Alpha 1-Antitrypsin Deficiency
Conditions
Brief summary
This study will evaluate the efficacy, safety and pharmacokinetics (PK) of VX-814 in PiZZ subjects.
Interventions
DRUGPlacebo
Placebo matched to VX-814 for oral administration.
DRUGVX-814
Tablet for oral administration.
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Subjects must have a PiZZ genotype confirmed at screening * Plasma AAT levels indicating severe deficiency at screening Key
Exclusion criteria
* History of a medical condition that could negatively impact the ability to complete the study * Solid organ, or hematological transplantation or is currently on a transplant list * History of use of gene therapy or RNAi therapy at any time previously Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in Plasma Functional Alpha-1 Antitrypsin (AAT) Levels | From Baseline at Day 28 |
| Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Day 1 up to Week 8 |
Secondary
| Measure | Time frame |
|---|---|
| Change in Plasma Antigenic AAT Levels | From Baseline at Day 28 |
| Observed Pre-dose Plasma Concentration of VX-814 | Pre-dose at Day 7, Day 14, Day 21, and Day 28 |
Countries
Canada, Germany, Ireland, United States
Participant flow
Recruitment details
There were 3 parts in the study: Parts A1, A2 and B. As pre-specified in SAP, data collected for the placebo group for Parts A1, A2 and B were pooled and reported as a single combined arm (Parts A1, A2 and B Combined: Placebo) and data collected for VX-814 400 mg for Parts A1 and A2 were pooled and reported as a single combined arm (Parts A1 and A2 Combined: VX-814 400 milligrams \[mg\]) in the below presented results.
Pre-assignment details
This study was conducted in participants 18 through 80 of years of age, inclusive with the PiZZ genotype.
Participants by arm
| Arm | Count |
|---|---|
| Parts A1, A2 and B Combined: Placebo Participants received placebo matched to VX-814 in the treatment period for 28 days. | 10 |
| Part A1: VX-814 100 mg Participants received VX-814 100 mg q12h in the treatment period for 28 days. | 4 |
| Part A1: VX-814 200 mg Participants received VX-814 200 mg q12h in the treatment period for 28 days. | 3 |
| Parts A1 and A2 Combined: VX-814 400 mg Participants received VX-814 400 mg q12h in the treatment period for 28 days. | 13 |
| Part B: VX-814 600 mg Participants received VX-814 600 mg q12h in the treatment period for 28 days. | 18 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Other | 1 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Parts A1, A2 and B Combined: Placebo | Part A1: VX-814 100 mg | Part A1: VX-814 200 mg | Parts A1 and A2 Combined: VX-814 400 mg | Part B: VX-814 600 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 54.6 years STANDARD_DEVIATION 11.3 | 51.8 years STANDARD_DEVIATION 14.8 | 55.5 years STANDARD_DEVIATION 7.8 | 57.9 years STANDARD_DEVIATION 13.2 | 57.9 years STANDARD_DEVIATION 9.1 | 56.5 years STANDARD_DEVIATION 10.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 3 Participants | 3 Participants | 12 Participants | 14 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants | 5 Participants |
| Plasma Functional Alpha-1 Antitrypsin (AAT) Levels | 4.2 micromole per liter STANDARD_DEVIATION 1.2 | 5.1 micromole per liter STANDARD_DEVIATION 2.3 | 3.9 micromole per liter STANDARD_DEVIATION 0.4 | 3.9 micromole per liter STANDARD_DEVIATION 0.7 | 4.5 micromole per liter STANDARD_DEVIATION 1 | 4.3 micromole per liter STANDARD_DEVIATION 1.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 4 Participants | 3 Participants | 13 Participants | 18 Participants | 48 Participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 0 Participants | 7 Participants | 12 Participants | 27 Participants |
| Sex: Female, Male Male | 5 Participants | 1 Participants | 3 Participants | 6 Participants | 6 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 4 | 0 / 3 | 0 / 13 | 0 / 18 |
| other Total, other adverse events | 4 / 10 | 1 / 4 | 0 / 3 | 9 / 13 | 14 / 18 |
| serious Total, serious adverse events | 0 / 10 | 2 / 4 | 1 / 3 | 1 / 13 | 0 / 18 |
Outcome results
Primary
Change in Plasma Functional Alpha-1 Antitrypsin (AAT) Levels
Time frame: From Baseline at Day 28
Population: Full analysis set (FAS) included all randomized participants who received at least 1 dose of study drug. The overall number of participants analyzed signifies participants who were evaluable at the specified time point. As pre-specified in SAP, statistical comparison with placebo were planned only for VX-814 400 mg and 600 mg treatment arms.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Parts A1, A2 and B Combined: Placebo | Change in Plasma Functional Alpha-1 Antitrypsin (AAT) Levels | -0.4 micromole per liter | Standard Deviation 0.3 |
| Part A1: VX-814 100 mg | Change in Plasma Functional Alpha-1 Antitrypsin (AAT) Levels | 0.2 micromole per liter | Standard Deviation 0.1 |
| Part A1: VX-814 200 mg | Change in Plasma Functional Alpha-1 Antitrypsin (AAT) Levels | 0.3 micromole per liter | Standard Deviation 0.5 |
| Parts A1 and A2 Combined: VX-814 400 mg | Change in Plasma Functional Alpha-1 Antitrypsin (AAT) Levels | 1.4 micromole per liter | Standard Deviation 0.6 |
| Part B: VX-814 600 mg | Change in Plasma Functional Alpha-1 Antitrypsin (AAT) Levels | 1.6 micromole per liter | Standard Deviation 1 |
