Cystic Fibrosis
Conditions
Brief summary
The purpose of this study is to evaluate the safety and efficacy of treatment with VX-371 in hypertonic saline compared to hypertonic saline alone in subjects with cystic fibrosis (CF) who are ≥12 years of age, homozygous for the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutation, and being treated with Orkambi
Interventions
Sponsors
Vertex Pharmaceuticals Incorporated
Parion Sciences
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Willing and able to use the delivery device as directed by the study manual. * Confirmed diagnosis of CF, defined as a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis. * Homozygous for the F508del CFTR mutation. If the CFTR screening genotype result is not received before randomization, a previous CFTR genotype lab report may be used to establish eligibility. * Percent predicted forced expiratory volume at one second (FEV1) of ≥40 to \<90 percentage points adjusted for age, sex, and height according to the Global Lung Initiative (GLI) at the Screening Visit. * Willing to discontinue physician-prescribed saline use. * Female subjects of childbearing potential with a negative serum pregnancy test at the Screening Visit.
Exclusion criteria
* History of any comorbidity, which in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject. * Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject. * 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). * A 12 lead ECG demonstrating QTcF \>450 msec at the Screening Visit. * History of solid organ or hematological transplantation. * Used diuretics or renin-angiotensin aldosterone system antihypertensive drugs in the 28 days prior to Screening or an anticipated need for any of these medications during the study. * Ongoing or prior participation in an investigational drug study within 30 days of the Screening Visit. * Inability to withhold short-acting, long-acting, or once-daily, long-acting bronchodilator use for 4, 12, or 24 hours prior to clinic visit, respectively. * History of significant intolerance to inhaled saline, or intolerance to the single dose of saline at Screening * Known hypersensitivity or history of intolerance to Orkambi. * Pregnant and nursing females. * Subjects who have participated in Parion Sciences Study NCT02343445.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Baseline (Day 1) up to 28 days post last administration of study drug (up to 112 days) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AEs included abnormal clinically significant findings for spirometry, clinical laboratory parameters, standard 12-lead electrocardiograms (ECGs), vital signs and ophthalmologic examinations. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 112 days (up to 28 days after last dose) that were absent before treatment or that worsened relative to pretreatment state. TEAEs included both serious and non-serious TEAEs. |
| Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28 | Study baseline, Day 28 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Study Baseline was defined as the most recent non-missing measurement before the first dose of inhaled study drug in the study. Day 28 measurements after treatment discontinuation from the treatment period in which discontinuation occurred were included in the analysis. |
Secondary
| Measure | Time frame |
|---|---|
| Plasma Concentrations of VX-371 | Pre-dose (90 minutes prior inhaled study drug administration) and 60 minutes post-dose on Days 1, 14 and 28 within treatment period 1 and 2 |
| Urine Concentrations of VX-371 | Pre-dose (90 minutes prior inhaled study drug administration) and 60 minutes post-dose on Days 1, 14 and 28 within treatment period 1 and 2 |
Countries
France, Ireland, United Kingdom, United States
Participant flow
Pre-assignment details
Total 147 participants entered in this study, 5 participants discontinued from the study before the randomization. Of which 142 participants were randomized to receive 1 of the 4 treatment sequences: 1) VX-371 + hypertonic saline (HS), Then HS; 2) HS, Then VX-371 + HS; 3) VX-371 + Placebo, Then Placebo; 4) Placebo, Then VX-371 + Placebo.
