search
Back to results

A Proof of Concept Pilot Trial of Alpha-1-Antitrypsin for Pre-Emption Of Steroid-Refractory Acute GVHD

Primary Purpose

Graft-versus-host-disease, GVHD

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Alpha 1-Antitrypsin
Sponsored by
John Levine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Graft-versus-host-disease

Eligibility Criteria

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

Inclusion Criteria:

  • High risk prediction score as determined by the Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm at either day 7 or day 14 post Hematopoietic cell transplant (HCT).
  • Any donor type (e.g., related, unrelated) or stem cell source (bone marrow, peripheral blood, cord blood).
  • Donor and recipient match each other for at least 7/8 HLA-loci (HLA-A, B, C, and DR)
  • Any conditioning regimen (non-myeloablative, myeloablative, or reduced intensity) is acceptable.
  • GVHD prophylaxis must include a calcineurin inhibitor combined with methotrexate or mycophenolate.
  • The use of serotherapy to prevent GVHD (e.g., antithymocyte globulin) prior to day 3 post-HCT is permitted
  • Direct bilirubin must be <2 mg/dL unless the elevation is known to be due to Gilbert syndrome within 3 days prior to enrollment.
  • ALT/SGPT and AST/SGOT must be <5 x the upper limit of the normal range within 3 days prior to enrollment.
  • Signed and dated written informed consent obtained from patient or legal representative.

Exclusion Criteria:

  • Patients who develop acute GVHD prior to start of study drug
  • Patients at very high risk for relapse post HCT as defined by very high disease risk index
  • Patients participating in a clinical trial where prevention of GVHD is the primary endpoint
  • Uncontrolled active infection (i.e., progressive symptoms related to infection despite treatment or persistently positive microbiological cultures despite treatment or any other evidence of severe sepsis)
  • Patients who are pregnant
  • Patients on dialysis within 7 days of enrollment
  • Patients requiring ventilator support or oxygen supplementation exceeding 40% FiO2 within 14 days of enrollment.
  • Patients receiving investigational agent within 30 days of enrollment. However, the Principal Investigator (PI) may approve prior use of an investigational agent if the agent is not expected to interfere with the safety or the efficacy of alpha-1-antitrypsin.
  • History of allergic reaction to alpha-1-antitrypsin

Sites / Locations

  • City of Hope
  • Massachusetts General Hospital
  • Icahn School of Medicine at Mount Sinai
  • Ohio State University
  • Vanderbilt University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

alpha-1-antitrypsin (AAT)

Arm Description

16 doses of AAT through a catheter placed into a blood vessel over eight weeks.

Outcomes

Primary Outcome Measures

Number of High Risk Patients Who Develop Steroid Refractory GVHD
Number of High Risk patients who develop steroid refractory GVHD by day 100 post Hematopoietic cell transplant (HCT) . Steroid refractory GVHD defined as patients who did not achieve Complete Response (CR) or Partial Response (PR) by day 28 of systemic steroid treatment OR if additional immunosuppression beyond steroids was given for treatment of GVHD prior to 28 days of steroid treatment. CR: All evaluable organs (skin, liver, GI tract) stage 0. For a response to be scored as CR on day 28, the patient must be in CR on that day and have had no intervening additional GVHD therapy. PR: An improvement in one or more organ involved with GVHD symptoms without worsening in others. For a response to be scored as PR on day 28, the patient must be in PR on that day and have had no intervening additional GVHD therapy.

Secondary Outcome Measures

Number of Participants Alive at 6 Months and 1 Year
Overall survival - The number of that patients are still alive from the start of treatment at 6 months and 1 year
Number of Participants With Non-relapse Mortality (NRM)
Number of participants with NRM - deaths which could not be attributed to disease relapse or progression. Non-relapse mortality defined as death without prior relapse.
Number of Participants With Relapse
Number of participants with relapse at one year. Relapse defined as recurrence of disease that required transplant.
Number of Participants With Clinically Relevant GVHD States Grade II-IV GVHD
Number of participants with clinically relevant GVHD states grade II-IV GVHD requiring systemic treatment. GVHD grades II-IV are defined as Rash covering more than 50% of the body surface area, AND/OR Total bilirubin > 2 mg/dl AND/OR Persistent nausea or vomiting, AND/OR Diarrhea > 500 ml/day AND/OR Severe abdominal pain requiring treatment or blood present in the diarrhea
Number of Participants Achieving Overall Response
For patients who develop GVHD prior to day 100 post-HCT, the number of participants achieving overall response. The overall response rate = complete remission and partial remission (CR + PR) 28 days after initiation of systemic steroid treatment.
Number of Participants With Severe GI GVHD Stage 3 or 4
Number of participants with severe GI GVHD stage 3 or 4. GI GVHD stage 3 or 4 is defined as diarrhea >1000 ml/day OR severe abdominal pain requiring treatment OR blood present in the diarrhea.
Number of Participants With Chronic GVHD Requiring Systemic Steroid Treatment
Number of participants with chronic GVHD requiring systemic steroid treatment. Chronic GVHD Requiring Systemic Steroid Treatment: defined as the development of symptoms of chronic GVHD according to NIH Consensus Criteria that require treatment with oral or intravenous corticosteroids.
Number of Participants With Serious Infections
Number of participants with serious infections (defined as grade 3 by the Blood and Marrow Transplant Clinical Trials Network). Serious Infection: Defined as bacterial, fungal, viral or parasitic infections that required oral or intravenous treatments such as antibiotics.

