Alpha 1-Antitrypsin Deficiency
Conditions
Keywords
Severe congenital Alpha1-Proteinase Inhibitor (Alpha1-PI) deficiency
Brief summary
The primary purpose of this study is to characterize the pharmacokinetic profile of intravenous Aralast Fraction (Fr.) IV-1, a sterile, stable, lyophilized preparation of functionally intact human Alpha1- Proteinase Inhibitor (α1-PI). This pharmacokinetic study will be a randomized controlled clinical trial with a cross-over design. Twenty-four subjects will be enrolled into the study. Overall study duration will be approximately 6-8 months.
Interventions
BIOLOGICALDose of 60 mg/kg Fraction IV-1 Alpha1-Proteinase Inhibitor
Subjects meeting the eligibility criteria were randomized to receive either single dose ARALAST alpha1-proteinase inhibitor 60 mg/kg or single-dose ARALAST alpha1-proteinase inhibitor Fr. IV-1 60 mg/kg at 0.2 mL/kg/min during the first treatment period with crossover to the alternate study product during the second treatment period, with a minimum of 7 days between the two treatment periods.
BIOLOGICALDose of 60 mg/kg alpha1-proteinase inhibitor
Subjects meeting the eligibility criteria were randomized to receive either single dose ARALAST alpha1-proteinase inhibitor 60 mg/kg or single-dose ARALAST alpha1-proteinase inhibitor Fr. IV-1 60 mg/kg at 0.2 mL/kg/min during the first treatment period with crossover to the alternate study product during the second treatment period, with a minimum of 7 days between the two treatment periods.
Sponsors
Baxter Healthcare, Ltd. (New Zealand), Baxter Healthcare Pty. Ltd. (Australia)
Baxalta now part of Shire
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The subject or subject´s legally authorized representative has provided written informed consent * Subject is 18 years of age or older * Subject has a documented, endogenous plasma Alpha1-PI level \< 8 Micromolar * Subject is of the genotype Pi\*Z/Z, Pi\*Z/Null, Pi\*Null/Null, Pi\*Malton/Z, or others, dependent on the approval by the Sponsor * If the subject is female or of childbearing potential, the subject has a negative urine test for pregnancy within 7 days prior to first study product administration and agrees to employ adequate birth control measures for the duration of the study * Laboratory results obtained at the screening visit, meeting the following criteria: * Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) \<= 2 times the upper limit of normal (ULN) * Serum total bilirubin \<= 2 times ULN * Proteinuria \< +2 on dipstick analysis * Serum creatinine \<= 1.5 times ULN * Absolute neutrophil count (ANC) \>= 1500 cells/mm3 * Hemoglobin \>= 10.0 g/dL * Platelet count \>= 10\^5/mm3 * If the subject is treated with any respiratory medications, including inhaled bronchodilators and inhaled or oral corticosteroids, the subjects´ medication doses were unchanged for at least 14 days prior to first study product administration * Nonsmoker for a minimum of 3 months prior to first study product administration
Exclusion criteria
* The subject has received any Alpha1-PI augmentation therapy (including Aralast and investigational Alpha1-PIs, by any route including intravenous and inhaled) within 42 days prior to first study product administration * The subject has received an investigational drug or device within 1 month prior to first study product administration, or the subject is currently receiving an investigational drug * The subject has a known selective immunoglobulin A (IgA) deficiency (IgA level \< 15 mg/dL) and/or antibody to IgA * The subject has a pulmonary exacerbation or had a pulmonary exacerbation in the past 14 days prior to first study product administration * The subject is pregnant or lactating, or intends to become pregnant during the course of the study * The subject has a clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect subject safety or compliance
