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A Pilot Study of Alpha-1-Antitrypsin (AAT) in Steroid Refractory Acute Graft vs Host Disease

Primary Purpose

Graft vs Host Disease

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Alpha-1-Antitrypsin (AAT)
Sponsored by
University of Michigan Rogel Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Graft vs Host Disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age >18 years

  • Patients must have clinical evidence* of steroid-refractory acute Graft vs Host Disease (any organ) defined as one of the following:

    • No change or progression in the stage of skin GvHD after at least 1 week of 2mg/kg/day methylprednisolone (or po equivalent)
    • lack of response of visceral (liver, GI) GvHD despite treatment with 2mg/kg/day methylprednisolone for at least 72h.
    • progression of visceral GvHD despite treatment with 2mg/kg/day methylprednisolone for at least 48h
    • visceral GvHD progressing to stage 4 after 24h of 2mg/kg/d methylprednisolone
    • Patients with protracted acute GvHD who have not responded to at least 0.5mg/kg/d of prednisone are considered eligible.
  • Ability to understand and the willingness to sign a written informed consent document.
  • * As GvHD is a clinical diagnosis, and patients will have already been initiated on steroid therapy at the discretion of the attending physician, tissue confirmation of refractory GvHD by biopsy is not required for entry to this study. It is anticipated that most, but not all, patients will have undergone tissue confirmation of the initial diagnosis of GvHD; however lack of tissue confirmation for this clinical syndrome is not exclusionary.

Exclusion Criteria:

  • As patients with steroid refractory acute GvHD are quite ill with multiple abnormal labs and organ dysfunction, there are no explicit laboratory values or degree of organ dysfunction that specifically preclude enrollment on this study. Baseline lab studies will be obtained and followed throughout this trial as the standard of care for patients with GvHD.
  • Pregnancy or Nursing Mother
  • Vasopressor requirement
  • Patients may not be receiving any other investigational agents for the treatment of GvHD at time of study entry or at any time while on study or be on another investigational agent that can impact on the primary clinical outcome analyses or has known pharmacodynamics or pharmacokinetic effects on AAT.
  • Patients with known antibodies to IgA

Sites / Locations

  • Dana-Farber Cancer Institute
  • University of Michigan Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment arm

Arm Description

Alpha-1-Antitrypsin (AAT) for the treatment of Steroid Refractory Acute Graft vs Host Disease.

Outcomes

Primary Outcome Measures

Percentage of Patients That Respond to Treatment
To estimate the proportion of patients with steroid refractory acute Graft vs Host Disease) GvHD who respond (achieve either PR or CR) to Alpha-1 Antitrypsin (AAT) at a dose of 60mg/kg twice weekly for 8 doses Partial Response (PR) is defined as a decrease of at least one grade in the severity of GVHD without deterioration of any organ systems by d28 of therapy. Complete Response (CR) is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.

Secondary Outcome Measures

Percentage of Patients Who Achieve a Complete Response to Treatment
To estimate the proportion of patients in complete remission without additional therapy at four weeks after the last dose of AAT Complete remission is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.
Percentage of Patients With Documented Infection
To estimate the incidence of infection during and following treatment of steroid refractory acute GVHD with AAT
The Percentage of Patients Alive at 6 Months for Patients in CR or PR
Survival at 6 months in patients receiving AAT treatment for steroid refractory acute GVHD for patients that achieved a CR or PR. Partial Response (PR) is defined as a decrease of at least one grade in the severity of GVHD without deterioration of any organ systems by d28 of therapy. Complete Response (CR) is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.
Mean Fold Change in Plasma Biomarkers
The fold change in levels of plasma biomarkers IL-6, TNF-alpha and ST2 will be measured pre-treatment and after the administration of AAT treatment for steroid refractory GvHD.
Mean Plasma Levels for Alpha-1-Antitrypsin (AAT)
Plasma levels of Alpha-1-Antitrypsin(AAT)will be measured.

Full Information

First Posted
October 2, 2012
Last Updated
October 29, 2018
Sponsor
University of Michigan Rogel Cancer Center
Collaborators
CSL Behring, The Leukemia and Lymphoma Society
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1. Study Identification

Unique Protocol Identification Number
NCT01700036
Brief Title
A Pilot Study of Alpha-1-Antitrypsin (AAT) in Steroid Refractory Acute Graft vs Host Disease
Official Title
A Pilot Study of Alpha-1-Antitrypsin (AAT) in Steroid Refractory Acute Graft vs Host Disease
Study Type
Interventional

2. Study Status

Record Verification Date
October 2018
Overall Recruitment Status
Completed
Study Start Date
July 2013 (undefined)
Primary Completion Date
October 2016 (Actual)
Study Completion Date
October 26, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Michigan Rogel Cancer Center
Collaborators
CSL Behring, The Leukemia and Lymphoma Society