Full Information

First Posted
March 2, 2018
Last Updated
June 17, 2021
Sponsor
John Levine
Collaborators
National Cancer Institute (NCI)
search

1. Study Identification

Unique Protocol Identification Number
NCT03459040
Brief Title
A Proof of Concept Pilot Trial of Alpha-1-Antitrypsin for Pre-Emption Of Steroid-Refractory Acute GVHD
Official Title
A Proof of Concept Pilot Trial of Alpha-1-Antitrypsin for Pre-Emption Of Steroid-Refractory Acute GVHD
Study Type
Interventional

2. Study Status

Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
August 17, 2018 (Actual)
Primary Completion Date
August 21, 2020 (Actual)
Study Completion Date
August 21, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
John Levine
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Bone marrow transplant (BMT) patients can develop graft-versus-host disease (GVHD), a serious and potentially fatal complication. The researchers have developed a blood test to identify patients most at risk for developing severe GVHD. Patients who consent to this study will have their blood tested up to two times after BMT to determine if they are at high risk for severe GVHD. The tests will be performed one week and two weeks after BMT. Patients who are high risk will be treated with a drug called alpha-1-antitrypsin (AAT) to see if it prevents the development of severe GVHD. Patients will receive 16 doses of AAT through a catheter placed into a blood vessel over eight weeks. AAT will be given either in the hospital or the outpatient clinic two times per week. Patients will be followed for the development of severe GVHD for up to four months from the BMT and will continue to be followed at routine clinic visits for up to one year after BMT.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft-versus-host-disease, GVHD

