Alpha 1-antitrypsin Deficiency (AATD), Emphysema
Conditions
Keywords
emphysema, alpha 1-antitrypsin, alpha 1-antitrypsin deficiency (AATD), alpha 1-proteinase inhibitor (Alpha-1 PI)
Brief summary
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).
Detailed description
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.
Interventions
BIOLOGICALProlastin-C, 60 mg/kg
60 mg/kg weekly infusion of Prolastin-C for 8 weeks
BIOLOGICALProlastin-C, 120 mg/kg
120 mg/kg weekly infusion of Prolastin-C for 8 weeks
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 * Have a documented diagnosis of congenital AATD * Have a post-bronchodilator Forced Expired Volume in 1 second (FEV1) of ≥30% and \<80% and FEV1/forced vital capacity (FVC) \<70% * If receiving alpha-1 PI augmentation therapy, be willing to discontinue the treatment for the duration of the study
Exclusion criteria
* Had a moderate or severe pulmonary exacerbation during the 4 weeks before the study * History of lung or liver transplant * Any lung surgery during the past 2 years * Confirmed liver cirrhosis * Elevated liver enzymes * Severe concurrent disease * Females who are pregnant or breast-feeding or unwilling to practice effective contraception during the study * Infection with hepatitis A, B, or C, human immunodeficiency or parvovirus B19 * Smoking during the past 6 months * Use of systemic steroids within 4 weeks of the study * Use of antibiotics for an exacerbation within 4 weeks of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment-Emergent Pulmonary Exacerbations | 22 Weeks | Total number of treatment-emergent pulmonary exacerbations. |
| Number of TEAEs | 22 Weeks | Total number of TEAEs reported. |
| Number of Drug-related TEAEs | 22 Weeks | Total number of drug-related TEAEs reported |
| Subjects With Treatment-Emergent Adverse Events (TEAEs) | 22 weeks | 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). |
| Subjects With Drug-Related TEAE(s) | 22 weeks | 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). |
| Subjects With Treatment-Emergent Serious Adverse Events (SAEs) | 22 weeks | Number of subjects who experienced at least one treatment-emergent SAE. |
| Subjects Withdrawn Due to an AE(s) | 22 weeks | Number of subjects who were withdrawn from the study due to at least one AE. |
| Subjects With Treatment-Emergent Pulmonary Exacerbation(s) | 22 weeks | Number of subjects with at least one treatment-emergent pulmonary exacerbation |
| Subjects With Severe TEAE(s) or Pulmonary Exacerbation(s) | 22 weeks | Number of subjects who experienced at least one severe TEAE or pulmonary exacerbation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Trough | Single measurment immediately prior to infusion at Weeks 6, 7, 8, 9 and Weeks 16, 17, 18, 19 | 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. |
| AUC0-7days | 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 | Area Under the Alpha-1 PI Concentration-Time Curve from Day 0 to Day 7 |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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) | 15 |
| 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) | 15 |
| Total | 30 |
Baseline characteristics
| Characteristic | 120 mg/kg - 60 mg/kg Prolastin-C Treatment Sequence | Total | 60 mg/kg - 120 mg/kg Prolastin-C Treatment Sequence |
|---|---|---|---|
| Age Continuous | 57.4 years STANDARD_DEVIATION 6.34 | 58.6 years STANDARD_DEVIATION 6.62 | 59.7 years STANDARD_DEVIATION 6.89 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 30 Participants | 15 Participants |
| Sex: Female, Male Female | 8 Participants | 16 Participants | 8 Participants |
| Sex: Female, Male Male | 7 Participants | 14 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 30 | 10 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 |
Outcome results
Primary
Number of Drug-related TEAEs
Total number of drug-related TEAEs reported
Time frame: 22 Weeks
Population: 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).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 60 mg/kg Prolastin-C | Number of Drug-related TEAEs | 5 Events |
| 120 mg/kg Prolastin-C | Number of Drug-related TEAEs | 1 Events |
Primary
Number of TEAEs
Total number of TEAEs reported.
Time frame: 22 Weeks
Population: 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).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 60 mg/kg Prolastin-C | Number of TEAEs | 69 Events |
| 120 mg/kg Prolastin-C | Number of TEAEs | 43 Events |
Primary
Number of Treatment-Emergent Pulmonary Exacerbations
Total number of treatment-emergent pulmonary exacerbations.
