The Safety and Efficacy of Alpha-1 Antitrypsin (AAT) for the Prevention of Graft-Versus-host Disease (GVHD) in Patients Receiving Hematopoietic Cell Transplant

Study Overview
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Brief Summary
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This study is a Phase 2/3 prospective, double-blind, randomized, multi-center, placebo-controlled study for prevention of acute GVHD (aGVHD) in subjects undergoing an allogeneic hematopoietic cell transplant (HCT).

Official Title
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A Phase 2/3, Multicenter, randOmized, Double-blind, Placebo-controlled, stUdy to evaLuate the Safety and Efficacy of Alpha-1 AntiTrypsin for the prEvention of Graft Versus-host Disease in Patients Receiving Hematopoietic Cell Transplant (MODULAATE Study)

Conditions
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Acute-graft-versus-host Disease

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects, ≥12 years of age (≥ 18 years of age for subjects at German sites only), undergoing HCT for hematological malignancies, including leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome and myeloproliferative neoplasms Planned myeloablative conditioning regimen Exclusion Criteria: Prior autologous or allogeneic HCT T-cell depleted transplant or planned use of anti-T cell antibody therapy either ex vivo or in vivo (ie, anti-thymocyte globulin [ATG], alemtuzumab) for GVHD prophylaxis Planned umbilical cord blood (UCB) transplant

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: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AAT (low dose)<br>Open label. Alpha-1 antitrypsin (AAT) is a lyophilized product for intravenous administration | Biological: Alpha-1 antitrypsin (AAT)<br>* Alpha-1 antitrypsin is a lyophilized product for intravenous administration.<br>* Other names: Alpha-1 proteinase inhibitor;|
| Experimental: AAT (medium dose)<br>Open label. AAT is a lyophilized product for intravenous administration | Biological: Alpha-1 antitrypsin (AAT)<br>* Alpha-1 antitrypsin is a lyophilized product for intravenous administration.<br>* Other names: Alpha-1 proteinase inhibitor;|
| Experimental: AAT (high dose)<br>Open label. AAT is a lyophilized product for intravenous administration | Biological: Alpha-1 antitrypsin (AAT)<br>* Alpha-1 antitrypsin is a lyophilized product for intravenous administration.<br>* Other names: Alpha-1 proteinase inhibitor;|
| Experimental: AAT (selected dose from open-label)<br>Double-blind. AAT is a lyophilized product for intravenous administration | Biological: Alpha-1 antitrypsin (AAT)<br>* Alpha-1 antitrypsin is a lyophilized product for intravenous administration.<br>* Other names: Alpha-1 proteinase inhibitor;|
| Placebo Comparator: Placebo<br>Albumin solution administered intravenously | Biological: 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 |
| --- | --- | --- |
| The time to Grade II-IV acute graft versus host disease (aGVHD) or death | Acute graft vs host disease (aGVHD) will be assessed using the modified Keystone GVHD scoring system. | Through 180 days after hematopoietic cell transplantation (HCT) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with lower GI aGVHD or Grade III-IV aGVHD in any organ |  | Through 180 days after HCT | 
| Proportion of subjects with severe infections defined by NCI-CTCAE ≥ Grade 3 |  | Through Day 60 after HCT | 
| Proportion of subjects with Grade II-IV aGVHD or death |  | Through 100 days and 180 days after HCT | 
| Proportion of subjects with lower GI aGVHD |  | Through Days 60, 100 and 180 after HCT | 
| Proportion of subjects with severe infections defined by NCI-CTCAE ≥ Grade 3 |  | Through 100 and 180 days after HCT | 
| Number of deaths (relapse and nonrelapse-related) | Death by any cause | Within 180, 365, and 730 days after HCT | 
| Proportion of subjects with Grade III-IV aGVHD or death |  | Through Days 60, 100, and 180 days after HCT | 
| Proportion of subjects with moderate-to-severe chronic GVHD | Moderate-to-severe chronic GVHD graded according to NIH scale | Within 180, 365, 545, and 730 days after HCT | 
| Proportion of subjects who have discontinued immune suppression therapies including standard- of- care GVHD prophylaxis and steroid treatment |  | Within 180 and 365 days after HCT | 
| Time to neutrophil engraftment | Time to the first of 3 consecutive days of absolute neutrophil counts ≥ 500/µL | Through 365 days after HCT | 
| Time to GVHD relapse-free survival | GVHD free, relapse free, survival defined as time to any of the following events: 1) Grade II-IV acute GVHD, 2) moderate-severe chronic GVHD, 3) primary malignancy relapse or 4) death. | Within 365 and 730 days after HCT | 
| Proportion of subjects with relapse of primary malignancies |  | Through 180, 365, and 730 days after HCT | 
| Proportion of subjects with Grade II-IV aGVHD with an overall (complete + partial) response, complete response and partial response |  | Approximately 4 weeks after the initiation of systemic steroids during 8-week Treatment Period | 
| Percent of subjects with study drug related adverse events |  | Up to 365 days after HCT | 
| Maximum concentration (Cmax) of AAT |  | Before and up to 72 after infusion of AAT | 
| Area under the concentration curve (AUC) for AAT |  | Before and up to 72 after infusion of AAT | 
| Clearance (CL) of AAT |  | Before and up to 72 after infusion of AAT | 
| Volume of distribution (V) for AAT |  | Before and up to 72 after infusion of AAT | 
| Ctrough of AAT |  | Before and up to 72 after infusion of AAT |