Cystic Fibrosis
Conditions
Brief summary
Study to evaluate the efficacy of VX-661 in combination with ivacaftor (IVA, VX-770) through Week 12 in participants with cystic fibrosis (CF) who are heterozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene and with a second CFTR mutation that is not likely to respond to VX-661 and/or IVA therapy (F508del/not responsive \[NR\]).
Interventions
DRUGIvacaftor
DRUGPlacebo (matched to VX-661 plus ivacaftor combination)
DRUGPlacebo (matched to ivacaftor)
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of CF defined as a sweat chloride value greater than or equal to (\>=)60 millimole per liter (mmol/L) by quantitative pilocarpine iontophoresis. * Heterozygous for the F508del-CFTR mutation and with a second CFTR mutation that is not likely to respond to VX-661 and/or ivacaftor therapy, genotype to be confirmed via assessment at the Screening Visit. * Forced Expiratory Volume in 1 Second (FEV1) \>=40 percent (%) and less than or equal to (\<=)90% of predicted normal for age, sex, and height at Screening Visit.
Exclusion criteria
* 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. * An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study drug). * History of solid organ or hematological transplantation. * Ongoing or prior participation in an investigational drug study or use of commercially available CFTR modulator within 30 days of screening. * Pregnant or nursing females.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 12 | Baseline, Through Week 12 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Pulmonary Exacerbation Events | Baseline through Week 12 | Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. The number of events were reported. |
| Number of Pulmonary Exacerbation Events Per Year | Baseline through Week 12 | Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. Total number of days on study is equal to the Week 12 date or the last dose date (whichever occurs last) minus first dose date plus 1. The total number of years (48 weeks) on study is equal to the total number of days on study divided by 336. Pulmonary exacerbation events per year (48 weeks) are reported. |
| Absolute Change From Baseline in Body Mass Index (BMI) at Week 12 | Baseline, Week 12 | BMI was defined as weight in kilogram (kg) divided by height\*height in square meter (m\^2). |
| Relative Change From Baseline in Percent Predicted FEV1 Through Week 12 | Baseline, Through Week 12 | 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. |
| Absolute Change From Baseline in Sweat Chloride Through Week 12 | Baseline, Through Week 12 | Sweat samples were collected using an approved collection device. |
| Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 12 | Baseline, Through Week 12 | 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), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. |
| Absolute Change From Baseline in BMI Z-score at Week 12 (in Participants Less Than [<] 20 Years Old at the Time of Screening) | Baseline, Week 12 | 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; where 0: same mean, \>0: a greater mean, and \<0: a lesser mean than the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age Z-score (BMI z-score). BMI-for-age z-score was calculated by using centers for disease control and prevention (CDC) growth charts for the paediatric population. |
| Absolute Change From Baseline in Body Weight at Week 12 | Baseline, Week 12 | — |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline up to Week 16 | 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, inpatient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Any AE that increased in severity or newly developed at or after initial dosing of study drug to Week 16 was considered treatment-emergent. |
| Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Pre-morning dose on Week 2, Week 4, Week 8 and Week 12 | This outcome was not planned to be assessed in Placebo arm. |
| Number of Participants With at Least One Pulmonary Exacerbation Through Week 12 | Baseline through Week 12 | Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. Time-to-first pulmonary exacerbation was planned to be estimated using Kaplan-Meier (KM) estimates. However, due to less than 50% of events, time-to-first event data was not estimated. Instead, number of participants with at least one pulmonary exacerbation event were collected and are reported. |
Countries
Australia, Austria, Canada, France, Israel, Spain, United States
Participant flow
Recruitment details
The study was conducted across 38 sites in 7 countries.
