A Non-inferiority Pharmacokinetic and Safety/Tolerability Study of Two Different Doses of Weekly SC Alpha1-PI 15% Compared With Corresponding Standard IV Alpha1-PI in Participants With Alpha1-Antitrypsin Deficiency (AATD)

Official title

An Open-Label, Multicenter, Randomized, Non-Inferiority Pharmacokinetic and Safety/Tolerability Study of Two Different Weekly Doses of Alpha1-Proteinase Inhibitor Subcutaneous (Human) 15% in Patients With Alpha1-Antitrypsin Deficiency Compared to Corresponding Standard 60 mg/kg/Week and 120 mg/kg/Week Doses of Intravenous Alpha1-Proteinase Inhibitor (5%)

Overview

This study is designed to compare two different weekly doses of a medicine called Alpha1-Proteinase Inhibitor given by injection under the skin with the standard doses of the same medicine given through a vein. Adults with Alpha-1 Antitrypsin Deficiency will take part. Participants will be randomly assigned to one of the treatment groups, and both the study doctors and participants will know which treatment is being given. The main goals of the study are to understand how the body processes the medicine (pharmacokinetics) and to assess how safe and well tolerated the different weekly doses are.

Interventions

• Drug Alpha-1 15%
  Alpha1-Proteinase Inhibitor Subcutaneous (Human), 15%
• Other Liquid Alpha1-PI
  Liquid Alpha1-Proteinase Inhibitor (Human) for Intravenous infusion

Primary outcome measures

• Steady-state AUC of alpha1-PI over the weekly dosing interval (from 0 to 7 days) (AUC0-7 days) in the IV Treatment Period 1 and in the SC Treatment Period 2 for both dose levels [Time frame: Week 1 to Week 16]

Secondary outcome measures (2)

• The average value of the steady-state trough alpha1-PI measurements obtained at Weeks 6, 7, 8, and 9 (Period 1) [Time frame: Weeks 6, 7, 8 and 9]
• The average value of the steady-state trough alpha1-PI measurements obtained at Weeks 14, 15, 16, and 17 (Period 2) [Time frame: Weeks 14, 15, 16 and 17]

Eligibility criteria

Inclusion criteria

• Have a diagnosis of congenital AATD with an allelic combination of ZZ, SZ, Z(null), (null)(null), S(null), or "at-risk" alleles (patients with "at-risk" alleles must be individually evaluated for eligibility by the Medical Monitor). If the genotype has yet to be documented, a blood draw for genotyping (i.e., allelic discrimination) and phenotyping will be obtained at the Screening Visit.
• Participants may be naïve to alpha1-PI augmentation therapy or may be currently receiving alpha1-PI augmentation therapy or received alpha1-PI augmentation therapy in the past. If the total alpha1-PI serum (alpha-1 antitrypsin \[AAT\]) level has yet to be documented as in a treatment-naïve patient, a blood draw for total alpha1-PI serum level will be obtained at the Screening Visit. For participants currently receiving alpha1-PI augmentation, a pre-alpha1-PI augmentation AAT level must be documented in the participant's medical history/records.
• All participants must have a documented total alpha1-PI serum level <11 μM (80mg/dL if measured by radial immunodiffusion or 50 mg/dL if measured by nephelometry) which is documented pre-alpha1-PI augmentation for participants receiving AAT augmentation.
• At the Screening Visit, have post-bronchodilator Forced Expiratory Volume in 1 second (FEV₁) ≥25% and <80% predicted of predicted FEV₁/Forced Vital Capacity (FVC) <70% (Global Initiative for Chronic Obstructive Lung Disease \[GOLD\] stage II-III, and some individuals are GOLD stage IV).
• If the participant has received alpha1-PI augmentation therapy of any kind, he/she must be willing to discontinue that treatment at the Week 1 (Baseline) Visit and remain off any kind of alpha1-PI treatment, other than the IPs of this study, while participating in the study.
• Willing and able to provide written informed consent indicating that they understand the purpose of, and procedures required for the study and are willing to participate in it.

Exclusion criteria

• Have had a moderate or severe chronic obstructive pulmonary disease (COPD) exacerbation during the 4 weeks before the Week 1 (Baseline) Visit.
• Have history of lung or liver transplant or on transplantation waiting list.
• Have any lung surgery during the past 1 year (excluding lung biopsy).
• At screening, have elevated liver enzymes (aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], and alkaline phosphatase \[ALP\]) ≥ 2.5 times the upper limit of normal (ULN).
• Have severe concomitant disease (e.g., congestive heart failure, clinically significant pulmonary fibrosis, malignant disease \[except for skin cancers other than melanoma\], history of acute hypersensitivity pneumonitis reaction, or current chronic hypersensitivity pneumonitis).
• Females who are 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 true abstinence\*) throughout the study. †Women of childbearing potential are defined as premenopausal and not surgically sterile, post tubal ligation, nor documented as infertile due to a concurrent medical condition.

\*True abstinence: When this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\], declaration of abstinence for the duration of a study, and withdrawal are not acceptable methods of contraception.)

• Have known previous infection with or clinical signs and symptoms consistent with current Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), or Human Immunodeficiency Virus (HIV) infection.
• Have smoked during the past 6 months (this includes electronic/vapor cigarettes) or a positive urine cotinine test at the Screening Visit that is due to smoking.
• Received IP in another study within 30 days prior to the Week 1 (Baseline) Visit or received any recombinant human AAT-Fc fusion protein (e.g., INBRX-101) or other extended half-life AAT products within 5 half-lives of the product relative to the Screening Visit date.
• Have history of anaphylaxis or severe systemic response to any plasma-derived alpha1- PI preparation or other blood product(s).
• Use 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 (Note: inhaled steroids are not considered systemic steroids). It is recommended to maintain the same dose throughout the study.
• Use systemic or aerosolized antibiotics for a COPD exacerbation within the 4 weeks prior to the Week 1 (Baseline) Visit.
• Have known selective or severe Immunoglobulin A (IgA) deficiency based on prior medical records.
• In the opinion of the Investigator, the participant may have compliance problems or any medical condition that may place them at safety risk with the protocol and the procedures of the protocol, or because of unstable health be unable to come to the study site for in-person clinic visits required by the protocol.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 10 centers

• GC2501 Study Site 106 — Birmingham
• GC2501 Study Site 102 — Phoenix
• GC2501 Study Site 107 — Scottsdale
• GC2501 Study Site 100 — Los Angelas
• GC2501 Study Site 103 — Gainesville
• GC2501 Study Site 105 — Miami
• GC2501 Study Site 108 — Rochester
• GC2501 Study Site 104 — Cleveland
• … and 2 more centers

Spain · 4 centers

• GC2501 Study Site 502 — San Cristóbal de La Laguna
• GC2501 Study Site 501 — Madrid
• GC2501 Study Site 503 — Seville
• GC2501 Study Site 500 — Vigo

Portugal · 2 centers

• GC2501 Study Site 450 — Guimarães
• GC2501 Study Site 451 — Loures

Denmark · 1 center

• GC2501 Study Site 150 — Vejle

Germany · 1 center

• GC2501 Study Site 250 — Freiburg im Breisgau

Ireland · 1 center

• GC2501 Study Site 300 — Dublin

Netherlands · 1 center

• GC2501 Study Site 350 — Leiden

Poland · 1 center

• GC2501 Study Site 400 — Warsaw

Sweden · 1 center

• GC2501 Study Site 550 — Malmö

Identifiers

NCT: NCT07555483 · GC2501 · 2025-522792-29-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