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve/Dose | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | Area under the plasma alpha1-proteinase inhibitor (α1-PI) concentration versus time curve (AUC) calculated by linear trapezoidal method per dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Systemic Clearance (CL) | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | Computed as dose divided by AUC 0-infinity (AUC 0-infinity was calculated as the sum of AUC from time 0 to the time of last quantifiable concentration plus a tail area correction) |
| Mean Residence Time (MRT) | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | Computed as total area under the moment curve (AUMC) divided by total AUC |
| Apparent Volume of Distribution at Steady State | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | Computed as weight-adjusted CL \* MRT |
| Terminal Half-life | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | Computed from the terminal or disposition rate constant obtained from log\_e -linear fitting using the least squares deviation to the last five quantifiable concentrations above pre-infusion level. |
| Total Area Under the Curve Per Dose | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | Total area under the α1-PI concentration vs. time curve from pharmacokinetic day 0 to time infinity (AUC 0-infinity) per dose |
| Time to Maximum α1-PI Concentration Post-infusion (Tmax) | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | Time to reach C-max. Tmax is the number of days from infusion to maximum concentration. Samples drawn at the end of infusion are considered to be time zero. |
| Incremental Recovery | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | Computed from Cmax (mg/ml) divided by dose per kg body weight (mg/kg). |
| Adverse Events (AEs) | Throughout study period (7 months) | Investigators assessed severity of AEs (occurring during or after infusions) based on: MILD: Transient discomfort, does not interfere in a significant manner with participant's normal functioning level; Resolves spontaneously or may require minimal therapeutic intervention MODERATE: AE produces limited impairment of function, can require therapeutic intervention; AE produces no sequelae; SEVERE: AE results in marked impairment of function, can lead to temporary inability to resume usual life pattern; AE produces sequelae, which require prolonged therapeutic intervention |
| Maximum Plasma Concentration (Cmax) | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | Maximum α1-PI concentration following infusion |
Countries
Australia, New Zealand
Participant flow
Recruitment details
Enrollment was conducted at seven clinical sites in Australia (4 sites) and New Zealand (3 sites) beginning in December 2005.
Pre-assignment details
All 25 enrolled subjects were assigned to groups.
Participants by arm
| Arm | Count |
|---|---|
| Subjects With Severe Congenital α1-PI Deficiency Subjects were randomized to receive either single dose ARALAST 60 mg/kg or single-dose ARALAST Fr. IV-1 60 mg/kg at 0.2 mL/kg/min during the first treatment period with crossover to the alternate study product during the second treatment period, with a minimum of 7 days between the two treatment periods. | 25 |
| Total | 25 |
Baseline characteristics
| Characteristic | Subjects With Severe Congenital α1-PI Deficiency |
|---|---|
| Age, Continuous | 59 years |
| Region of Enrollment Australia | 14 Participants |
| Region of Enrollment New Zealand | 11 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 23 / 25 | 19 / 25 |
| serious Total, serious adverse events | 0 / 25 | 0 / 25 |
Outcome results
Primary
Area Under the Curve/Dose
Area under the plasma alpha1-proteinase inhibitor (α1-PI) concentration versus time curve (AUC) calculated by linear trapezoidal method per dose.
