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This is a study to assess the safety and pharmacokinetics of weekly infusions of 120 mg/kg of Prolastin-C (alpha1-proteinase inhibitor [alpha1-PI] [Human]), compared to weekly infusions of 60 mg/kg of Prolastin-C in patients with alpha 1-antitrypsin deficiency (AATD).
The question of whether higher doses of alpha1-PI (>60 mg/kg) are able to provide better protection to patients with alpha 1-antitrypsin deficiency is currently unknown. As a first step to address this question, the present study has been undertaken. This is a multi-center, randomized, double-blind, crossover study to assess the safety and pharmacokinetics of weekly infusions of 120 mg/kg of Prolastin-C, compared to weekly infusions of 60 mg/kg of Prolastin-C in patients with alpha 1-antitrypsin deficiency. This study is a crossover design with 2 treatment sequences:
Treatment Sequence 1: 60 mg/kg weekly infusion of Prolastin-C for 8 weeks followed by 120 mg/kg weekly infusion of Prolastin-C for 8 weeks (starting at Week 1) (total of 16 treatment weeks)
Treatment Sequence 2: 120 mg/kg weekly infusion of Prolastin-C for 8 weeks followed by 60 mg/kg weekly infusion of Prolastin-C for 8 weeks (starting at Week 11) (total of 16 treatment weeks)
Approximately 15 subjects are planned to be entered into each treatment sequence.
At Weeks 8 to 11 and Weeks 18 to 21, a total of 15 serial blood samples for each subject will be drawn for pharmacokinetic analysis. The expected duration of the study subject's participation will be approximately 25 weeks (which includes a 3-Week Screening Phase, 2-Week Washout Period [between different alpha-1 PI treatment doses], and a 4-Week Follow-up Period). The following safety parameters will be assessed: adverse events, pulmonary exacerbations, vital signs, pulmonary function tests, and clinical laboratory tests.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Prolastin-C, 60 mg/kg | Active Comparator | 60 mg/kg weekly infusion of Prolastin-C for 8 weeks. Subjects were infused with 60 mg/kg Prolastin-C by means of one of two possible treatment sequences: 1) 60 mg/kg weekly infusion of Prolastin-C for 8 weeks followed by 120 mg/kg Prolastin-C for 8 weeks, or 2) 120 mg/kg Prolastin-C for 8 weeks followed by 60 mg/kg weekly infusion of Prolastin-C for 8 weeks (total of 16 weeks). |
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| Prolastin-C, 120 mg/kg | Experimental | 120 mg/kg weekly infusion of Prolastin-C for 8 weeks. Subjects were infused with 120 mg/kg Prolastin-C by means of one of two possible treatment sequences: 1) 60 mg/kg weekly infusion of Prolastin-C for 8 weeks followed by 120 mg/kg Prolastin-C for 8 weeks, or 2) 120 mg/kg Prolastin-C for 8 weeks followed by 60 mg/kg weekly infusion of Prolastin-C for 8 weeks (total of 16 weeks). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Prolastin-C, 60 mg/kg | Biological | 60 mg/kg weekly infusion of Prolastin-C for 8 weeks |
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| Measure | Description | Time Frame |
|---|---|---|
| Subjects With Treatment-Emergent Adverse Events (TEAEs) | Number of subjects experiencing at least one TEAE. TEAEs were defined as any adverse event (AE) during the study that began on or after the date of first dose of investigational product (i.e., Prolastin-C). | 22 weeks |
| Subjects With Drug-Related TEAE(s) | Number of subjects with at least one TEAE that was determined by the Investigator to be either "possibly related" or "related" to the investigational product (i.e., Prolastin-C). | 22 weeks |
| Subjects With Treatment-Emergent Serious Adverse Events (SAEs) | Number of subjects who experienced at least one treatment-emergent SAE. | 22 weeks |
| Subjects Withdrawn Due to an AE(s) | Number of subjects who were withdrawn from the study due to at least one AE. | 22 weeks |
| Subjects With Treatment-Emergent Pulmonary Exacerbation(s) | Number of subjects with at least one treatment-emergent pulmonary exacerbation | 22 weeks |
| Subjects With Severe TEAE(s) or Pulmonary Exacerbation(s) | Number of subjects who experienced at least one severe TEAE or pulmonary exacerbation. | 22 weeks |
| Number of TEAEs | Total number of TEAEs reported. | 22 Weeks |
| Measure | Description | Time Frame |
|---|---|---|
| AUC0-7days | Area Under the Alpha-1 PI Concentration-Time Curve from Day 0 to Day 7 | Week 8 and Week 18 at the following timepoints: 0 (pre-infusion), completion of first infusion bag, completion of 2nd infusion bag, and 15 min, 30 min, and 1, 2, 4, 8, 24, 48, 120, and 168 hours post-dose |
| Mean Trough |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Mark Brantly, MD | University of Florida | Principal Investigator |
| Michael Campos, MD | University of Miami | Principal Investigator |
| Friedrich Kueppers, MD | Temple University Hospital/Temple Lung Center | Principal Investigator |
| James Stocks, MD | The University of Texas Health Science Center at Tyler | Principal Investigator |
| Charlie Strange, MD | Medical University of South Carolina, Division of Pulmonary and Critical Care Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Florida College of Medicine | Gainesville | Florida | 32610-0225 | United States | ||
| University of Miami |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| Background | Willis T, Wee K, Mohn G. A high-purity Alpha-1 proteinase inhibitor from human plasma, TAL6004. Proceeding of the 19th European Respiratory Society Annual Congress; 2009 Sep 12-16; Vienna, Austria. Abstracts;34:S53. |
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Subjects entered a Screening Phase (up to 21 days in duration) to determine subject eligibility and for wash-out of prior alpha1-PI augmentation therapy, if applicable, prior to randomization to one of two treatment sequences.
