Cystic Fibrosis
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy and safety of VX-661 in combination with ivacaftor (IVA, VX-770) and IVA monotherapy in participants with Cystic Fibrosis (CF) who are heterozygous for F508del-CFTR allele and a second allele with a CFTR mutation predicted to have residual function.
Interventions
DRUGVX-661/Ivacaftor
Fixed dose combination tablet, oral use
DRUGIvacaftor
Tablet, oral use
DRUGPlacebo matched to VX-661/ ivacaftor
Fixed dose combination tablet, oral use
Tablet, oral use
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Heterozygous for F508del-CFTR and a second allele with a CFTR mutation predicted to have residual function * 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 during screening * Sweat chloride value ≥60 millimole per liter (mmol/L) during screening OR as documented in the participant's medical record * Stable CF disease as judged by the investigator
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 * History of solid organ or hematological transplantation * Ongoing or prior participation in an investigational drug study (including studies investigating VX-661, lumacaftor \[VX-809\], and/or ivacaftor) within 30 days of screening * Pregnant and nursing females * Sexually active participants of reproductive potential who are not willing to follow the contraception requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Week 4 and Week 8 | Baseline, Week 4 and Week 8 of each treatment period | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Study Baseline in Sweat Chloride at Average of Week 4 and Week 8 | Baseline, Week 4 and Week 8 of each treatment period | — |
| Absolute Change From Study Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Week 4 and Week 8 | Baseline, Week 4 and Week 8 of each treatment period | The CFQ-R assessed respiratory symptoms on a scale with scores ranging from 0 to 100; where higher scores indicated fewer symptoms and better health-related quality of life. |
| Relative Change From Study Baseline in ppFEV1 at Average of Week 4 and Week 8 | Baseline, Week 4 and Week 8 of each treatment period | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. |
| Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661), IVA and IVA Metabolite (M1 IVA) After Administration of VX-661/IVA Combination Therapy | Pre-morning dose on Week 8 of each treatment period | — |
| Ctrough of IVA and IVA Metabolite (M1 IVA) After Administration of IVA Monotherapy | Pre-morning dose on Week 8 of each treatment period | — |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Day 1 up to Week 28 | — |
Countries
Australia, Belgium, Canada, France, Germany, Israel, Italy, Netherlands, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
A total of 248 participants were enrolled. Out of which, 246 received at least 1 dose of study drug were included in safety set and 244 participants who carried intended cystic fibrosis transmembrane conductance regulator (CFTR) mutations were included in Full analysis set.
Pre-assignment details
Participants were randomized to 1 of 6 treatment sequences, each of which included 2 treatment periods and 2 of 3 potential treatments (placebo, VX-661/ivacaftor \[IVA\], IVA). Treatment periods were separated by an 8 week wash-out period.