Pre-assignment details
A total of 168 participants were randomized and treated in the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA film-coated tablet administered orally in the evening up to Week 12. | 85 |
| VX-661/IVA VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12. | 83 |
| Total | 168 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | VX-661/IVA | Total |
|---|---|---|---|
| Age, Continuous | 26 years STANDARD_DEVIATION 8.8 | 26.2 years STANDARD_DEVIATION 9.6 | 26.1 years STANDARD_DEVIATION 9.2 |
| Sex: Female, Male Female | 42 Participants | 39 Participants | 81 Participants |
| Sex: Female, Male Male | 43 Participants | 44 Participants | 87 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 85 | 0 / 83 |
| other Total, other adverse events | 63 / 85 | 62 / 83 |
| serious Total, serious adverse events | 14 / 85 | 11 / 83 |
Outcome results
Primary
Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 12
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.
Time frame: Baseline, Through Week 12
Population: Full Analysis Set (FAS) included all randomized participants who received at least 1 dose of study drug. Here 'Number of participants analysed' signifies those 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) Through Week 12 | -0.1 Percentage of predicted FEV1 | Standard Error 0.6 |
| VX-661/IVA | Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 12 | 1 Percentage of predicted FEV1 | Standard Error 0.6 |
p-value: =0.117695% CI: [-0.3, 2.6]Mixed-effect repeated measure (MMRM)
Secondary
Absolute Change From Baseline in BMI Z-score at Week 12 (in Participants Less Than [<] 20 Years Old at the Time of Screening)
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; where 0: same mean, \>0: a greater mean, and \<0: a lesser mean than the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age Z-score (BMI z-score). BMI-for-age z-score was calculated by using centers for disease control and prevention (CDC) growth charts for the paediatric population.
Time frame: Baseline, Week 12
Population: Analysis population included all randomized participants who received at least 1 dose of study drug and were \<20 years of age at the time of screening.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline in BMI Z-score at Week 12 (in Participants Less Than [<] 20 Years Old at the Time of Screening) | 0.07 Z-score |
| VX-661/IVA | Absolute Change From Baseline in BMI Z-score at Week 12 (in Participants Less Than [<] 20 Years Old at the Time of Screening) | 0.02 Z-score |
Secondary
Absolute Change From Baseline in Body Mass Index (BMI) at Week 12
BMI was defined as weight in kilogram (kg) divided by height\*height in square meter (m\^2).
Time frame: Baseline, Week 12
Population: FAS included all randomized participants who received at least 1 dose of study drug. Here 'Number of participants analysed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline in Body Mass Index (BMI) at Week 12 | 0.22 Kg/m^2 |
| VX-661/IVA | Absolute Change From Baseline in Body Mass Index (BMI) at Week 12 | 0.14 Kg/m^2 |
Secondary
Absolute Change From Baseline in Body Weight at Week 12
Time frame: Baseline, Week 12
Population: FAS included all randomized participants who received at least 1 dose of study drug. Here 'Number of participants analysed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline in Body Weight at Week 12 | 0.7 Kilograms (kg) |
| VX-661/IVA | Absolute Change From Baseline in Body Weight at Week 12 | 0.6 Kilograms (kg) |
Secondary
Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 12
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), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
Time frame: Baseline, Through Week 12
Population: FAS included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 12 | 3.8 Units on a scale |
| VX-661/IVA | Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 12 | 5.9 Units on a scale |
Secondary
Absolute Change From Baseline in Sweat Chloride Through Week 12
Sweat samples were collected using an approved collection device.
Time frame: Baseline, Through Week 12
Population: FAS included all randomized participants who received at least 1 dose of study drug. Here 'Number of participants analysed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline in Sweat Chloride Through Week 12 | -1.2 Millimole per liter (mmol/L) |
| VX-661/IVA | Absolute Change From Baseline in Sweat Chloride Through Week 12 | -4.7 Millimole per liter (mmol/L) |
Secondary
Number of Participants With at Least One Pulmonary Exacerbation Through Week 12
Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. Time-to-first pulmonary exacerbation was planned to be estimated using Kaplan-Meier (KM) estimates. However, due to less than 50% of events, time-to-first event data was not estimated. Instead, number of participants with at least one pulmonary exacerbation event were collected and are reported.