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| ID | Title | Description |
|---|---|---|
| FG000 | 60 mg/kg - 120 mg/kg Prolastin-C Treatment Sequence | Weekly infusions of 60 mg/kg Prolastin-C for 8 weeks followed by a 2-week off-treatment washout period followed by weekly infusions of 120 mg/kg Prolastin-C for 8 weeks (total of 16 treatment weeks) |
| FG001 | 120 mg/kg - 60 mg/kg Prolastin-C Treatment Sequence |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Treatment Period 1 |
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| Prolastin-C, 120 mg/kg | Biological | 120 mg/kg weekly infusion of Prolastin-C for 8 weeks |
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| Number of Drug-related TEAEs | Total number of drug-related TEAEs reported | 22 Weeks |
| Number of Treatment-Emergent Pulmonary Exacerbations | Total number of treatment-emergent pulmonary exacerbations. | 22 Weeks |
The average trough concentration at steady-state, calculated as the mean value using the four Trough measurements obtained at Weeks 6, 7, 8 and at 7 days (168 hours) post infusion at Week 8 for the first treatment period or prior to the start of the infusions at Weeks 16, 17, 18, and at 7 days (168 hours) post infusion at Week 18 for the second treatment period. |
| Single measurment immediately prior to infusion at Weeks 6, 7, 8, 9 and Weeks 16, 17, 18, 19 |
| Miami |
| Florida |
| 33136 |
| United States |
| Temple University Hosptial/Temple Lung Center | Philadelphia | Pennsylvania | 19140 | United States |
| Medical University of South Carolina, Division of Pulmonary and Critical Care Medicine | Charleston | South Carolina | 29425-6300 | United States |
| The University of Texas Health Science Center at Tyler | Tyler | Texas | 75708 | United States |
Weekly infusions of 120 mg/kg Prolastin-C for 8 weeks followed by a 2-week off-treatment washout period followed by weekly infusions of 60 mg/kg Prolastin-C for 8 weeks (total of 16 treatment weeks) |
| COMPLETED |
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| NOT COMPLETED |
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| Washout Period |
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| Treatment Period 2 |
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| Follow-up |
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Demographic and other baseline characteristics were analyzed on the intent-to-treat population, which included all subjects who were randomized.
