A Study to Assess Safety and PK of Liquid Alpha₁-Proteinase Inhibitor (Human) in Treating Alpha₁-Antitrypsin Deficiency

Study Overview
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Brief Summary
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Grifols Therapeutics Inc. conducted a multi-center, randomized, double-blind, crossover study to evaluate the safety, immunogenicity, and pharmacokinetics (PK) of Liquid Alpha₁-PI compared to the currently licensed product, Prolastin-C, in subjects with Alpha₁-Antitrypsin Deficiency (AATD).

Official Title
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A Multi-center, Randomized, Double-blind, Crossover Study to Assess the Safety and Pharmacokinetics of Liquid Alpha₁-Proteinase Inhibitor (Human) Compared to Prolastin®-C in Subjects With Alpha₁-Antitrypsin Deficiency

Conditions
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Alpha₁-Antitrypsin Deficiency

Intervention / Treatment
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* Biological: Liquid Alpha₁-PI
* Biological: Prolastin-C


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be between 18 and 70 years of age, inclusive Had a diagnosis of congenital AATD Had a documented total alpha₁-PI level < 11 µM. If the total alpha₁-PI level had yet to be documented, a blood draw for total alpha₁-PI level was obtained at the Screening Visit Had a post-bronchodilator Forced expiratory volume in 1 second (FEV1) ≥ 30% and < 80% of predicted and FEV1/forced vital capacity (FVC) < 70% If the subject had received alpha₁-PI augmentation therapy of any kind, he/she must have been be willing to discontinue that treatment at the Week 1 (Baseline) Visit and remain off any kind of alpha₁-PI treatment, other than the investigational products for this study, while participating in the study Exclusion Criteria: Subject had a moderate or severe pulmonary exacerbation during the 4 weeks before the Week 1 (Baseline) Visit History of lung or liver transplant Any lung surgery during the past 2 years (excluding lung biopsy) Liver cirrhosis confirmed by biopsy Elevated liver enzymes (aspartate transaminase [AST], alanine aminotransferase [ALT], and alkaline phosphatase [ALP]) equal to or greater than 2.5 times the upper limit of normal Severe concomitant disease (e.g., congestive heart failure, clinically significant pulmonary fibrosis, malignant disease [with the exception of skin cancers other than melanoma], history of acute hypersensitivity pneumonitis reaction, or current chronic hypersensitivity pneumonitis) Females who were pregnant, breastfeeding or, if of child-bearing potential, unwilling to practice a highly effective method of contraception (oral, injectable or implanted hormonal methods of contraception, placement of an intrauterine device (IUD) or intrauterine system (IUS), condom or occlusive cap with spermicidal foam/gel/film/cream/suppository, male sterilization, or abstinence) throughout the study Known previous infection with or clinical signs and symptoms consistent with current hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infection Smoking during the past 6 months or a positive urine cotinine test at the Screening Visit that is due to smoking Participation in another investigational drug study within one month prior to the Week 1 (Baseline) Visit History of anaphylaxis or severe systemic response to any plasma-derived alpha1-PI preparation or other blood product(s) Use of systemic steroids above a stable dose equivalent to 5 mg/day prednisone (i.e.,10 mg every 2 days) within the 4 weeks prior to the Week 1 (Baseline) Visit inhaled steroids are not considered systemic steroids) Use of systemic or aerosolized antibiotics for an exacerbation within the 4 weeks prior to the Week 1 (Baseline) Visit Known selective or severe Immunoglobulin A (IgA) deficiency

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Treatment Sequence 1<br>Subjects were treated first with Liquid Alpha₁-PI and then treated with Prolastin-C | Biological: Liquid Alpha₁-PI<br>* Liquid Alpha₁-PI, 60 mg/kg, 8 weekly intravenous infusions<br>Biological: Prolastin-C<br>* Prolastin-C, 60 mg/kg, 8 weekly intravenous infusions<br>|
| Other: Treatment Sequence 2<br>Subjects were treated first with Prolastin-C and then treated with Liquid Alpha₁-PI | Biological: Liquid Alpha₁-PI<br>* Liquid Alpha₁-PI, 60 mg/kg, 8 weekly intravenous infusions<br>Biological: Prolastin-C<br>* Prolastin-C, 60 mg/kg, 8 weekly intravenous infusions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC(0-7 Days) Based on Antigenic Content | The primary PK objective of this study was to demonstrate the bioequivalence of Liquid Alpha₁-PI 60 mg/kg to Prolastin-C 60 mg/kg, as measured by AUC from 0 to 7 days (AUC0-7days) using an antigenic content assay of alpha₁-PI, at approximate steady state in subjects with AATD. | pre-dose, 0, 15 min, 30 min, 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 2 days, 5 days, 7 days post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC(0-7 Days) Based on Functional Activity | The exploratory PK objective of this study was to demonstrate the bioequivalence of Liquid Alpha₁-PI 60 mg/kg to Prolastin-C 60 mg/kg, as measured by AUC from 0 to 7 days (AUC 0-7 days) using a functional activity assay of alpha₁-PI, at approximate steady state in subjects with AATD. | pre-dose, 0, 15 min, 30 min, 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 2 days, 5 days, 7 days post dose | 
| Number of Subjects With Immunogenicity Response | Blood samples for immunogenicity testing were collected at Weeks 1 (Baseline), 9, 17, and 20. Any samples that tested positive for alpha₁-PI antibodies were tested for neutralizing antibodies and antibody titer. Immunogenicity testing was performed using validated assays in a multitiered approach. Samples collected at Week 1 (Baseline) and at Weeks 9 and 20 were tested for immunogenicity while samples collected at Week 17 were to be tested for immunogenicity only if deemed appropriate (eg, unexpected PK profile). | Weeks 1, 9, 17, and 20 |