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

NCT01700036 | Completed Phase 2 Results DMC

• 2 other identifiers: umcc 2012.043HUM 67889
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 2

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.

Conditions

Graft vs Host Disease

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Percentage of Patients Who Achieve a Complete Response to Treatment

  4 weeks

• Percentage of Patients With Documented Infection

  30 days

• The Percentage of Patients Alive at 6 Months for Patients in CR or PR

  6 months

• Mean Fold Change in Plasma Biomarkers

  Baseline, 2 weeks, and 4 weeks

• Mean Plasma Levels for Alpha-1-Antitrypsin (AAT)

  4 weeks

Study Arms (1)

Treatment arm

EXPERIMENTAL

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

Drug: Alpha-1-Antitrypsin (AAT)

Interventions

Alpha-1-Antitrypsin (AAT) DRUG

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.

Also known as: Zemaira

Treatment arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Michigan Rogel Cancer Center: lead
• CSL Behring: collaborator
• The Leukemia and Lymphoma Society: collaborator

Study Sites (2)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

University of Michigan Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

Related Publications (1)

• 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.

  PMID: 29437593 DERIVED

MeSH Terms

Conditions

Graft vs Host Disease

Interventions

alpha 1-Antitrypsin

Condition Hierarchy (Ancestors)

Immune System Diseases

Intervention Hierarchy (Ancestors)

Glycoproteins; Glycoconjugates; Carbohydrates; Serpins; Peptides; Amino Acids, Peptides, and Proteins; Acute-Phase Proteins; Blood Proteins; Proteins; Alpha-Globulins; Serum Globulins; Globulins

Results Point of Contact

• Title: Dr. Pavan Reddy, MD
• Organization: University of Michigan Cancer Center

reddypr@umich.edu

734-936-8785

Study Officials

• Pavan Reddy, MD

  University of Michigan Rogel Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 2, 2012
• First Posted: October 4, 2012
• Study Start: July 1, 2013
• Primary Completion: October 1, 2016
• Study Completion: October 26, 2018
• Last Updated: November 27, 2018
• Results First Posted: January 5, 2018

Record last verified: 2018-10

Locations

US (2)