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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by University of Michigan Cancer Center
Sponsor:
Collaborators:
CSL Behring
The Leukemia and Lymphoma Society
Information provided by (Responsible Party):
Pavan Reddy, MD, University of Michigan Cancer Center
ClinicalTrials.gov Identifier:
NCT01700036
First received: October 2, 2012
Last updated: May 19, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Graft vs Host Disease
Drug: Alpha-1-Antitrypsin (AAT)
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study of Alpha-1-Antitrypsin (AAT) in Steroid Refractory Acute Graft vs Host Disease

Resource links provided by NLM:


Further study details as provided by University of Michigan Cancer Center:

Primary Outcome Measures:
  • Response to Treatment [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
    To estimate the proportion of patients with steroid refractory acute Graft vs Host Disease) GvHD who respond (PR + CR) to Alpha-1 Antitrypsin (AAT) at a dose of 60mg/kg twice weekly for 8 doses


Secondary Outcome Measures:
  • Complete Response to Treatment [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
    To estimate the proportion of patients in complete remission (CR) without additional therapy at four weeks after the last dose of AAT

  • Infection Rates [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
    To estimate the incidence of infection during and following treatment of steroid refractory acute GVHD with AAT

  • Six month survival without additional GVHD therapy [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    survival at 6 months without additional therapy in patients receiving AAT treatment for steroid refractory acute GVHD.

  • Analysis of plasma cytokine levels [ Time Frame: 56 days ] [ Designated as safety issue: No ]
    Plasma levels of six plasma biomarkers IL2Rα, TNFR1,HGF, IL8, elafin, and reg3α will be measured before, during and after administration of AAT treatment for steroid refractory GvHD.

  • Analysis of plasma levels for Alpha-1-Antitrypsin (AAT) [ Time Frame: 56 days ] [ Designated as safety issue: No ]
    Plasma levels of Alpha-1-Antitrypsin(AAT)will be measured before, during and after AAT treatment for steroid refractory GvHD.


Estimated Enrollment: 40
Study Start Date: July 2013
Estimated Study Completion Date: June 2018
Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment arm
Alpha-1-Antitrypsin (AAT) for the treatment of Steroid Refractory Acute Graft vs Host Disease.
Drug: Alpha-1-Antitrypsin (AAT)
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.
Other Name: Zemaira

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 at time of study entry
  • Patients with known antibodies to IgA
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01700036

Locations
United States, Massachusetts
Dana-Farber Cancer Institute Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: John Koreth, DPhil, MBBS    617-632-2949    jkoreth@partners.org   
Principal Investigator: John Koreth, MD, PhD         
United States, Michigan
University of Michigan Cancer Center Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Steven Goldstein, MD    734-936-6884    stevengo@umich.edu   
Contact: Pavan Reddy, MD    734-936-8785    reddypr@umich.edu   
Principal Investigator: Pavan Reddy, MD         
Sub-Investigator: Steven Goldstein, MD         
Sponsors and Collaborators
Pavan Reddy, MD
CSL Behring
The Leukemia and Lymphoma Society
Investigators
Principal Investigator: Pavan Reddy, MD University of Michigan Cancer Center
  More Information

No publications provided

Responsible Party: Pavan Reddy, MD, Associate Professor of Internal Medicine, University of Michigan Cancer Center
ClinicalTrials.gov Identifier: NCT01700036     History of Changes
Other Study ID Numbers: umcc 2012.043, HUM 67889
Study First Received: October 2, 2012
Last Updated: May 19, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases
Alpha 1-Antitrypsin
Protein C Inhibitor
Trypsin Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 19, 2014