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1: VX-371 + HS, Then HS Participants received 85 mcg VX-371 diluted in 3 milliliter (mL) 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care. | 49 |
| Sequence 2: HS, Then VX-371 + HS Participants received 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 85 mcg VX-371 diluted in 3 mL 4.2% HS through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care. | 47 |
| Sequence 3: VX-371 + Placebo, Then Placebo Participants received 85 mcg VX-371 diluted in 3 mL 0.17% Saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care. | 22 |
| Sequence 4: Placebo, Then VX-371 + Placebo Participants received 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 1 to Day 28) in treatment period 1 followed by a 28 days washout period (Day 29 to Day 56) and then received 85 mcg VX-371 diluted in 3 mL 0.17% saline (placebo) through oral nebulized inhalation twice daily for 28 days (Day 57 to Day 84) in treatment period 2. Participants also received a stable dose of 2 tablets of Orkambi (lumacaftor 400 mg/ivacaftor 250 mg) orally every 12 hours with fat-containing food throughout the study as part of their CF standard of care. | 24 |
| Total | 142 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Treatment Period 1 (28 Days) | Adverse Event | 3 | 3 | 1 | 0 |
| Treatment Period 1 (28 Days) | Non-compliance with study drug | 1 | 0 | 0 | 0 |
| Treatment Period 1 (28 Days) | Participant refused further dosing | 0 | 2 | 0 | 0 |
| Treatment Period 2 (28 Days) | Adverse Event | 2 | 3 | 0 | 0 |
| Treatment Period 2 (28 Days) | Other | 0 | 0 | 1 | 0 |
| Treatment Period 2 (28 Days) | Other non-compliance | 0 | 1 | 1 | 0 |
| Treatment Period 2 (28 Days) | Requires prohibited medication | 0 | 0 | 1 | 0 |
| Washout Period (28 Days) | Other | 2 | 2 | 3 | 0 |
Baseline characteristics
| Characteristic | Sequence 1: VX-371 + HS, Then HS | Sequence 2: HS, Then VX-371 + HS | Sequence 3: VX-371 + Placebo, Then Placebo | Sequence 4: Placebo, Then VX-371 + Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 23.6 years STANDARD_DEVIATION 9.07 | 22.3 years STANDARD_DEVIATION 8.75 | 26.0 years STANDARD_DEVIATION 10.95 | 22.1 years STANDARD_DEVIATION 7.8 | 23.3 years STANDARD_DEVIATION 9.08 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 49 Participants | 45 Participants | 22 Participants | 23 Participants | 139 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 49 Participants | 45 Participants | 22 Participants | 23 Participants | 139 Participants |
| Sex: Female, Male Female | 21 Participants | 16 Participants | 7 Participants | 11 Participants | 55 Participants |
| Sex: Female, Male Male | 28 Participants | 31 Participants | 15 Participants | 13 Participants | 87 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 89 | 0 / 90 | 0 / 46 | 0 / 42 |
| other Total, other adverse events | 49 / 89 | 55 / 90 | 26 / 46 | 20 / 42 |
| serious Total, serious adverse events | 8 / 89 | 4 / 90 | 6 / 46 | 3 / 42 |
Outcome results
Primary
Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Study Baseline was defined as the most recent non-missing measurement before the first dose of inhaled study drug in the study. Day 28 measurements after treatment discontinuation from the treatment period in which discontinuation occurred were included in the analysis.
Time frame: Study baseline, Day 28
Population: The full analysis set (FAS) included all randomized participants who carried the intended homozygous F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutation and received at least 1 dose of inhaled study drug. Here, overall number of participants analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| VX-371 + Hypertonic Saline | Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28 | 0.1 percentage points | Standard Error 0.8 |
| Hypertonic Saline | Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28 | -0.1 percentage points | Standard Error 0.8 |
| VX-371 + Placebo | Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28 | -0.8 percentage points | Standard Error 1.1 |
| Placebo | Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 28 | 0.8 percentage points | Standard Error 1.1 |
p-value: 0.817395% CI: [-1.4, 1.8]Mixed-effects Model for Repeated Measure
p-value: 0.590395% CI: [-3.3, 1.9]Mixed-effects Model for Repeated Measure
p-value: 0.591795% CI: [-3.4, 1.9]Mixed-effects Model for Repeated Measure
p-value: 0.502195% CI: [-3.6, 1.8]Mixed-effects Model for Repeated Measure
p-value: 0.138295% CI: [-3.8, 0.5]Mixed-effects Model for Repeated Measure
p-value: 0.496295% CI: [-1.7, 3.5]Mixed-effects Model for Repeated Measure
Primary
Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AEs included abnormal clinically significant findings for spirometry, clinical laboratory parameters, standard 12-lead electrocardiograms (ECGs), vital signs and ophthalmologic examinations. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 112 days (up to 28 days after last dose) that were absent before treatment or that worsened relative to pretreatment state. TEAEs included both serious and non-serious TEAEs.
