Cochran-Mantel-Haenszel
Comparison: Analysis was performed as described in Statistical Analysis 1.p-value: 0.000295% CI: [0.2863, 0.6851]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Response Based on Percent Predicted FEV1
A participant was considered as a responder if the participant had \>=5% increase from baseline in average percent predicted FEV1 at Week 16 and at Week 24 (relative change). FEV1 and percent predicted FEV1 are defined in OM 1. A participant with a missing average relative change from baseline in percent predicted FEV1 at Week 16 and at Week 24 was considered as a non-responder.
Time frame: Week 16 and 24
Population: FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Response Based on Percent Predicted FEV1 | 22.5 percentage of participants |
| LUM 600 mg qd/IVA 250 mg q12h | Percentage of Participants With Response Based on Percent Predicted FEV1 | 45.9 percentage of participants |
| LUM 400 mg q12h/ IVA 250 mg q12h | Percentage of Participants With Response Based on Percent Predicted FEV1 | 41.2 percentage of participants |
Comparison: Odds Ratio (OR) and 95% confidence intervals (Cis) are Mantel-Haenszel estimates. P values are from a Cochran-Mantel-Haenszel test stratified by sex (male versus female), age group at baseline (\<18 versus \>=18 years old), and percent predicted FEV1 severity at Screening (\<70 versus \>=70).p-value: <0.000195% CI: [1.8829, 4.6431]Cochran-Mantel-Haenszel
Comparison: Analysis was performed as described in Statistical Analysis 1.p-value: 0.000195% CI: [1.5234, 3.7286]Cochran-Mantel-Haenszel
Secondary
Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg)
Ctrough, Ctrough,avg, C3-6h, and C3-6h,avg for lumacaftor, M28 lumacaftor (lumacaftor metabolite), ivacaftor, M1 ivacaftor (ivacaftor metabolite), and M6 ivacaftor (ivacaftor metabolite) were calculated. C3-6h,avg is average of individual 3 to 6 hours post-dose observed concentrations across Day 15, and Weeks 4 and 8 and Ctrough,avg is average of individual pre-dose observed concentrations across Weeks 4, 8, and 16. This outcome was not planned to be assessed in Placebo arm.
Time frame: For C3-6h: 3 to 6 hours after morning dose on Day 1 and 15, Week 4 and 8; For C3-6h,avg 3 to 6 hours after morning dose on Day 15, Week 4 and 8; For Ctrough and Ctrough,avg: before morning dose on Week 4, 8, and 16
Population: Pharmacokinetic (PK) population included all randomized participants who received at least one dose of study drug and had a PK assessment. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure and n signifies participants evaluable for specified category for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM, Day 1: C3-6h (n = 181, 180) | 30.8 microgram per milliliter (mcg/mL) | Standard Deviation 12.6 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM, Day 15: C3-6h (n = 174, 176) | 30.4 microgram per milliliter (mcg/mL) | Standard Deviation 11.2 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM, Week 4: Ctrough (n = 174, 179) | 8.11 microgram per milliliter (mcg/mL) | Standard Deviation 5.21 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM, Week 4: C3-6h (n = 164, 168) | 29.2 microgram per milliliter (mcg/mL) | Standard Deviation 12.1 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM, Week 8: Ctrough (n = 177, 177) | 7.87 microgram per milliliter (mcg/mL) | Standard Deviation 5.71 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM, Week 8: C3-6h (n = 174, 170) | 30.4 microgram per milliliter (mcg/mL) | Standard Deviation 11.6 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM, Week 16: Ctrough (n = 171, 173) | 7.53 microgram per milliliter (mcg/mL) | Standard Deviation 6.05 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM, Day 1: C3-6h (n = 181, 180) | 0.226 microgram per milliliter (mcg/mL) | Standard Deviation 0.103 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM, Day 15: C3-6h (n = 174, 176) | 1.43 microgram per milliliter (mcg/mL) | Standard Deviation 0.588 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM, Week 4: Ctrough (n = 174, 179) | 1.32 microgram per milliliter (mcg/mL) | Standard Deviation 0.68 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM, Week 4: C3-6h (n = 164, 168) | 1.39 microgram per milliliter (mcg/mL) | Standard Deviation 0.657 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM, Week 8: Ctrough (n = 177, 177) | 1.34 microgram per milliliter (mcg/mL) | Standard Deviation 0.714 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM, Week 8: C3-6h (n = 174, 170) | 1.41 microgram per milliliter (mcg/mL) | Standard Deviation 0.702 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM, Week 16: Ctrough (n = 171, 173) | 1.27 microgram per milliliter (mcg/mL) | Standard