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| ID | Title | Description |
|---|---|---|
| BG000 | 60 mg/kg - 120 mg/kg Prolastin-C Treatment Sequence | Weekly infusions of 60 mg/kg Prolastin-C for 8 weeks followed by a 2-week off-treatment washout period followed by weekly infusions of 120 mg/kg Prolastin-C for 8 weeks (total of 16 treatment weeks) |
| BG001 | 120 mg/kg - 60 mg/kg Prolastin-C Treatment Sequence | Weekly infusions of 120 mg/kg Prolastin-C for 8 weeks followed by a 2-week off-treatment washout period followed by weekly infusions of 60 mg/kg Prolastin-C for 8 weeks (total of 16 treatment weeks) |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| 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 | Subjects With Treatment-Emergent Adverse Events (TEAEs) | Number of subjects experiencing at least one TEAE. TEAEs were defined as any adverse event (AE) during the study that began on or after the date of first dose of investigational product (i.e., Prolastin-C). | All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C). | Posted | Number | participants | 22 weeks |
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| Secondary | AUC0-7days | Area Under the Alpha-1 PI Concentration-Time Curve from Day 0 to Day 7 | Pharmacokinetic (PK) Population, which consisted of all subjects who received investigational product (Prolastin-C) and had sufficient and valid serum concentration data to facilitate calculation of PK parameters. | Posted | Mean | Standard Deviation | h*mg/mL | Week 8 and Week 18 at the following timepoints: 0 (pre-infusion), completion of first infusion bag, completion of 2nd infusion bag, and 15 min, 30 min, and 1, 2, 4, 8, 24, 48, 120, and 168 hours post-dose |
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| Primary | Subjects With Drug-Related TEAE(s) | Number of subjects with at least one TEAE that was determined by the Investigator to be either "possibly related" or "related" to the investigational product (i.e., Prolastin-C). | All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C). | Posted | Number | participants | 22 weeks |
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| Primary | Subjects With Treatment-Emergent Serious Adverse Events (SAEs) | Number of subjects who experienced at least one treatment-emergent SAE. | All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C). | Posted | Number | participants | 22 weeks |
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| Primary | Subjects Withdrawn Due to an AE(s) | Number of subjects who were withdrawn from the study due to at least one AE. | All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C). | Posted | Number | participants | 22 weeks |
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| Primary | Subjects With Treatment-Emergent Pulmonary Exacerbation(s) | Number of subjects with at least one treatment-emergent pulmonary exacerbation | All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C). | Posted | Number | participants | 22 weeks |
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| Primary | Subjects With Severe TEAE(s) or Pulmonary Exacerbation(s) | Number of subjects who experienced at least one severe TEAE or pulmonary exacerbation. | All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C). | Posted | Number | participants | 22 weeks |
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| Secondary | Mean Trough | The average trough concentration at steady-state, calculated as the mean value using the four Trough measurements obtained at Weeks 6, 7, 8 and at 7 days (168 hours) post infusion at Week 8 for the first treatment period or prior to the start of the infusions at Weeks 16, 17, 18, and at 7 days (168 hours) post infusion at Week 18 for the second treatment period. | PK Population, which consisted of all subjects who received investigational product (Prolastin-C) and had sufficient and valid serum concentration data to facilitate calculation of PK parameters. | Posted | Mean | Standard Deviation | μM | Single measurment immediately prior to infusion at Weeks 6, 7, 8, 9 and Weeks 16, 17, 18, 19 |
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| Primary | Number of TEAEs | Total number of TEAEs reported. | All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C). | Posted | Number | Events | 22 Weeks |
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| Primary | Number of Drug-related TEAEs | Total number of drug-related TEAEs reported | All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C). | Posted | Number | Events | 22 Weeks |
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| Primary | Number of Treatment-Emergent Pulmonary Exacerbations | Total number of treatment-emergent pulmonary exacerbations. | All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C). | Posted | Number | Events | 22 Weeks |
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Adverse events were assessed from the time of informed consent through the end of study visit; thus, AEs were assessed for up to 25 weeks.
Assessment of AEs were performed by questioning the subject at each scheduled study visit. Treatment Emergent adverse events were defined as any AE during the study that began on or after the date of first dose of investigational product (i.e., Prolastin-C).
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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 | 60 mg/kg Prolastin-C | 0 | 30 | 15 | 30 | |||
| EG001 | 120 mg/kg Prolastin-C | 0 | 30 | 10 | 30 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| COPD Exacerbation | Respiratory, thoracic and mediastinal disorders | MedDRA 13.0 | Systematic Assessment | This study used the American Thoracic Society (ATS)/European Respiratory Society (ERS) Task Force definition of exacerbation. |
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| Urinary Tract Infection | Infections and infestations | MedDRA 13.0 | Systematic Assessment |
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| Contusion | Injury, poisoning and procedural complications | MedDRA 13.0 | Systematic Assessment |
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| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA 13.0 | Systematic Assessment |
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| Proteinuria | Renal and urinary disorders | MedDRA 13.0 | Systematic Assessment |
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| Blood Creatinine Increased | Investigations | MedDRA 13.0 | Systematic Assessment |
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| Blood Glucose Increased | Investigations | MedDRA 13.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Benjamin King, PhD | Grifols Therapeutics Inc. | ben.king@grifols.com |
| ID | Term |
|---|---|
| D004646 | Emphysema |
| D019896 | alpha 1-Antitrypsin Deficiency |
| ID | Term |
|---|---|
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D013352 | Subcutaneous Emphysema |
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| ID | Term |
|---|---|
| D000515 | alpha 1-Antitrypsin |
| C114276 | Mp alpha1 receptor |
| ID | Term |
|---|---|
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D015843 | Serpins |
| 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 |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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