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

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

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

Study Overview

• Status: Completed
• Conditions: Graft Versus Host Disease (GVHD)
• Intervention / Treatment: Biological: Alpha-1 antitrypsin (AAT); Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 136
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Northside Hospital
    • Atlanta, Georgia, United States, 30322-1059
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • IU Hospital
  • Kansas
    • Westwood, Kansas, United States, 66205
      • Univ. of Kansas Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0312
      • U-M Medical Center
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University
  • New York
    • New York, New York, United States, 10065
      • MSKCC
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Center
    • Durham, North Carolina, United States, 27705
      • Duke
  • Ohio
    • Cleveland, Ohio, United States, 44124
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43210
      • Ohio State Univ.Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
    • Houston, Texas, United States, 77030
      • Center for Gene Therapy
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth Univ.
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Clinic
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) to Acute Graft-versus-Host Disease (GVHD) Treatment	The overall response is defined as having a CR or PR at Day 28, along with: being alive, free of any next-line GVHD therapy, and free of escalation of prednisone-equivalent steroid dose to 2.5 milligrams per kilogram (mg/kg)/day or more. The percentage of participants with CR or PR is reported here. Wilson score confidence intervals (CIs) are reported here as a measure of dispersion. The CR was defined as a score of 0 for the GVHD staging in all evaluable organs. The PR was defined as an improvement in one or more organs involved with GVHD symptoms without progression in others. Acute GVHD was graded and assessed for response based on Harris (Mount Sinai Acute GVHD International Consortium [MAGIC]) criteria (stage 0, 1, 2, 3, 4) for skin, liver, upper gastrointestinal (GI) tract, and lower GI tract. Participants who had an escalation of prednisone-equivalent steroid dose to 2.5 mg/kg/day or higher were classified as non-responders (NR).	At Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DOR)	The DOR was defined as time from the Day 28 response (CR or PR) until the first of the following events occurs: progression of acute GVHD, death, any next-line GVHD therapy, or escalation of prednisone-equivalent steroids to greater than or equal to (>=) 2.5 mg/kg/day. Wald CIs are reported here as a measure of dispersion.	Up to 12 months
Number of Participants With Non-relapse Mortality (NRM) Event	An event of NRM was death without prior evidence of relapse/progression of the primary disease, where relapse/progression was treated as a competing risk. Cumulative incidence of NRM at 6 and 12 months post-randomization is reported here for this outcome measure.	At 6 and 12 months
Number of Overall and Progression-free Survival Events	An event for overall survival (OS) was death from any cause, while an event for progression-free survival (PFS) was death from any cause or relapse/progression of the primary disease.	At 6 and 12 months
Number of Participants With GVHD-free Survival	GVHD-free survival was defined as participants being alive, free of acute or chronic GVHD, and free of any next-line GVHD therapy or escalation of steroids to >=2.5 mg/kg/day prednisone or equivalent for treatment of GVHD.	At Day 56
Percentage of Participants With Response	The percentage of participants with CR, PR (including subset with very good partial response [VGPR]), and treatment failure (TF). The designation of TF consisted of participants with NR, mixed response (MR) or progression. The initiation of additional systemic (next-line) GVHD therapies, escalation of prednisone equivalent steroid dose to >= 2.5 mg/kg/day, or death from any cause prior to the assessment timepoint was also considered a TF. Simultaneous Goodman CIs are provided for category proportions for each arm at each assessment time.	At Day 7, 14, 21, 28, 56, and 86
Percentage of Participants With Response Allowing for Approved Next-line Therapy	The percentage of participants with CR, PR (including subset with VGPR), and TF allowing for treatment with next-line therapy. The designation of TF consisted of participants with NR, MR, or progression. The escalation of prednisone-equivalent steroid dose to >= 2.5 mg/kg/day or death from any cause prior to the assessment timepoint was also considered a TF. Simultaneous Goodman CIs are provided for category proportions for each arm at each assessment time.	At Day 7, 14, 21, 28, 56, and 86
Incidence of Grade 2 to 3 Systemic Infections	The cumulative incidence of Grade 2 to 3 systemic infections. Grade 2 to 3 systemic infections were defined according to the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Manual of Procedures.	Up to 90 days (including 30 days after last dose of study drug)
Percentage 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). Wilson score CIs are reported here as a measure of dispersion.	Up to 30 days after the last dose of study drug
Cumulative Incidence of Chronic GVHD	Chronic GVHD was defined per National Institutes of Health (NIH) Consensus Criteria. Diagnosis of chronic GVHD of any severity (mild, moderate, or severe) was considered an event for this outcome measure, where death before cGVHD was treated as a competing risk.	At 6 and 12 months
Cumulative Incidence of Disease Relapse/ Progression of Primary Disease	The cumulative incidence of relapse/progression of the primary disease, with death prior to relapse/progression treated as a competing risk. Death without prior relapse/progression was treated as a competing risk for relapse/progression.	At 6 months and 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
DOR - Supplementary Analysis	The DOR was defined as time from the Day 28 response (CR or PR) until the first of the following events occurs: death, any next-line GVHD therapy, or escalation of prednisone-equivalent steroids to >= 2.5 mg/kg/day. Wald CIs are reported here as a measure of dispersion.	Up to 12 months

Collaborators and Investigators

• Sponsor: CSL Behring
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health (NIH); Blood and Marrow Transplant Clinical Trials Network
• Investigators: Study Director: Study Director, CSL Behring

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2020
• Primary Completion (Actual): September 11, 2023
• Study Completion (Actual): June 26, 2024

Study Registration Dates

• First Submitted: November 15, 2019
• First Submitted That Met QC Criteria: November 15, 2019
• First Posted (Actual): November 19, 2019

Study Record Updates

• Last Update Posted (Estimated): August 29, 2025
• Last Update Submitted That Met QC Criteria: August 28, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Substandard Drugs; Pharmaceutical Preparations; Carbohydrates; Blood Proteins; Serum Globulins; Globulins; Glycoproteins; Glycoconjugates; Acute-Phase Proteins; Serpins; Alpha-Globulins; Counterfeit Drugs; alpha 1-Antitrypsin
• Other Study ID Numbers: CSL964_5001 / BMT CTN 1705; BMT CTN Protocol 1705 (Other Identifier: Blood and Marrow Transplant Clinical Trials Network (BMT CTN))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: CSL will consider on a case-by-case basis requests to share Individual Patient Data (IPD) with external bona-fide, qualified scientific and medical researchers. For information on the process and requirements for submitting a voluntary data sharing request for IPD, please contact CSL at clinicaltrials@cslbehring.com.
• IPD Sharing Time Frame: Requests for IPD will generally be considered once review by major regulatory authorities (ie FDA, EMA) is complete and the primary publication is available.

IPD Sharing Access Criteria

Proposed research should seek to answer a previously unanswered important medical or scientific question.

Applicable country specific privacy and other laws and regulations will be considered and may prevent sharing of IPD.

If the request is approved and the researcher has executed an appropriate data sharing agreement, IPD that has been appropriately anonymized will be available.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No