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Open label single arm
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
alpha-1-antitrypsin (AAT)
Arm Type
Experimental
Arm Description
16 doses of AAT through a catheter placed into a blood vessel over eight weeks.
Intervention Type
Drug
Intervention Name(s)
Alpha 1-Antitrypsin
Other Intervention Name(s)
AAT
Intervention Description
AAT will be given either in the hospital or the outpatient clinic two times per week.
Primary Outcome Measure Information:
Title
Number of High Risk Patients Who Develop Steroid Refractory GVHD
Description
Number of High Risk patients who develop steroid refractory GVHD by day 100 post Hematopoietic cell transplant (HCT) . Steroid refractory GVHD defined as patients who did not achieve Complete Response (CR) or Partial Response (PR) by day 28 of systemic steroid treatment OR if additional immunosuppression beyond steroids was given for treatment of GVHD prior to 28 days of steroid treatment. CR: All evaluable organs (skin, liver, GI tract) stage 0. For a response to be scored as CR on day 28, the patient must be in CR on that day and have had no intervening additional GVHD therapy. PR: An improvement in one or more organ involved with GVHD symptoms without worsening in others. For a response to be scored as PR on day 28, the patient must be in PR on that day and have had no intervening additional GVHD therapy.
Time Frame
Day 100 post HCT.
Secondary Outcome Measure Information:
Title
Number of Participants Alive at 6 Months and 1 Year
Description
Overall survival - The number of that patients are still alive from the start of treatment at 6 months and 1 year
Time Frame
6 months and 1 year
Title
Number of Participants With Non-relapse Mortality (NRM)
Description
Number of participants with NRM - deaths which could not be attributed to disease relapse or progression. Non-relapse mortality defined as death without prior relapse.
Time Frame
6 months and 1 year
Title
Number of Participants With Relapse
Description
Number of participants with relapse at one year. Relapse defined as recurrence of disease that required transplant.
Time Frame
1 year
Title
Number of Participants With Clinically Relevant GVHD States Grade II-IV GVHD
Description
Number of participants with clinically relevant GVHD states grade II-IV GVHD requiring systemic treatment. GVHD grades II-IV are defined as Rash covering more than 50% of the body surface area, AND/OR Total bilirubin > 2 mg/dl AND/OR Persistent nausea or vomiting, AND/OR Diarrhea > 500 ml/day AND/OR Severe abdominal pain requiring treatment or blood present in the diarrhea
Time Frame
100 days
Title
Number of Participants Achieving Overall Response
Description
For patients who develop GVHD prior to day 100 post-HCT, the number of participants achieving overall response. The overall response rate = complete remission and partial remission (CR + PR) 28 days after initiation of systemic steroid treatment.
Time Frame
Day 28
Title
Number of Participants With Severe GI GVHD Stage 3 or 4
Description
Number of participants with severe GI GVHD stage 3 or 4. GI GVHD stage 3 or 4 is defined as diarrhea >1000 ml/day OR severe abdominal pain requiring treatment OR blood present in the diarrhea.
Time Frame
By day 100 post-HCT
Title
Number of Participants With Chronic GVHD Requiring Systemic Steroid Treatment
Description
Number of participants with chronic GVHD requiring systemic steroid treatment. Chronic GVHD Requiring Systemic Steroid Treatment: defined as the development of symptoms of chronic GVHD according to NIH Consensus Criteria that require treatment with oral or intravenous corticosteroids.
Time Frame
1 year
Title
Number of Participants With Serious Infections
Description
Number of participants with serious infections (defined as grade 3 by the Blood and Marrow Transplant Clinical Trials Network). Serious Infection: Defined as bacterial, fungal, viral or parasitic infections that required oral or intravenous treatments such as antibiotics.
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: High risk prediction score as determined by the Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm at either day 7 or day 14 post Hematopoietic cell transplant (HCT). Any donor type (e.g., related, unrelated) or stem cell source (bone marrow, peripheral blood, cord blood). Donor and recipient match each other for at least 7/8 HLA-loci (HLA-A, B, C, and DR) Any conditioning regimen (non-myeloablative, myeloablative, or reduced intensity) is acceptable. GVHD prophylaxis must include a calcineurin inhibitor combined with methotrexate or mycophenolate. The use of serotherapy to prevent GVHD (e.g., antithymocyte globulin) prior to day 3 post-HCT is permitted Direct bilirubin must be <2 mg/dL unless the elevation is known to be due to Gilbert syndrome within 3 days prior to enrollment. ALT/SGPT and AST/SGOT must be <5 x the upper limit of the normal range within 3 days prior to enrollment. Signed and dated written informed consent obtained from patient or legal representative. Exclusion Criteria: Patients who develop acute GVHD prior to start of study drug Patients at very high risk for relapse post HCT as defined by very high disease risk index Patients participating in a clinical trial where prevention of GVHD is the primary endpoint Uncontrolled active infection (i.e., progressive symptoms related to infection despite treatment or persistently positive microbiological cultures despite treatment or any other evidence of severe sepsis) Patients who are pregnant Patients on dialysis within 7 days of enrollment Patients requiring ventilator support or oxygen supplementation exceeding 40% FiO2 within 14 days of enrollment. Patients receiving investigational agent within 30 days of enrollment. However, the Principal Investigator (PI) may approve prior use of an investigational agent if the agent is not expected to interfere with the safety or the efficacy of alpha-1-antitrypsin. History of allergic reaction to alpha-1-antitrypsin
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John Levine, MD
Organizational Affiliation
Icahn School of Medicine at Mount Sinai
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Icahn School of Medicine at Mount Sinai
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Ohio State University
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
Vanderbilt University
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
33351103
Citation
Gergoudis SC, DeFilipp Z, Ozbek U, Sandhu KS, Etra AM, Choe HK, Kitko CL, Ayuk F, Aziz M, Baez J, Ben-David K, Bunworasate U, Gandhi I, Hexner EO, Hogan WJ, Holler E, Kasikis S, Kowalyk SM, Lin JY, Merli P, Morales G, Nakamura R, Reshef R, Rosler W, Srinagesh H, Young R, Chen YB, Ferrara JLM, Levine JE. Biomarker-guided preemption of steroid-refractory graft-versus-host disease with alpha-1-antitrypsin. Blood Adv. 2020 Dec 22;4(24):6098-6105. doi: 10.1182/bloodadvances.2020003336.
Results Reference
result

Learn more about this trial

A Proof of Concept Pilot Trial of Alpha-1-Antitrypsin for Pre-Emption Of Steroid-Refractory Acute GVHD

We'll reach out to this number within 24 hrs