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

Study Overview
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Brief Summary
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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.

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

Conditions
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Graft vs Host Disease

Intervention / Treatment
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* Drug: Alpha-1-Antitrypsin (AAT)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment arm<br>Alpha-1-Antitrypsin (AAT) for the treatment of Steroid Refractory Acute Graft vs Host Disease. | Drug: Alpha-1-Antitrypsin (AAT)<br>* 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.<br>* Other names: Zemaira;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 4 weeks | 
| Percentage of Patients With Documented Infection | To estimate the incidence of infection during and following treatment of steroid refractory acute GVHD with AAT | 30 days | 
| 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. | 6 months | 
| 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. | Baseline, 2 weeks, and 4 weeks | 
| Mean Plasma Levels for Alpha-1-Antitrypsin (AAT) | Plasma levels of Alpha-1-Antitrypsin(AAT)will be measured. | 4 weeks |