Time frame: Baseline through Week 12
Population: FAS included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With at Least One Pulmonary Exacerbation Through Week 12 | 21 Participants |
| VX-661/IVA | Number of Participants With at Least One Pulmonary Exacerbation Through Week 12 | 19 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (AEs) and 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, inpatient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Any AE that increased in severity or newly developed at or after initial dosing of study drug to Week 16 was considered treatment-emergent.
Time frame: Baseline up to Week 16
Population: Safety Set included all participants who received at least 1 dose of the study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with any AEs | 68 Participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with any SAEs | 14 Participants |
| VX-661/IVA | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with any AEs | 64 Participants |
| VX-661/IVA | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with any SAEs | 11 Participants |
Secondary
Number of Pulmonary Exacerbation Events
Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. The number of events were reported.
Time frame: Baseline through Week 12
Population: FAS included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Pulmonary Exacerbation Events | 23 Pulmonary exacerbation events |
| VX-661/IVA | Number of Pulmonary Exacerbation Events | 22 Pulmonary exacerbation events |
Secondary
Number of Pulmonary Exacerbation Events Per Year
Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. Total number of days on study is equal to the Week 12 date or the last dose date (whichever occurs last) minus first dose date plus 1. The total number of years (48 weeks) on study is equal to the total number of days on study divided by 336. Pulmonary exacerbation events per year (48 weeks) are reported.
Time frame: Baseline through Week 12
Population: FAS included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Pulmonary Exacerbation Events Per Year | 0.98 Pulmonary exacerbation events per year |
| VX-661/IVA | Number of Pulmonary Exacerbation Events Per Year | 0.97 Pulmonary exacerbation events per year |
Secondary
Relative Change From Baseline in Percent Predicted FEV1 Through Week 12
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.
Time frame: Baseline, Through Week 12
Population: FAS included all randomized participants who received at least 1 dose of study drug. Here 'Number of participants analysed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Relative Change From Baseline in Percent Predicted FEV1 Through Week 12 | 0.1 Percent Change |
| VX-661/IVA | Relative Change From Baseline in Percent Predicted FEV1 Through Week 12 | 2.1 Percent Change |
Secondary
Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA)
This outcome was not planned to be assessed in Placebo arm.
Time frame: Pre-morning dose on Week 2, Week 4, Week 8 and Week 12
Population: Pharmacokinetic (PK) set included all randomized participants who received any amount of study drug and had a PK assessment. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Week 4: M1-IVA | 1500 nanogram per milliliter (ng/mL) | Standard Deviation 898 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Week 2: VX-661 | 1880 nanogram per milliliter (ng/mL) | Standard Deviation 1230 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Week 2: M1 VX-661 | 4600 nanogram per milliliter (ng/mL) | Standard Deviation 1430 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Week 2: IVA | 831 nanogram per milliliter (ng/mL) | Standard Deviation 607 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Week 2: M1-IVA | 1580 nanogram per milliliter (ng/mL) | Standard Deviation 879 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Week 4: VX-661 | 1780 nanogram per milliliter (ng/mL) | Standard Deviation 1010 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Week 4: M1 VX-661 | 4420 nanogram per milliliter (ng/mL) | Standard Deviation 1340 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Week 4: IVA | 770 nanogram per milliliter (ng/mL) | Standard Deviation 596 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Week 8: VX-661 | 1920 nanogram per milliliter (ng/mL) | Standard Deviation 2170 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Week 8: M1 VX-661 | 4330 nanogram per milliliter (ng/mL) | Standard Deviation 1980 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Week 8: IVA | 747 nanogram per milliliter (ng/mL) | Standard Deviation 745 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Week 8: M1-IVA | 1370 nanogram per milliliter (ng/mL) | Standard Deviation 1070 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Week 12: VX-661 | 1700 nanogram per milliliter (ng/mL) | Standard Deviation 1220 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Week 12: M1 VX-661 | 4290 nanogram per milliliter (ng/mL) | Standard Deviation 1730 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Week 12: IVA | 776 nanogram per milliliter (ng/mL) | Standard Deviation 690 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Week 12: M1-IVA | 1620 nanogram per milliliter (ng/mL) | Standard Deviation 1160 |