Evaluation of Human Alpha1-Proteinase Inhibitor for Prevention of Acute Graft-Versus-Host Disease in Hematopoietic Cell Transplant Recipients

The primary objective of this study is to evaluate the **efficacy** of Alpha-1 Antitrypsin (AAT) at the selected dose for the prevention of acute Graft versus Host Disease (GVHD) following hematopoietic cell transplant (HCT). This is clinically relevant as acute GVHD is a significant complication post-HCT, impacting patient outcomes and survival rates.

Secondary objectives include:

• Evaluating the efficacy of AAT for the prevention of severe acute GVHD and infections following HCT.
• Further assessing the efficacy of AAT in preventing complications after HCT.
• Evaluating the safety of AAT based on investigational product-related adverse events.
• Assessing the steady-state pharmacokinetics of AAT in HCT recipients.

The clinical trial involves a total of **265 participants** who are being studied for the prevention of **acute Graft versus host disease** (GVHD) following hematopoietic cell transplantation (HCT). The study population includes both male and female subjects aged 12 years and older, with a specific age requirement of 18 years and older for participants at German sites. Participants are undergoing HCT for various hematological malignancies, such as leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome, and myeloproliferative neoplasms. The trial population was selected based on their planned myeloablative conditioning regimen. The study includes a vulnerable population, indicating that special considerations are in place to ensure their safety and well-being throughout the trial. Lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is a **randomized**, **double-blind**, placebo-controlled study designed to evaluate the safety and efficacy of **Alpha-1 Antitrypsin** (AAT) for the prevention of **acute Graft versus host disease** (aGVHD) in patients undergoing hematopoietic cell transplantation (HCT). The trial is structured as a Phase II/III study and is expected to conclude by May 2027. Participants will be randomly assigned to receive either the investigational product, **Respreeza**, or a placebo, both administered intravenously. The primary objective is to assess the efficacy of AAT in preventing aGVHD, with the primary endpoint being the time to Grade II-IV aGVHD or death within 180 days post-transplantation.

The trial will commence with a screening visit to determine eligibility based on inclusion criteria, such as age and planned myeloablative conditioning regimen. Eligible participants will then proceed to the baseline visit, where they will be randomized and receive their first dose of the study drug. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and any adverse events. These visits will include assessments for the presence of aGVHD, infections, and other health parameters. The end-of-study visit will mark the conclusion of the participant's involvement, which is anticipated to last up to 730 days, depending on the occurrence of endpoints such as relapse or death.

Participants may be withdrawn from the study early if they experience severe adverse events, fail to comply with the study protocol, or withdraw consent. The study will also monitor secondary endpoints, including the proportion of subjects with lower GI aGVHD, severe infections, and the time to neutrophil engraftment. The trial will ensure rigorous data collection and analysis to provide comprehensive insights into the potential benefits and risks associated with AAT therapy in this patient population.

The clinical trial involves the administration of **Respreeza**, a **human alpha1-proteinase inhibitor**, which is provided as a **powder and solvent for solution for infusion**. This investigational product is manufactured by CSL Behring GmbH and is authorized under the marketing authorization number EU/1/15/1006/001. The pharmaceutical form is a solution for infusion, and the route of administration is intravenous. The dosing regimen involves a maximum daily dose of 180 mg/kg, with a total maximum dose of 2200 mg/kg over a treatment period of up to 56 days. The primary objective of the trial is to evaluate the efficacy of this treatment in preventing acute graft versus-host disease (GVHD) following hematopoietic cell transplant (HCT).

In addition to the investigational product, the trial also includes the use of an **albumin solution** administered intravenously. This solution serves as a non-experimental treatment within the study, potentially acting as a placebo or comparator treatment. The albumin solution is not associated with a specific pharmaceutical form or active substance name in the provided data. The administration of this solution is also conducted intravenously, aligning with the route used for the investigational product. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol and to accurately assess the efficacy and safety of the investigational treatment.

Efficacy in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the time to Grade II-IV **acute graft-versus-host disease (aGVHD)** or death through 180 days after hematopoietic cell transplantation (HCT). Secondary endpoints include the proportion of subjects with lower gastrointestinal aGVHD or Grade III-IV aGVHD in any organ, the proportion of subjects with severe infections defined by NCI-CTCAE ≥ Grade 3, and the proportion of subjects with Grade II-IV aGVHD or death, all measured through various timepoints up to 180 days after HCT. Additional secondary endpoints involve the assessment of deaths (relapse and nonrelapse-related) within 180, 365, and 730 days after HCT, the proportion of subjects with moderate-to-severe chronic GVHD, and the time to neutrophil engraftment, among others.

Pharmacokinetic parameters of Alpha-1 Antitrypsin (AAT) will also be evaluated, including maximum concentration (Cmax), area under the concentration curve, clearance, volume of distribution, and Ctrough, measured before and up to 72 hours after infusion of AAT. These efficacy parameters will be collected and analyzed at specified timepoints throughout the study duration, ensuring a comprehensive evaluation of the treatment's impact on preventing aGVHD in patients undergoing HCT.