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| Name | Class |
|---|---|
| Baxter Healthcare, Ltd. (New Zealand), Baxter Healthcare Pty. Ltd. (Australia) | INDUSTRY |
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| ARALAST Fr. IV-1 | Experimental | 60 mg/kg |
|
| ARALAST | Active Comparator | 60mg/kg |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dose of 60 mg/kg Fraction IV-1 Alpha1-Proteinase Inhibitor | Biological | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
| Systemic Clearance (CL) |
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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:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Study Director | Takeda | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Adelaide | South Australia | Australia | ||||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36001294 | Derived | Li Z, Franke RM, Morris DN, Yel L. Pharmacokinetics and Biochemical Efficacy of an alpha1-Proteinase Inhibitor (Aralast NP) in alpha1-Antitrypsin Deficiency: a Cross-Product Retrospective Comparability Analysis. Pulm Ther. 2022 Sep;8(3):311-326. doi: 10.1007/s41030-022-00199-4. Epub 2022 Aug 24. |
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All 25 enrolled subjects were assigned to groups.
Enrollment was conducted at seven clinical sites in Australia (4 sites) and New Zealand (3 sites) beginning in December 2005.
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| ID | Title | Description |
|---|---|---|
| FG000 | ARALAST Fr. IV-1 Then Aralast | 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. |
| FG001 | ARALAST Then ARALAST Fr. IV-1 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 |
| |||||||||||||
| Period 2 |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | All study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis | Posted | Median | Full Range | days*kg/mL | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
|
Throughout the entire study period (7 months)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | ARALAST Fr. IV-1 | Subjects received a single dose of ARALAST Fr. IV-1 60 mg/kg at 0.2 mL/kg/min |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | MedDRA (Unspecified) |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Shire | +1 866 842 5335 | ClinicalTransparency@shire.com |
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| ID | Term |
|---|---|
| D019896 | alpha 1-Antitrypsin Deficiency |
| ID | Term |
|---|---|
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D000515 | alpha 1-Antitrypsin |
| ID | Term |
|---|---|
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D015843 | Serpins |
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|
| Dose of 60 mg/kg alpha1-proteinase inhibitor | Biological | 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. |
|
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) |
| Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
| Mean Residence Time (MRT) | Computed as total area under the moment curve (AUMC) divided by total AUC | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
| Apparent Volume of Distribution at Steady State | Computed as weight-adjusted CL * MRT | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
| 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. | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
| Maximum Plasma Concentration (Cmax) | Maximum α1-PI concentration following infusion | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
| 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. | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
| Incremental Recovery | Computed from Cmax (mg/ml) divided by dose per kg body weight (mg/kg). | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
| 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 | Throughout study period (7 months) |
| Woodville |
| South Australia |
| Australia |
| Fitzroy | Victoria | Australia |
| Nedlands | Western Australia | Australia |
| Otahuhu | Auckland | New Zealand |
| Christchurch | New Zealand |
| Hamilton | New Zealand |
| NOT COMPLETED |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
|
|
|
| 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 | Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis | Posted | Median | Full Range | days*kg/mL | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
|
|
|
|
| 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) | Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis | Posted | Median | Full Range | mL/day | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
|
|
|
| Secondary | Mean Residence Time (MRT) | Computed as total area under the moment curve (AUMC) divided by total AUC | Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis | Posted | Mean | Standard Deviation | days | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
|
|
|
| Secondary | Apparent Volume of Distribution at Steady State | Computed as weight-adjusted CL * MRT | Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis | Posted | Median | Full Range | mL | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
|
|
|
| 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. | Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis | Posted | Median | Full Range | days | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
|
|
|
| Secondary | Maximum Plasma Concentration (Cmax) | Maximum α1-PI concentration following infusion | Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis | Posted | Median | Full Range | mg/mL | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
|
|
|
| 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. | Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis | Posted | Median | Full Range | days | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
|
|
|
| Secondary | Incremental Recovery | Computed from Cmax (mg/ml) divided by dose per kg body weight (mg/kg). | Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis | Posted | Median | Full Range | (mg/mL) / (mg/kg) | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion |
|
|
|
| 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 | Safety Analysis Data Set - all study subjects who had evidence of receiving at least one dose of study medication regardless of any protocol violation. | Posted | Number | Events | Throughout study period (7 months) |
|
|
|
| 0 |
| 25 |
| 23 |
| 25 |
| EG001 | ARALAST | Subjects received a single dose of ARALAST 60 mg/kg at 0.2 mL/kg/min | 0 | 25 | 19 | 25 |
| Vessel puncture site bruise | General disorders | MedDRA (Unspecified) |
|
| Nasopharyngitis | Infections and infestations | MedDRA (Unspecified) |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA (Unspecified) |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA (Unspecified) |
|
| Muscle strain | Musculoskeletal and connective tissue disorders | MedDRA (Unspecified) |
|
| Musculoskeletal discomfort | Musculoskeletal and connective tissue disorders | MedDRA (Unspecified) |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA (Unspecified) |
|
| Headache | Nervous system disorders | MedDRA (Unspecified) |
|
| Lethargy | Nervous system disorders | MedDRA (Unspecified) |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (Unspecified) |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (Unspecified) |
|
| Pharyngolaryngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (Unspecified) |
|
| Blister | Skin and subcutaneous tissue disorders | MedDRA (Unspecified) |
|
Baxter's agreements with PIs vary per individual PI, but contain common elements. Baxter requires a review of results communications (e.g., for confidential information) ≥60 days prior to submission or communication. Baxter may request an additional delay of up to 60 days (e.g., to allow for intellectual property protection).
| D030342 |
| Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D013352 | Subcutaneous Emphysema |
| D004646 | Emphysema |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D010455 |
| Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000209 | Acute-Phase Proteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000510 | Alpha-Globulins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| Non-Serious AEs - Moderate |
|
| Non-Serious AEs - Severe |
|