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This clinical trial will study the safety and efficacy of using the drug Zemaira, an Alpha 1-Antitrypsin (AAT) medication (also known as an Alpha1-Proteinase Inhibitor [Human]) for the treatment of steroid refractory GVHD. For bone marrow transplant patients, the most common, serious complication is Graft vs Host Disease (GVHD), which at its most severe is a life-threatening, complication and a significant cause of treatment related death, following stem cell transplantation. GVHD is a major obstacle to the overall success of transplant treatment, a strategy that would otherwise provide the possibility of a cure for patients with blood cancers or severe blood disorders. GVHD primarily affects the skin, gut, and liver of the recipient, and involves the interaction of the recipient's (the host's) cells and tissues with the donor's immune system cells that see the host tissues as foreign, and attack the host's cells resulting in tissue and organ damage. The severity of acute GvHD ranges from mild to severe, and for patients who don't respond to steroid therapy, the complication is nearly always fatal, either from organ damage or opportunistic infection as a consequence of high dose, steroid treatments. There is currently no known effective therapy for patients with acute graft vs host disease that's refractory (nonresponsive) to steroid therapy. As stated earlier,the overwhelming majority of these patients may ultimately die from infection. The incidence of acute GvHD that requires intervention, is higher for unrelated donor transplants, the most common treatment option available, and therefore, these patients are at higher risk for treatment related complications from GVHD. Approximately 20,000 unrelated donor transplants are performed each year. The magnitude of this problem then is significant for patients who otherwise might be cured of their blood cancer or disease.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft vs Host Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment arm
Arm Type
Experimental
Arm Description
Alpha-1-Antitrypsin (AAT) for the treatment of Steroid Refractory Acute Graft vs Host Disease.
Intervention Type
Drug
Intervention Name(s)
Alpha-1-Antitrypsin (AAT)
Other Intervention Name(s)
Zemaira
Intervention Description
AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28. A second course of treatment will not be given.
Primary Outcome Measure Information:
Title
Percentage of Patients That Respond to Treatment
Description
To estimate the proportion of patients with steroid refractory acute Graft vs Host Disease) GvHD who respond (achieve either PR or CR) to Alpha-1 Antitrypsin (AAT) at a dose of 60mg/kg twice weekly for 8 doses Partial Response (PR) is defined as a decrease of at least one grade in the severity of GVHD without deterioration of any organ systems by d28 of therapy. Complete Response (CR) is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.
Time Frame
4 weeks
Secondary Outcome Measure Information:
Title
Percentage of Patients Who Achieve a Complete Response to Treatment
Description
To estimate the proportion of patients in complete remission without additional therapy at four weeks after the last dose of AAT Complete remission is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.
Time Frame
4 weeks
Title
Percentage of Patients With Documented Infection
Description
To estimate the incidence of infection during and following treatment of steroid refractory acute GVHD with AAT
Time Frame
30 days
Title
The Percentage of Patients Alive at 6 Months for Patients in CR or PR
Description
Survival at 6 months in patients receiving AAT treatment for steroid refractory acute GVHD for patients that achieved a CR or PR. Partial Response (PR) is defined as a decrease of at least one grade in the severity of GVHD without deterioration of any organ systems by d28 of therapy. Complete Response (CR) is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.
Time Frame
6 months
Title
Mean Fold Change in Plasma Biomarkers
Description
The fold change in levels of plasma biomarkers IL-6, TNF-alpha and ST2 will be measured pre-treatment and after the administration of AAT treatment for steroid refractory GvHD.
Time Frame
Baseline, 2 weeks, and 4 weeks
Title
Mean Plasma Levels for Alpha-1-Antitrypsin (AAT)
Description
Plasma levels of Alpha-1-Antitrypsin(AAT)will be measured.
Time Frame
4 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age >18 years Patients must have clinical evidence* of steroid-refractory acute Graft vs Host Disease (any organ) defined as one of the following: No change or progression in the stage of skin GvHD after at least 1 week of 2mg/kg/day methylprednisolone (or po equivalent) lack of response of visceral (liver, GI) GvHD despite treatment with 2mg/kg/day methylprednisolone for at least 72h. progression of visceral GvHD despite treatment with 2mg/kg/day methylprednisolone for at least 48h visceral GvHD progressing to stage 4 after 24h of 2mg/kg/d methylprednisolone Patients with protracted acute GvHD who have not responded to at least 0.5mg/kg/d of prednisone are considered eligible. Ability to understand and the willingness to sign a written informed consent document. * As GvHD is a clinical diagnosis, and patients will have already been initiated on steroid therapy at the discretion of the attending physician, tissue confirmation of refractory GvHD by biopsy is not required for entry to this study. It is anticipated that most, but not all, patients will have undergone tissue confirmation of the initial diagnosis of GvHD; however lack of tissue confirmation for this clinical syndrome is not exclusionary. Exclusion Criteria: As patients with steroid refractory acute GvHD are quite ill with multiple abnormal labs and organ dysfunction, there are no explicit laboratory values or degree of organ dysfunction that specifically preclude enrollment on this study. Baseline lab studies will be obtained and followed throughout this trial as the standard of care for patients with GvHD. Pregnancy or Nursing Mother Vasopressor requirement Patients may not be receiving any other investigational agents for the treatment of GvHD at time of study entry or at any time while on study or be on another investigational agent that can impact on the primary clinical outcome analyses or has known pharmacodynamics or pharmacokinetic effects on AAT. Patients with known antibodies to IgA
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Pavan Reddy, MD
Organizational Affiliation
University of Michigan Rogel Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
University of Michigan Cancer Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
29437593
Citation
Magenau JM, Goldstein SC, Peltier D, Soiffer RJ, Braun T, Pawarode A, Riwes MM, Kennel M, Antin JH, Cutler CS, Ho VT, Alyea EP 3rd, Parkin BL, Yanik GA, Choi SW, Lewis EC, Dinarello CA, Koreth J, Reddy P. alpha1-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease. Blood. 2018 Mar 22;131(12):1372-1379. doi: 10.1182/blood-2017-11-815746. Epub 2018 Feb 2.
Results Reference
derived

Learn more about this trial

A Pilot Study of Alpha-1-Antitrypsin (AAT) in Steroid Refractory Acute Graft vs Host Disease

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