Time frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Population: All study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ARALAST Fr. IV-1 | Area Under the Curve/Dose | 0.0822 days*kg/mL |
| ARALAST | Area Under the Curve/Dose | 0.0920 days*kg/mL |
90% CI: [0.858, 1.002]
Secondary
Adverse Events (AEs)
Investigators assessed severity of AEs (occurring during or after infusions) based on: MILD: Transient discomfort, does not interfere in a significant manner with participant's normal functioning level; Resolves spontaneously or may require minimal therapeutic intervention MODERATE: AE produces limited impairment of function, can require therapeutic intervention; AE produces no sequelae; SEVERE: AE results in marked impairment of function, can lead to temporary inability to resume usual life pattern; AE produces sequelae, which require prolonged therapeutic intervention
Time frame: Throughout study period (7 months)
Population: Safety Analysis Data Set - all study subjects who had evidence of receiving at least one dose of study medication regardless of any protocol violation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ARALAST Fr. IV-1 | Adverse Events (AEs) | Non-Serious AEs - Mild | 43 Events |
| ARALAST Fr. IV-1 | Adverse Events (AEs) | Serious AEs | 0 Events |
| ARALAST Fr. IV-1 | Adverse Events (AEs) | Non-Serious AEs - Severe | 2 Events |
| ARALAST Fr. IV-1 | Adverse Events (AEs) | Non-Serious AEs - Moderate | 16 Events |
| ARALAST | Adverse Events (AEs) | Non-Serious AEs - Severe | 3 Events |
| ARALAST | Adverse Events (AEs) | Serious AEs | 0 Events |
| ARALAST | Adverse Events (AEs) | Non-Serious AEs - Mild | 45 Events |
| ARALAST | Adverse Events (AEs) | Non-Serious AEs - Moderate | 12 Events |
Secondary
Apparent Volume of Distribution at Steady State
Computed as weight-adjusted CL \* MRT
Time frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Population: Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ARALAST Fr. IV-1 | Apparent Volume of Distribution at Steady State | 5606 mL |
| ARALAST | Apparent Volume of Distribution at Steady State | 5405 mL |
Secondary
Incremental Recovery
Computed from Cmax (mg/ml) divided by dose per kg body weight (mg/kg).
Time frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Population: Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ARALAST Fr. IV-1 | Incremental Recovery | 0.0259 (mg/mL) / (mg/kg) |
| ARALAST | Incremental Recovery | 0.0258 (mg/mL) / (mg/kg) |
Secondary
Maximum Plasma Concentration (Cmax)
Maximum α1-PI concentration following infusion
Time frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Population: Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ARALAST Fr. IV-1 | Maximum Plasma Concentration (Cmax) | 1.7 mg/mL |
| ARALAST | Maximum Plasma Concentration (Cmax) | 1.7 mg/mL |
Secondary
Mean Residence Time (MRT)
Computed as total area under the moment curve (AUMC) divided by total AUC
Time frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Population: Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ARALAST Fr. IV-1 | Mean Residence Time (MRT) | 6.8 days | Standard Deviation 3.9 |
| ARALAST | Mean Residence Time (MRT) | 6.9 days | Standard Deviation 2.8 |
Secondary
Systemic Clearance (CL)
Computed as dose divided by AUC 0-infinity (AUC 0-infinity was calculated as the sum of AUC from time 0 to the time of last quantifiable concentration plus a tail area correction)
Time frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Population: Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ARALAST Fr. IV-1 | Systemic Clearance (CL) | 951 mL/day |
| ARALAST | Systemic Clearance (CL) | 856 mL/day |
Secondary
Terminal Half-life
Computed from the terminal or disposition rate constant obtained from log\_e -linear fitting using the least squares deviation to the last five quantifiable concentrations above pre-infusion level.
Time frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Population: Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ARALAST Fr. IV-1 | Terminal Half-life | 4.1 days |
| ARALAST | Terminal Half-life | 4.2 days |
Secondary
Time to Maximum α1-PI Concentration Post-infusion (Tmax)
Time to reach C-max. Tmax is the number of days from infusion to maximum concentration. Samples drawn at the end of infusion are considered to be time zero.
Time frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Population: Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ARALAST Fr. IV-1 | Time to Maximum α1-PI Concentration Post-infusion (Tmax) | 0.00 days |
| ARALAST | Time to Maximum α1-PI Concentration Post-infusion (Tmax) | 0.00 days |
Secondary
Total Area Under the Curve Per Dose
Total area under the α1-PI concentration vs. time curve from pharmacokinetic day 0 to time infinity (AUC 0-infinity) per dose
Time frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Population: Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ARALAST Fr. IV-1 | Total Area Under the Curve Per Dose | 0.0825 days*kg/mL |
| ARALAST | Total Area Under the Curve Per Dose | 0.0928 days*kg/mL |
90% CI: [0.855, 1.021]