p-value: <0.000195% CI: [1.1, 2.3]t-test, 2 sided
p-value: <0.000195% CI: [1.1, 2.9]t-test, 2 sided
Primary
Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: Day 1 up to Week 8
Population: The safety set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Parts A1, A2 and B Combined: Placebo | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With AEs | 4 participants |
| Parts A1, A2 and B Combined: Placebo | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With SAEs | 0 participants |
| Part A1: VX-814 100 mg | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With AEs | 3 participants |
| Part A1: VX-814 100 mg | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With SAEs | 2 participants |
| Part A1: VX-814 200 mg | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With AEs | 1 participants |
| Part A1: VX-814 200 mg | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With SAEs | 1 participants |
| Parts A1 and A2 Combined: VX-814 400 mg | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With SAEs | 1 participants |
| Parts A1 and A2 Combined: VX-814 400 mg | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With AEs | 10 participants |
| Part B: VX-814 600 mg | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With AEs | 14 participants |
| Part B: VX-814 600 mg | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With SAEs | 0 participants |
Secondary
Change in Plasma Antigenic AAT Levels
Time frame: From Baseline at Day 28
Population: FAS. The overall number of participants analyzed signifies participants who were evaluable at the specified time point. As pre-specified in SAP, statistical comparisons with placebo were planned only for VX-814 400 mg and 600 mg treatment arms.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Parts A1, A2 and B Combined: Placebo | Change in Plasma Antigenic AAT Levels | 0.4 micromole per liter | Standard Deviation 1.3 |
| Part A1: VX-814 100 mg | Change in Plasma Antigenic AAT Levels | 0.1 micromole per liter | Standard Deviation 0.2 |
| Part A1: VX-814 200 mg | Change in Plasma Antigenic AAT Levels | 0.7 micromole per liter | Standard Deviation 0.7 |
| Parts A1 and A2 Combined: VX-814 400 mg | Change in Plasma Antigenic AAT Levels | 2.4 micromole per liter | Standard Deviation 1.2 |
| Part B: VX-814 600 mg | Change in Plasma Antigenic AAT Levels | 2.6 micromole per liter | Standard Deviation 1.1 |
p-value: 0.011495% CI: [0.5, 3.4]t-test, 2 sided
p-value: 0.000995% CI: [1.1, 3.5]t-test, 2 sided
Secondary
Observed Pre-dose Plasma Concentration of VX-814
Time frame: Pre-dose at Day 7, Day 14, Day 21, and Day 28
Population: Pharmacokinetic analysis included all randomized participants who received at least 1 dose of study drug. Here number analyzed signifies participants who were evaluable at the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Parts A1, A2 and B Combined: Placebo | Observed Pre-dose Plasma Concentration of VX-814 | Day 7 | 0.476 microgram per milliliter | Standard Deviation 0.375 |
| Parts A1, A2 and B Combined: Placebo | Observed Pre-dose Plasma Concentration of VX-814 | Day 14 | 0.244 microgram per milliliter | Standard Deviation 0.0919 |
| Parts A1, A2 and B Combined: Placebo | Observed Pre-dose Plasma Concentration of VX-814 | Day 21 | 0.700 microgram per milliliter | — |
| Parts A1, A2 and B Combined: Placebo | Observed Pre-dose Plasma Concentration of VX-814 | Day 28 | 0.326 microgram per milliliter | Standard Deviation 0.0282 |
| Part A1: VX-814 100 mg | Observed Pre-dose Plasma Concentration of VX-814 | Day 14 | 1.07 microgram per milliliter | Standard Deviation 0.152 |
| Part A1: VX-814 100 mg | Observed Pre-dose Plasma Concentration of VX-814 | Day 21 | 1.45 microgram per milliliter | — |
| Part A1: VX-814 100 mg | Observed Pre-dose Plasma Concentration of VX-814 | Day 28 | 0.993 microgram per milliliter | Standard Deviation 0.03 |
| Part A1: VX-814 100 mg | Observed Pre-dose Plasma Concentration of VX-814 | Day 7 | 0.948 microgram per milliliter | Standard Deviation 0.512 |
| Part A1: VX-814 200 mg | Observed Pre-dose Plasma Concentration of VX-814 | Day 21 | 3.68 microgram per milliliter | Standard Deviation 3.4 |
| Part A1: VX-814 200 mg | Observed Pre-dose Plasma Concentration of VX-814 | Day 14 | 3.25 microgram per milliliter | Standard Deviation 2.23 |
| Part A1: VX-814 200 mg | Observed Pre-dose Plasma Concentration of VX-814 | Day 28 | 3.23 microgram per milliliter | Standard Deviation 2.82 |
| Part A1: VX-814 200 mg | Observed Pre-dose Plasma Concentration of VX-814 | Day 7 | 3.53 microgram per milliliter | Standard Deviation 1.72 |
| Parts A1 and A2 Combined: VX-814 400 mg | Observed Pre-dose Plasma Concentration of VX-814 | Day 28 | 5.80 microgram per milliliter | Standard Deviation 3.73 |
| Parts A1 and A2 Combined: VX-814 400 mg | Observed Pre-dose Plasma Concentration of VX-814 | Day 14 | 8.53 microgram per milliliter | Standard Deviation 11.8 |
| Parts A1 and A2 Combined: VX-814 400 mg | Observed Pre-dose Plasma Concentration of VX-814 | Day 7 | 10.3 microgram per milliliter | Standard Deviation 6.55 |
| Parts A1 and A2 Combined: VX-814 400 mg | Observed Pre-dose Plasma Concentration of VX-814 | Day 21 | 7.20 microgram per milliliter | Standard Deviation 6.05 |