Deviation 0.763 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA, Day 1: C3-6h (n = 181, 180) | 1.34 microgram per milliliter (mcg/mL) | Standard Deviation 0.643 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA, Day 15: C3-6h (n = 174, 176) | 0.647 microgram per milliliter (mcg/mL) | Standard Deviation 0.492 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA, Week 4: Ctrough (n = 174, 179) | 0.164 microgram per milliliter (mcg/mL) | Standard Deviation 0.207 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA, Week 4: C3-6h (n = 164, 168) | 0.636 microgram per milliliter (mcg/mL) | Standard Deviation 0.38 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA, Week 8: Ctrough (n = 177, 177) | 0.182 microgram per milliliter (mcg/mL) | Standard Deviation 0.293 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA, Week 8: C3-6h (n = 174, 170) | 0.710 microgram per milliliter (mcg/mL) | Standard Deviation 0.567 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA, Week 16: Ctrough (n = 171, 173) | 0.163 microgram per milliliter (mcg/mL) | Standard Deviation 0.237 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-1 IVA, Day 1: C3-6h (n = 181, 180) | 2.51 microgram per milliliter (mcg/mL) | Standard Deviation 1.3 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-1 IVA, Day 15: C3-6h (n = 174, 176) | 2.21 microgram per milliliter (mcg/mL) | Standard Deviation 1.08 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-1 IVA, Week 4: Ctrough (n = 174, 179) | 0.676 microgram per milliliter (mcg/mL) | Standard Deviation 0.612 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-1 IVA, Week 4: C3-6h (n = 164, 168) | 2.11 microgram per milliliter (mcg/mL) | Standard Deviation 1.12 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-1 IVA, Week 8: Ctrough (n = 177, 177) | 0.672 microgram per milliliter (mcg/mL) | Standard Deviation 0.704 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-1 IVA, Week 8: C3-6h (n = 174, 170) | 2.15 microgram per milliliter (mcg/mL) | Standard Deviation 1.19 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-1 IVA, Week 16: Ctrough (n = 171, 173) | 0.643 microgram per milliliter (mcg/mL) | Standard Deviation 0.594 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-6 IVA, Day 1: C3-6h (n = 181, 180) | 0.993 microgram per milliliter (mcg/mL) | Standard Deviation 0.82 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-6 IVA, Day 15: C3-6h (n = 174, 176) | 3.62 microgram per milliliter (mcg/mL) | Standard Deviation 2.18 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-6 IVA, Week 4: Ctrough (n = 174, 179) | 1.73 microgram per milliliter (mcg/mL) | Standard Deviation 1.34 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-6 IVA, Week 4: C3-6h (n = 164, 168) | 3.07 microgram per milliliter (mcg/mL) | Standard Deviation 1.84 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-6 IVA, Week 8: Ctrough (n = 177, 177) | 1.60 microgram per milliliter (mcg/mL) | Standard Deviation 1.22 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-6 IVA, Week 8: C3-6h (n = 174, 170) | 3.00 microgram per milliliter (mcg/mL) | Standard Deviation 2.01 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-6 IVA, Week 16: Ctrough (n = 171, 173) | 1.51 microgram per milliliter (mcg/mL) | Standard Deviation 1.29 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM: Ctrough,avg (n = 179, 182) | 7.81 microgram per milliliter (mcg/mL) | Standard Deviation 4.26 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM: C3-6h,avg (n = 182, 181) | 29.9 microgram per milliliter (mcg/mL) | Standard Deviation 9.19 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM: Ctrough,avg (n = 179, 182) | 1.31 microgram per milliliter (mcg/mL) | Standard Deviation 0.672 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM: C3-6h,avg (n = 182, 181) | 1.41 microgram per milliliter (mcg/mL) | Standard Deviation 0.62 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA: Ctrough,avg (n = 179, 182) | 0.170 microgram per milliliter (mcg/mL) | Standard Deviation 0.196 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA: C3-6h,avg (n = 182, 181) | 0.668 microgram per milliliter (mcg/mL) | Standard Deviation 0.392 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M1-IVA: Ctrough,avg (n = 179, 182) | 0.660 microgram per milliliter (mcg/mL) | Standard Deviation 0.504 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M1-IVA: C3-6h,avg (n = 182, 181) | 2.14 microgram per milliliter (mcg/mL) | Standard Deviation 0.951 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M6-IVA: Ctrough,avg (n = 179, 182) | 1.60 microgram per milliliter (mcg/mL) | Standard Deviation 1.08 |