Participants by arm
| Arm | Count |
|---|---|
| First VX- 661/IVA, Then IVA VX-661 100 mg plus IVA 150 mg FDC tablet and placebo matched to IVA in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 followed by IVA 150 mg tablet and placebo matched to VX-661 plus IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period. | 41 |
| First VX-661/IVA, Then Placebo VX-661 100 mg plus IVA 150 mg FDC tablet and placebo matched to IVA in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 followed by placebo matched to VX-661 plus IVA FDC tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period. | 43 |
| First IVA, Then Placebo IVA 150 mg tablet and placebo matched to VX-661 plus IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 followed by placebo matched to VX-661 plus IVA FDC tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period. | 40 |
| First IVA, Then VX- 661/IVA IVA 150 mg tablet and placebo matched to VX-661 plus IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 followed by VX-661 100 mg plus IVA 150 mg FDC tablet and placebo matched to IVA tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period. | 42 |
| First Placebo, Then VX- 661/IVA Placebo matched to VX-661 plus IVA FDC tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 1 followed by VX-661 100 mg plus IVA 150 mg FDC tablet and placebo matched to IVA tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period. | 41 |
| First Placebo, Then IVA Placebo matched to VX-661 plus IVA FDC tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 1 followed by IVA 150 mg tablet and placebo matched to VX-661 plus IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period. | 41 |
| Total | 248 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment Period 1 (8 Weeks) | Adverse Event | 1 | 0 | 1 | 0 | 1 | 1 |
| Treatment Period 1 (8 Weeks) | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 |
| Treatment Period 1 (8 Weeks) | Noncompliance | 0 | 0 | 0 | 0 | 0 | 1 |
| Treatment Period 1 (8 Weeks) | Other | 1 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period 1 (8 Weeks) | Pregnancy | 1 | 0 | 0 | 1 | 0 | 0 |
| Treatment Period 1 (8 Weeks) | Randomized but not treated | 0 | 0 | 1 | 0 | 1 | 0 |
| Treatment Period 1 (8 Weeks) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 2 | 0 |
| Treatment Period 2 (8 Weeks) | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | First VX- 661/IVA, Then IVA | First VX-661/IVA, Then Placebo | First IVA, Then Placebo | First IVA, Then VX- 661/IVA | First Placebo, Then VX- 661/IVA | First Placebo, Then IVA | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 6 Participants | 7 Participants | 5 Participants | 5 Participants | 6 Participants | 34 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 36 Participants | 37 Participants | 33 Participants | 37 Participants | 34 Participants | 35 Participants | 212 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 3 Participants | 2 Participants | 2 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 43 Participants | 39 Participants | 39 Participants | 37 Participants | 39 Participants | 237 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 39 Participants | 42 Participants | 40 Participants | 42 Participants | 39 Participants | 39 Participants | 241 Participants |
| Sex: Female, Male Female | 23 Participants | 25 Participants | 19 Participants | 21 Participants | 23 Participants | 23 Participants | 134 Participants |
| Sex: Female, Male Male | 18 Participants | 18 Participants | 21 Participants | 21 Participants | 18 Participants | 18 Participants | 114 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 162 | 0 / 157 | 0 / 162 |
| other Total, other adverse events | 87 / 162 | 54 / 157 | 80 / 162 |
| serious Total, serious adverse events | 14 / 162 | 10 / 157 | 8 / 162 |
Outcome results
Primary
Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Week 4 and Week 8
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time frame: Baseline, Week 4 and Week 8 of each treatment period
Population: Full Analysis Set (FAS) included all randomized participants who carry the protocol specified cystic fibrosis transmembrane conductance regulator gene (CFTR) mutations and had received at least 1 dose of study drug. Here 'Overall Number of participants analyzed' signifies those participants who had evaluable data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Week 4 and Week 8 | -0.3 percentage of predicted FEV1 |
| Ivacaftor | Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Week 4 and Week 8 | 4.4 percentage of predicted FEV1 |
| VX-661/IVA | Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Week 4 and Week 8 | 6.5 percentage of predicted FEV1 |
p-value: <0.000195% CI: [3.7, 5.8]Linear Mixed Effects Model
p-value: <0.000195% CI: [5.7, 7.8]Linear Mixed Effects Model
Secondary
Absolute Change From Study Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Week 4 and Week 8
The CFQ-R assessed respiratory symptoms on a scale with scores ranging from 0 to 100; where higher scores indicated fewer symptoms and better health-related quality of life.
