Alpha₁-Antitrypsin Deficiency
Conditions
Brief summary
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).
Interventions
BIOLOGICALLiquid Alpha₁-PI
Liquid Alpha₁-PI, 60 mg/kg, 8 weekly intravenous infusions
BIOLOGICALProlastin-C
Prolastin-C, 60 mg/kg, 8 weekly intravenous infusions
Sponsors
Grifols Therapeutics LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC(0-7 Days) Based on Antigenic Content | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC(0-7 Days) Based on Functional Activity | 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 | 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. |
| Number of Subjects With Immunogenicity Response | Weeks 1, 9, 17, and 20 | 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). |
Countries
United States
Participant flow
Recruitment details
This study was performed at 6 investigative centers in the US.
Participants by arm
| Arm | Count |
|---|---|
| Liquid Alpha₁-PI/Prolastin-C Subjects were treated first with Liquid Alpha₁-PI and then treated with Prolastin-C
Liquid Alpha₁-PI: Liquid Alpha₁-PI, 60 mg/kg, 8 weekly intravenous infusions
Prolastin-C: Prolastin-C, 60 mg/kg, 8 weekly intravenous infusions | 16 |
| Prolastin-C/Liquid Alpha₁-PI Subjects were treated first with Prolastin-C and then treated with Liquid Alpha₁-PI
Prolastin-C: Prolastin-C, 60 mg/kg, 8 weekly intravenous infusions
Liquid Alpha₁-PI: Liquid Alpha₁-PI, 60 mg/kg, 8 weekly intravenous infusions | 16 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of home health aid | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Liquid Alpha₁-PI/Prolastin-C | Total | Prolastin-C/Liquid Alpha₁-PI |
|---|---|---|---|
| Age, Continuous | 60.7 years STANDARD_DEVIATION 7.94 | 61.9 years STANDARD_DEVIATION 7 | 63.1 years STANDARD_DEVIATION 5.93 |
| Alpha1-PI concentration Naive | 0.31 mg/mL | 0.24 mg/mL STANDARD_DEVIATION 0.059 | 0.21 mg/mL STANDARD_DEVIATION 0.04 |
| Alpha1-PI concentration Non-naive | 0.72 mg/mL STANDARD_DEVIATION 0.283 | 0.70 mg/mL STANDARD_DEVIATION 0.248 | 0.69 mg/mL STANDARD_DEVIATION 0.215 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 31 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 16 participants | 32 participants | 16 participants |
| Sex: Female, Male Female | 8 Participants | 14 Participants | 6 Participants |
| Sex: Female, Male Male | 8 Participants | 18 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 32 | 3 / 31 |
| serious Total, serious adverse events | 0 / 32 | 1 / 31 |
Outcome results
Primary
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.
Time frame: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liquid Alpha₁-PI | AUC(0-7 Days) Based on Antigenic Content | 203.20 mg*h/mL | Standard Deviation 23.041 |
| Prolastin-C | AUC(0-7 Days) Based on Antigenic Content | 198.38 mg*h/mL | Standard Deviation 25.23 |
Secondary
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.
Time frame: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liquid Alpha₁-PI | AUC(0-7 Days) Based on Functional Activity | 171.16 mg*h/mL | Standard Deviation 28.764 |
| Prolastin-C | AUC(0-7 Days) Based on Functional Activity | 168.50 mg*h/mL | Standard Deviation 27.473 |
Secondary
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).
Time frame: Weeks 1, 9, 17, and 20
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Liquid Alpha₁-PI | Number of Subjects With Immunogenicity Response | 0 Participants |
| Prolastin-C | Number of Subjects With Immunogenicity Response | 0 Participants |