Treatment of GVHD in Hematopoietic Stem Cell Transplant (HSCT) Recipients Using AAT Plus Corticosteroids (CS) Compared With Corticosteroids Alone (BMT CTN 1705)

Study Overview
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Brief Summary
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Study CSL964_5001 will investigate the efficacy of AAT with corticosteroids compared with corticosteroids alone as first line therapy for patients with high-risk acute GVHD

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Multicenter Phase III Trial of Alpha 1 - Antitrypsin (AAT) Combined With Corticosteroids vs Corticosteroids Alone for the Treatment of High Risk Acute Graft-versus-Host Disease (GVHD) Following Allogeneic Hematopoietic Stem Cell Transplant (BMT CTN 1705)

Conditions
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Graft Versus Host Disease (GVHD)

Intervention / Treatment
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* Biological: Alpha-1 antitrypsin (AAT)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 12 years of age or older Initial presentation of acute GVHD after allogeneic hematopoietic cell transplantation for any indication Any graft or donor source or conditioning intensity Clinical diagnosis of acute GVHD requiring systemic therapy with corticosteroids Exclusion Criteria: Prior exogenous AAT exposure for GVHD prophylaxis Relapsed, progressing, or persistent malignancy de novo chronic GVHD or overlap syndrome developing before or present at the time of enrollment Receiving other drugs for the treatment of GVHD Receiving systemic CS for any indication within 7 days before the onset of acute GVHD

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AAT<br>Alpha-1 antitrypsin (AAT) is a lyophilized powder for intravenous administration | Biological: Alpha-1 antitrypsin (AAT)<br>* AAT is a lyophilized product for intravenous administration<br>* Other names: Alpha-1 proteinase inhibitor (A1-P1);|
| Placebo Comparator: Placebo<br>Albumin solution administered intravenously | Drug: Placebo<br>* Albumin solution administered intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of participants with complete or partial response to acute Graft-versus-Host Disease (GVHD) treatment | Acute GVHD will be graded and assessed for response based on Harris criteria (stage 0, 1, 2, 3, 4) for skin, liver, upper gastrointestinal (GI) tract, and lower GI tract. Complete response (CR) is defined as a score of 0 for the GVHD staging in all evaluable organs. Partial response (PR) is defined as improvement in one or more organs involved with GVHD symptoms without progression in others. | 28 days post-randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DOR) | DOR is defined as time from the Day 28 response (CR or PR) to any of the following events: relapse/progression of acute GVHD, new systemic salvage therapy for acute GVHD, re-escalation of steroids to greater or equal to 2.5 mg/kg prednisone or equivalent, or death from any cause. | up to 12 months post-randomization | 
| Percent of participants with non-relapse mortality (NRM) | An event of NRM is death without prior evidence of relapse/progression of the primary disease, where relapse/progression is treated as a competing risk. | up to 12 months post-randomization | 
| Percent of participants with overall survival and progression-free survival | An event for overall survival is death from any cause, while an event for progression-free survival is death from any cause or relapse/progression of the primary disease. | up to 12 months post-randomization | 
| Percent of participants with GVHD-free survival | Patients alive, free of active acute or chronic GVHD, and without other systemic agents or escalation of steroids added for treatment of GVHD will be considered successes for this endpoint. | Day 56 post-randomization | 
| Percent of participants with response | The proportion of patients with CR, PR (including subset with VGPR), and treatment failure (TF). The designation of TF will consist of patients with no response (NR), mixed response (MR), progression or initiation of additional systemic (second-line) GVHD therapies or escalation of steroids. Death from any cause will also be considered a TF. | At Day 7, 14, 21, 28, 56, and 86 post-randomization | 
| Percent of participants with Grade 2 to 3 systemic infections | The incidence of Grade 2 to 3 systemic infections. Grade 2 to 3 systemic infections will be defined according to BMT CTN Manual of Procedures. | up to 30 days after the last dose of study drug | 
| Percent of participants with Grade 3 to 5 treatment-emergent adverse events (TEAEs) | The incidence of Grade 3 to 5 TEAEs (per Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0) | up to 30 days after the last dose of study drug | 
| Percent of participants with chronic GVHD | Chronic GVHD is defined per National Institutes of Health (NIH) Consensus Criteria. Diagnosis of chronic GVHD of any severity (mild, moderate, or severe) is considered an event for this endpoint. | up to 12 months post-randomization | 
| Percent of participants with disease relapse | The cumulative incidence of relapse/progression of the primary disease, with death prior to relapse/progression treated as a competing risk. | up to 12 months post-randomization |