Time frame: Baseline, Week 4 and Week 8 of each treatment period
Population: FAS was used. Here 'Overall Number of participants analyzed' signifies those participants who had evaluable data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Study Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Week 4 and Week 8 | -1.0 units on a scale |
| Ivacaftor | Absolute Change From Study Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Week 4 and Week 8 | 8.7 units on a scale |
| VX-661/IVA | Absolute Change From Study Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Week 4 and Week 8 | 10.1 units on a scale |
p-value: <0.000195% CI: [7.2, 12.2]Linear Mixed Effects Model
p-value: <0.000195% CI: [8.7, 13.6]Linear Mixed Effects Model
Secondary
Absolute Change From Study Baseline in Sweat Chloride at Average of Week 4 and Week 8
Time frame: Baseline, Week 4 and Week 8 of each treatment period
Population: FAS was used. Here 'Overall Number of participants analyzed' signifies those participants who had evaluable data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Study Baseline in Sweat Chloride at Average of Week 4 and Week 8 | -0.4 millimoles per liter (mmol/L) |
| Ivacaftor | Absolute Change From Study Baseline in Sweat Chloride at Average of Week 4 and Week 8 | -4.9 millimoles per liter (mmol/L) |
| VX-661/IVA | Absolute Change From Study Baseline in Sweat Chloride at Average of Week 4 and Week 8 | -9.9 millimoles per liter (mmol/L) |
p-value: <0.000195% CI: [-6.7, -2.3]Linear Mixed Effects Model
p-value: <0.000195% CI: [-11.7, -7.3]Linear Mixed Effects Model
Secondary
Ctrough of IVA and IVA Metabolite (M1 IVA) After Administration of IVA Monotherapy
Time frame: Pre-morning dose on Week 8 of each treatment period
Population: PK set was used. Here 'Overall Number of participants analyzed' signifies those participants who had evaluable data for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Ctrough of IVA and IVA Metabolite (M1 IVA) After Administration of IVA Monotherapy | IVA | 696 ng/mL | Standard Deviation 435 |
| Placebo | Ctrough of IVA and IVA Metabolite (M1 IVA) After Administration of IVA Monotherapy | M1 IVA | 1550 ng/mL | Standard Deviation 808 |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: Day 1 up to Week 28
Population: Safety Set included all participants who received at least 1 dose of 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 | 126 participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 14 participants |
| Ivacaftor | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with any AEs | 114 participants |
| Ivacaftor | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 10 participants |
| VX-661/IVA | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with any AEs | 117 participants |
| VX-661/IVA | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 8 participants |
Secondary
Relative Change From Study Baseline in ppFEV1 at Average of Week 4 and Week 8
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time frame: Baseline, Week 4 and Week 8 of each treatment period
Population: FAS was used. Here 'Overall Number of participants analyzed' signifies those participants who had evaluable data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Relative Change From Study Baseline in ppFEV1 at Average of Week 4 and Week 8 | -0.2 percent change |
| Ivacaftor | Relative Change From Study Baseline in ppFEV1 at Average of Week 4 and Week 8 | 7.9 percent change |
| VX-661/IVA | Relative Change From Study Baseline in ppFEV1 at Average of Week 4 and Week 8 | 11.2 percent change |
p-value: <0.000195% CI: [6.3, 9.9]Linear Mixed Effects Model
p-value: <0.000195% CI: [9.6, 13.2]Linear Mixed Effects Model
Secondary
Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661), IVA and IVA Metabolite (M1 IVA) After Administration of VX-661/IVA Combination Therapy
Time frame: Pre-morning dose on Week 8 of each treatment period
Population: Pharmacokinetic (PK) set included all randomized participants who received any amount of study drug and had a PK assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661), IVA and IVA Metabolite (M1 IVA) After Administration of VX-661/IVA Combination Therapy | VX-661 | 2370 nanogram per milliliter (ng/mL) | Standard Deviation 1330 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661), IVA and IVA Metabolite (M1 IVA) After Administration of VX-661/IVA Combination Therapy | M1 VX-661 | 5230 nanogram per milliliter (ng/mL) | Standard Deviation 1940 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661), IVA and IVA Metabolite (M1 IVA) After Administration of VX-661/IVA Combination Therapy | IVA | 909 nanogram per milliliter (ng/mL) | Standard Deviation 530 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661), IVA and IVA Metabolite (M1 IVA) After Administration of VX-661/IVA Combination Therapy | M1 IVA | 2010 nanogram per milliliter (ng/mL) | Standard Deviation 1050 |