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

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ClinicalTrials.gov Identifier: NCT03805789
Recruitment Status : Recruiting
First Posted : January 16, 2019
Last Update Posted : April 26, 2021
Sponsor:
Information provided by (Responsible Party):
CSL Behring

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Acute-graft-versus-host Disease Biological: Alpha-1 antitrypsin (AAT) Biological: Placebo Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 310 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: 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)
Actual Study Start Date : March 27, 2019
Estimated Primary Completion Date : March 6, 2024
Estimated Study Completion Date : September 6, 2024


Arm Intervention/treatment
Experimental: AAT (low dose)
Open label. Alpha-1 antitrypsin (AAT) is a lyophilized product for intravenous administration
Biological: Alpha-1 antitrypsin (AAT)
Alpha-1 antitrypsin is a lyophilized product for intravenous administration.
Other Name: Alpha-1 proteinase inhibitor

Experimental: AAT (medium dose)
Open label. AAT is a lyophilized product for intravenous administration
Biological: Alpha-1 antitrypsin (AAT)
Alpha-1 antitrypsin is a lyophilized product for intravenous administration.
Other Name: Alpha-1 proteinase inhibitor

Experimental: AAT (high dose)
Open label. AAT is a lyophilized product for intravenous administration
Biological: Alpha-1 antitrypsin (AAT)
Alpha-1 antitrypsin is a lyophilized product for intravenous administration.
Other Name: Alpha-1 proteinase inhibitor

Experimental: AAT (selected dose from open-label)
Double-blind. AAT is a lyophilized product for intravenous administration
Biological: Alpha-1 antitrypsin (AAT)
Alpha-1 antitrypsin is a lyophilized product for intravenous administration.
Other Name: Alpha-1 proteinase inhibitor

Placebo Comparator: Placebo
Albumin solution administered intravenously
Biological: Placebo
Albumin solution administered intravenously




Primary Outcome Measures :
  1. The time to Grade II-IV acute graft versus host disease (aGVHD) or death [ Time Frame: Through 180 days after hematopoietic cell transplantation (HCT) ]
    Acute graft vs host disease (aGVHD) will be assessed using the modified Keystone GVHD scoring system.


Secondary Outcome Measures :
  1. Proportion of subjects with lower GI aGVHD or Grade III-IV aGVHD in any organ [ Time Frame: Through 180 days after HCT ]
  2. Proportion of subjects with severe infections defined by NCI-CTCAE ≥ Grade 3 [ Time Frame: Through Day 60 after HCT ]
  3. Proportion of subjects with Grade II-IV aGVHD or death [ Time Frame: Through 100 days and 180 days after HCT ]
  4. Proportion of subjects with lower GI aGVHD [ Time Frame: Through Days 60, 100 and 180 after HCT ]
  5. Proportion of subjects with severe infections defined by NCI-CTCAE ≥ Grade 3 [ Time Frame: Through 100 and 180 days after HCT ]
  6. Number of deaths (relapse and nonrelapse-related) [ Time Frame: Within 180 and 365 days after HCT ]
    Death by any cause

  7. Proportion of subjects with Grade III-IV aGVHD or death [ Time Frame: Through Days 60, 100, and 180 days after HCT ]
  8. Proportion of subjects with moderate-to-severe chronic GVHD [ Time Frame: Within 180 and 365 days after HCT ]
    Moderate-to-severe chronic GVHD graded according to NIH scale

  9. Proportion of subjects who have discontinued immune suppression therapies including standard- of- care GVHD prophylaxis and steroid treatment [ Time Frame: Within 180 and 365 days after HCT ]
  10. Time to neutrophil engraftment [ Time Frame: Through 365 days after HCT ]
    Time to the first of 3 consecutive days of absolute neutrophil counts ≥ 500/µL

  11. Time to GVHD relapse-free survival [ Time Frame: Within 365 days after HCT ]
    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.

  12. Proportion of subjects with relapse of primary malignancies [ Time Frame: Through 180 and 365 days after HCT ]
  13. Proportion of subjects with Grade II-IV aGVHD with an overall (complete + partial) response, complete response and partial response [ Time Frame: Approximately 4 weeks after the initiation of systemic steroids during 8-week Treatment Period ]
  14. Percent of subjects with study drug related adverse events [ Time Frame: Up to 365 days after HCT ]
  15. Maximum concentration (Cmax) of AAT [ Time Frame: Before and up to 72 after infusion of AAT ]
  16. Area under the concentration curve (AUC) for AAT [ Time Frame: Before and up to 72 after infusion of AAT ]
  17. Clearance (CL) of AAT [ Time Frame: Before and up to 72 after infusion of AAT ]
  18. Volume of distribution (V) for AAT [ Time Frame: Before and up to 72 after infusion of AAT ]
  19. Ctrough of AAT [ Time Frame: Before and up to 72 after infusion of AAT ]


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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03805789


Contacts
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Contact: Trial Registration Coordinator 610-878-4000 clinicaltrials@cslbehring.com

Locations
Show Show 17 study locations
Sponsors and Collaborators
CSL Behring
Investigators
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Study Director: Study Physician CSL Behring
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Responsible Party: CSL Behring
ClinicalTrials.gov Identifier: NCT03805789    
Other Study ID Numbers: CSL964_2001
2018-000329-29 ( EudraCT Number )
First Posted: January 16, 2019    Key Record Dates
Last Update Posted: April 26, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Alpha 1-Antitrypsin Deficiency
Graft vs Host Disease
Immune System Diseases
Liver Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Subcutaneous Emphysema
Emphysema
Pathologic Processes
Protease Inhibitors
Alpha 1-Antitrypsin
Protein C Inhibitor
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Trypsin Inhibitors
Serine Proteinase Inhibitors