Safety and Pharmacokinetics of Alpha-1 Proteinase Inhibitor in Subjects With Alpha1-Antitrypsin Deficiency

Phase 2

Completed

Conditions: Emphysema
Alpha 1-antitrypsin Deficiency (AATD)

Interventions: Biological: Prolastin-C, 60 mg/kg
Biological: Prolastin-C, 120 mg/kg

Registration Number: NCT01213043

Lead Sponsor: Grifols Therapeutics LLC

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 30

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Prolastin-C, 60 mg/kg	Prolastin-C, 60 mg/kg	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).
Prolastin-C, 120 mg/kg	Prolastin-C, 120 mg/kg	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).

Primary Outcome Measures

Name	Time	Method
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.
Number of TEAEs	22 Weeks	Total number of TEAEs reported.
Number of Drug-related TEAEs	22 Weeks	Total number of drug-related TEAEs reported
Number of Treatment-Emergent Pulmonary Exacerbations	22 Weeks	Total number of treatment-emergent pulmonary exacerbations.

Secondary Outcome Measures

Name	Time	Method
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
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.

Trial Locations

Locations (5): University of Florida College of Medicine
🇺🇸
Gainesville, Florida, United States
University of Miami
🇺🇸
Miami, Florida, United States
Temple University Hosptial/Temple Lung Center
🇺🇸
Philadelphia, Pennsylvania, United States
Medical University of South Carolina, Division of Pulmonary and Critical Care Medicine
🇺🇸
Charleston, South Carolina, United States
The University of Texas Health Science Center at Tyler
🇺🇸
Tyler, Texas, United States