| Placebo | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M6-IVA: C3-6h,avg (n = 182, 181) | 3.18 microgram per milliliter (mcg/mL) | Standard Deviation 1.65 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-1 IVA, Day 15: C3-6h (n = 174, 176) | 1.85 microgram per milliliter (mcg/mL) | Standard Deviation 0.86 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM, Day 1: C3-6h (n = 181, 180) | 20.2 microgram per milliliter (mcg/mL) | Standard Deviation 8.33 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA: Ctrough,avg (n = 179, 182) | 0.110 microgram per milliliter (mcg/mL) | Standard Deviation 0.124 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM, Day 15: C3-6h (n = 174, 176) | 23.9 microgram per milliliter (mcg/mL) | Standard Deviation 8.87 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-1 IVA, Week 4: Ctrough (n = 174, 179) | 0.501 microgram per milliliter (mcg/mL) | Standard Deviation 0.455 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM, Week 4: Ctrough (n = 174, 179) | 13.2 microgram per milliliter (mcg/mL) | Standard Deviation 6.28 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-6 IVA, Week 16: Ctrough (n = 171, 173) | 1.42 microgram per milliliter (mcg/mL) | Standard Deviation 1.05 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM, Week 4: C3-6h (n = 164, 168) | 24.5 microgram per milliliter (mcg/mL) | Standard Deviation 8.75 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-1 IVA, Week 4: C3-6h (n = 164, 168) | 1.88 microgram per milliliter (mcg/mL) | Standard Deviation 0.953 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM, Week 8: Ctrough (n = 177, 177) | 12.4 microgram per milliliter (mcg/mL) | Standard Deviation 6.87 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M1-IVA: C3-6h,avg (n = 182, 181) | 1.87 microgram per milliliter (mcg/mL) | Standard Deviation 0.71 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM, Week 8: C3-6h (n = 174, 170) | 24.9 microgram per milliliter (mcg/mL) | Standard Deviation 9.79 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-1 IVA, Week 8: Ctrough (n = 177, 177) | 0.463 microgram per milliliter (mcg/mL) | Standard Deviation 0.495 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM, Week 16: Ctrough (n = 171, 173) | 12.2 microgram per milliliter (mcg/mL) | Standard Deviation 6.87 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM: Ctrough,avg (n = 179, 182) | 12.7 microgram per milliliter (mcg/mL) | Standard Deviation 5.6 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM, Day 1: C3-6h (n = 181, 180) | 0.181 microgram per milliliter (mcg/mL) | Standard Deviation 0.079 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-1 IVA, Week 8: C3-6h (n = 174, 170) | 1.91 microgram per milliliter (mcg/mL) | Standard Deviation 0.91 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM, Day 15: C3-6h (n = 174, 176) | 1.39 microgram per milliliter (mcg/mL) | Standard Deviation 0.606 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA: C3-6h,avg (n = 182, 181) | 0.484 microgram per milliliter (mcg/mL) | Standard Deviation 0.21 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM, Week 4: Ctrough (n = 174, 179) | 1.42 microgram per milliliter (mcg/mL) | Standard Deviation 0.661 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-1 IVA, Week 16: Ctrough (n = 171, 173) | 0.465 microgram per milliliter (mcg/mL) | Standard Deviation 0.449 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM, Week 4: C3-6h (n = 164, 168) | 1.45 microgram per milliliter (mcg/mL) | Standard Deviation 0.675 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | LUM: C3-6h,avg (n = 182, 181) | 24.3 microgram per milliliter (mcg/mL) | Standard Deviation 7.72 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM, Week 8: Ctrough (n = 177, 177) | 1.44 microgram per milliliter (mcg/mL) | Standard Deviation 0.722 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-6 IVA, Day 1: C3-6h (n = 181, 180) | 0.996 microgram per milliliter (mcg/mL) | Standard Deviation 0.797 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM, Week 8: C3-6h (n = 174, 170) | 1.48 microgram per milliliter (mcg/mL) | Standard Deviation 0.711 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M6-IVA: C3-6h,avg (n = 182, 181) | 2.70 microgram per milliliter (mcg/mL) | Standard Deviation 1.23 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM, Week 16: Ctrough (n = 171, 173) | 1.43 microgram per milliliter (mcg/mL) | Standard Deviation 0.775 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-6 IVA, Day 15: C3-6h (n = 174, 176) | 2.99 microgram per milliliter (mcg/mL) | Standard Deviation 1.68 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA, Day 1: C3-6h (n = 181, 180) | 1.36 microgram per milliliter (mcg/mL) | Standard Deviation 0.647 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM: Ctrough,avg (n = 179, 182) | 1.42 microgram per milliliter (mcg/mL) | Standard Deviation 0.676 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA, Day 15: C3-6h (n = 174, 176) | 0.469 microgram per milliliter (mcg/mL) | Standard Deviation 0.282 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-6 IVA, Week 4: Ctrough (n = 174, 179) | 1.64 microgram per milliliter (mcg/mL) | Standard Deviation 1.2 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA, Week 4: Ctrough (n = 174, 179) | 0.108 microgram per milliliter (mcg/mL) | Standard Deviation 0.112 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M1-IVA: Ctrough,avg (n = 179, 182) | 0.484 microgram per milliliter (mcg/mL) | Standard Deviation 0.391 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA, Week 4: C3-6h (n = 164, 168) | 0.473 microgram per milliliter (mcg/mL) | Standard Deviation 0.239 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-6 IVA, Week 4: C3-6h (n = 164, 168) | 2.64 microgram per milliliter (mcg/mL) | Standard Deviation 1.45 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA, Week 8: Ctrough (n = 177, 177) | 0.102 microgram per milliliter (mcg/mL) | Standard Deviation 0.13 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-28 LUM: C3-6h,avg (n = 182, 181) | 1.43 microgram per milliliter (mcg/mL) | Standard Deviation 0.64 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA, Week 8: C3-6h (n = 174, 170) | 0.513 microgram per milliliter (mcg/mL) | Standard Deviation 0.277 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-6 IVA, Week 8: Ctrough (n = 177, 177) | 1.47 microgram per milliliter (mcg/mL) | Standard Deviation 1.17 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | IVA, Week 16: Ctrough (n = 171, 173) | 0.113 microgram per milliliter (mcg/mL) | Standard Deviation 0.218 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M6-IVA: Ctrough,avg (n = 179, 182) | 1.50 microgram per milliliter (mcg/mL) | Standard Deviation 0.897 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-1 IVA, Day 1: C3-6h (n = 181, 180) | 2.65 microgram per milliliter (mcg/mL) | Standard Deviation 1.29 |
| LUM 600 mg qd/IVA 250 mg q12h | Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) | M-6 IVA, Week 8: C3-6h (n = 174, 170) | 2.56 microgram per milliliter (mcg/mL) | Standard Deviation 1.48 |
Secondary
Relative Change From Baseline in Percent Predicted FEV1 at Week 24
Assessed as the average treatment effect at Week 16 and at Week 24. FEV1 and percent predicted FEV1 are defined in Outcome Measure (OM) 1.
Time frame: Baseline, Week 16 and 24
Population: FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Relative Change From Baseline in Percent Predicted FEV1 at Week 24 | 0.00 percent change | Standard Error 0.96 |
| LUM 600 mg qd/IVA 250 mg q12h | Relative Change From Baseline in Percent Predicted FEV1 at Week 24 | 4.42 percent change | Standard Error 0.961 |
| LUM 400 mg q12h/ IVA 250 mg q12h | Relative Change From Baseline in Percent Predicted FEV1 at Week 24 | 5.25 percent change | Standard Error 0.961 |
Comparison: Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (\<18 versus \>=18 years old), and percent predicted FEV1 severity at Screening (\<70 versus \>=70).p-value: 0.000795% CI: [1.86, 6.98]MMRM
Comparison: Analysis was performed using MMRM model, as described in Statistical Analysis 1.p-value: <0.000195% CI: [2.69, 7.81]MMRM
Secondary
Time-to-First Pulmonary Exacerbation
Time to first pulmonary exacerbation was assessed using Cox Regression method. For participants who completed 24 weeks of treatment, participants without a pulmonary exacerbation before treatment completion were considered censored at the time of treatment completion or at the Week 24 Visit (whichever occurred last). For participants who prematurely discontinued study treatment, participants without a pulmonary exacerbation through the Week 24 Visit were considered censored at the time of the Week 24 Visit.
Time frame: through Week 24
Population: FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time-to-First Pulmonary Exacerbation | NA days |
| LUM 600 mg qd/IVA 250 mg q12h | Time-to-First Pulmonary Exacerbation | NA days |
| LUM 400 mg q12h/ IVA 250 mg q12h | Time-to-First Pulmonary Exacerbation | NA days |
Comparison: Analysis was performed using Cox proportional hazard regression, time is the time-to-first event or censoring, with adjustment for sex (male versus female), age group at baseline (\<18 versus \>=18 years old), and percent predicted FEV1 severity at Screening (\<70 versus \>=70).p-value: 0.0384Cox Proportional Hazard Regression
Comparison: Analysis was performed as described in Statistical Analysis 1.p-value: 0.0003Cox Proportional Hazard Regression