Time frame: Baseline (Day 1) up to 28 days post last administration of study drug (up to 112 days)
Population: Safety set included all participants who received at least 1 dose of inhaled study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| VX-371 + Hypertonic Saline | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants With Serious TEAEs | 8 Participants |
| VX-371 + Hypertonic Saline | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants With TEAEs | 65 Participants |
| Hypertonic Saline | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants With Serious TEAEs | 4 Participants |
| Hypertonic Saline | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants With TEAEs | 66 Participants |
| VX-371 + Placebo | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants With TEAEs | 32 Participants |
| VX-371 + Placebo | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants With Serious TEAEs | 6 Participants |
| Placebo | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants With Serious TEAEs | 3 Participants |
| Placebo | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Participants With TEAEs | 28 Participants |
Secondary
Plasma Concentrations of VX-371
Time frame: Pre-dose (90 minutes prior inhaled study drug administration) and 60 minutes post-dose on Days 1, 14 and 28 within treatment period 1 and 2
Population: The Pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of VX-371. Here, overall number of participants analyzed signifies participants evaluable for this outcome measure and number analyzed signifies those participants who were evaluable at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VX-371 + Hypertonic Saline | Plasma Concentrations of VX-371 | Day 1: Pre-dose | 0.00 Picograms per milliliter (pg/mL) | Standard Deviation 0 |
| VX-371 + Hypertonic Saline | Plasma Concentrations of VX-371 | Day 1: Post-dose | 2.57 Picograms per milliliter (pg/mL) | Standard Deviation 2.35 |
| VX-371 + Hypertonic Saline | Plasma Concentrations of VX-371 | Day 14: Pre-dose | 1.63 Picograms per milliliter (pg/mL) | Standard Deviation 3.06 |
| VX-371 + Hypertonic Saline | Plasma Concentrations of VX-371 | Day 14: Post-dose | 5.81 Picograms per milliliter (pg/mL) | Standard Deviation 5.44 |
| VX-371 + Hypertonic Saline | Plasma Concentrations of VX-371 | Day 28: Pre-dose | 2.68 Picograms per milliliter (pg/mL) | Standard Deviation 4.75 |
| VX-371 + Hypertonic Saline | Plasma Concentrations of VX-371 | Day 28: Post-dose | 6.41 Picograms per milliliter (pg/mL) | Standard Deviation 6.92 |
| Hypertonic Saline | Plasma Concentrations of VX-371 | Day 28: Pre-dose | 3.67 Picograms per milliliter (pg/mL) | Standard Deviation 5.59 |
| Hypertonic Saline | Plasma Concentrations of VX-371 | Day 1: Pre-dose | 0.18 Picograms per milliliter (pg/mL) | Standard Deviation 1.17 |
| Hypertonic Saline | Plasma Concentrations of VX-371 | Day 14: Post-dose | 11.0 Picograms per milliliter (pg/mL) | Standard Deviation 9.74 |
| Hypertonic Saline | Plasma Concentrations of VX-371 | Day 1: Post-dose | 5.64 Picograms per milliliter (pg/mL) | Standard Deviation 4.27 |
| Hypertonic Saline | Plasma Concentrations of VX-371 | Day 28: Post-dose | 10.9 Picograms per milliliter (pg/mL) | Standard Deviation 9.48 |
| Hypertonic Saline | Plasma Concentrations of VX-371 | Day 14: Pre-dose | 2.77 Picograms per milliliter (pg/mL) | Standard Deviation 4.77 |
Secondary
Urine Concentrations of VX-371
Time frame: Pre-dose (90 minutes prior inhaled study drug administration) and 60 minutes post-dose on Days 1, 14 and 28 within treatment period 1 and 2
Population: The PK analysis set included all participants who received at least 1 dose of VX-371. Here, overall number of participants analyzed signifies participants evaluable for this outcome measure and number analyzed signifies those participants who were evaluable at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VX-371 + Hypertonic Saline | Urine Concentrations of VX-371 | Day 1: Pre-dose | 0.0745 pg/mL | Standard Deviation 0.699 |
| VX-371 + Hypertonic Saline | Urine Concentrations of VX-371 | Day 1: Post-dose | 7.78 pg/mL | Standard Deviation 11.8 |
| VX-371 + Hypertonic Saline | Urine Concentrations of VX-371 | Day 14: Pre-dose | 41.0 pg/mL | Standard Deviation 97.2 |
| VX-371 + Hypertonic Saline | Urine Concentrations of VX-371 | Day 14: Post-dose | 38.9 pg/mL | Standard Deviation 64.8 |
| VX-371 + Hypertonic Saline | Urine Concentrations of VX-371 | Day 28: Pre-dose | 65.3 pg/mL | Standard Deviation 155 |
| VX-371 + Hypertonic Saline | Urine Concentrations of VX-371 | Day 28: Post-dose | 49.1 pg/mL | Standard Deviation 120 |
| Hypertonic Saline | Urine Concentrations of VX-371 | Day 28: Pre-dose | 98.6 pg/mL | Standard Deviation 175 |
| Hypertonic Saline | Urine Concentrations of VX-371 | Day 1: Pre-dose | 0.00 pg/mL | Standard Deviation 0 |
| Hypertonic Saline | Urine Concentrations of VX-371 | Day 14: Post-dose | 75.0 pg/mL | Standard Deviation 98.7 |
| Hypertonic Saline | Urine Concentrations of VX-371 | Day 1: Post-dose | 22.1 pg/mL | Standard Deviation 38.4 |
| Hypertonic Saline | Urine Concentrations of VX-371 | Day 28: Post-dose | 75.1 pg/mL | Standard Deviation 108 |
| Hypertonic Saline | Urine Concentrations of VX-371 | Day 14: Pre-dose | 69.6 pg/mL | Standard Deviation 107 |