Time frame: 22 Weeks
Population: 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).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 60 mg/kg Prolastin-C | Number of Treatment-Emergent Pulmonary Exacerbations | 9 Events |
| 120 mg/kg Prolastin-C | Number of Treatment-Emergent Pulmonary Exacerbations | 6 Events |
Primary
Subjects Withdrawn Due to an AE(s)
Number of subjects who were withdrawn from the study due to at least one AE.
Time frame: 22 weeks
Population: 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).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 60 mg/kg Prolastin-C | Subjects Withdrawn Due to an AE(s) | 0 participants |
| 120 mg/kg Prolastin-C | Subjects Withdrawn Due to an AE(s) | 0 participants |
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).
Time frame: 22 weeks
Population: 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).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 60 mg/kg Prolastin-C | Subjects With Drug-Related TEAE(s) | 3 participants |
| 120 mg/kg Prolastin-C | Subjects With Drug-Related TEAE(s) | 1 participants |
Primary
Subjects With Severe TEAE(s) or Pulmonary Exacerbation(s)
Number of subjects who experienced at least one severe TEAE or pulmonary exacerbation.
Time frame: 22 weeks
Population: 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).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 60 mg/kg Prolastin-C | Subjects With Severe TEAE(s) or Pulmonary Exacerbation(s) | 0 participants |
| 120 mg/kg Prolastin-C | Subjects With Severe TEAE(s) or Pulmonary Exacerbation(s) | 0 participants |
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).
Time frame: 22 weeks
Population: 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).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 60 mg/kg Prolastin-C | Subjects With Treatment-Emergent Adverse Events (TEAEs) | 23 participants |
| 120 mg/kg Prolastin-C | Subjects With Treatment-Emergent Adverse Events (TEAEs) | 18 participants |
Primary
Subjects With Treatment-Emergent Pulmonary Exacerbation(s)
Number of subjects with at least one treatment-emergent pulmonary exacerbation
Time frame: 22 weeks
Population: 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).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 60 mg/kg Prolastin-C | Subjects With Treatment-Emergent Pulmonary Exacerbation(s) | 7 participants |
| 120 mg/kg Prolastin-C | Subjects With Treatment-Emergent Pulmonary Exacerbation(s) | 5 participants |
Primary
Subjects With Treatment-Emergent Serious Adverse Events (SAEs)
Number of subjects who experienced at least one treatment-emergent SAE.
Time frame: 22 weeks
Population: 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).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 60 mg/kg Prolastin-C | Subjects With Treatment-Emergent Serious Adverse Events (SAEs) | 0 participants |
| 120 mg/kg Prolastin-C | Subjects With Treatment-Emergent Serious Adverse Events (SAEs) | 0 participants |
Secondary
AUC0-7days
Area Under the Alpha-1 PI Concentration-Time Curve from Day 0 to Day 7
Time frame: 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
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 60 mg/kg Prolastin-C | AUC0-7days | 203.6 h*mg/mL | Standard Deviation 20.48 |
| 120 mg/kg Prolastin-C | AUC0-7days | 344.8 h*mg/mL | Standard Deviation 46.53 |
Comparison: Dose proportionality was analysed using an ANOVA model for the natural log-transformed AUC0-7days with treatment, period, and sequence as fixed effects and subject within sequence as a random effect. The treatment dose of 60 mg/kg was the reference treatment and 120 mg/kg was the test treatment. PK parameters in individual subjects for each treatment dose were dose normalized to 60mg/kg based on the actual dose administered at Week 8 or Week 18 (i.e., (AUC0-7days/Actual Dose in mg/kg)\*60mg/kg).p-value: <0.000190% CI: [0.83, 0.88]ANOVA
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.
Time frame: Single measurment immediately prior to infusion at Weeks 6, 7, 8, 9 and Weeks 16, 17, 18, 19
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 60 mg/kg Prolastin-C | Mean Trough | 17.3 μM | Standard Deviation 2.36 |
| 120 mg/kg Prolastin-C | Mean Trough | 27.7 μM | Standard Deviation 3.75 |