AATGVHD-MARK: α1-antitrypsin (AAT) Levels and Functions in Allogeneic Bone Marrow Transplantation and Throughout Progression Into GVHD

Sponsor

Rambam Health Care Campus (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03188601

Collaborator

Soroka University Medical Center (Other), Tel-Aviv Sourasky Medical Center (Other), Hadassah Medical Organization (Other)

150

Enrollment

Locations

54.1

Anticipated Duration (Months)

37.5

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Create a personalized time and context curve of patient circulating α1-antitrypsin (AAT) levels and functions before hematopoietic stem cell transplantation and throughout progression into GVHD.

PRIMARY ENDPOINT 1. Serum AAT levels and activity, before myeloablative preconditioning, as well as on days (-3),0,7,14,28 from HSCT and every 21 days thereafter.

SECONDARY ENDPOINTS 1. Correlation between AAT patterns and:

Circulating immune cell activation profiles on day of ablation, 28 days from HSCT and once GVHD is diagnosed.
Patient survival
Liver function tests
GVHD grade: skin manifestations, weight, GI and liver histopathology
Graft-versus-leukemia effect

Condition or Disease	Intervention/Treatment	Phase
GVHD Bone Marrow Transplant Failure Alpha 1-Antitrypsin

Detailed Description

This study will focus on each individual patient from the early point of myeloablative conditioning through HSCT and GVHD. The rationale for this individualized approach is to account for the anticipated variability in patient age and primary disease, background pathology and individual therapeutic course, considering the enormous heterogeneity of this condition. To compensate for this limitation, we intend to create an individualized algorithm, based on a novel dynamic biomarker, i.e., AAT functionality, individualized per patient and placed on a timeline, with the aim of minimizing future occurrences of GVHD, and by using readily available laboratory measurements. The study is designed around patient sample collection, there is no change in standard of care, therefore there is no intervention as well.

Three types of sample tubes will be collected per indicated time point:

Serum tube for protein levels and enzymatic activity assays.
EDTA tube for isolation of peripheral blood mononuclear cells (PBMCs), cells will be stimulated and then analyzed by FACS and lysed for RT-PCR
EDTA tube for whole blood stimulation assay for further FACS analysis and cytokine production measurement.

After donor and recipient informed consent forms were signed, a single blood sample should be obtained from the donor on the day of transplant extraction. Time points for recipient's samples include the day of myeloablation and again immediately prior to HSCT (set as day 0 and possibly -3 in MUDs). Serum and lysed blood samples will be collected on days 7, 14, 28, and every 21 days thereafter, through the development and progression of GVHD (where relevant). Blood samples for FACS will be collected by days 0 and 28. Sample collection is planned to end within 1 year from HSCT, or two months after appearance of symptoms of GVHD, or two months after a change is introduced in the immunosuppressive therapy.

Study Design

Study Type:

Observational [Patient Registry]

Anticipated Enrollment :

150 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Relative Inactivity of Alpha-1-antitrypsin After Bone Marrow Transplantation as a Dynamic Biomarker for GVHD and Prognosis: a Prospective Cohort Study

Actual Study Start Date :

Jan 27, 2018

Anticipated Primary Completion Date :

Feb 1, 2022

Anticipated Study Completion Date :

Aug 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Rambam Approximately 40 patients in total.No intervention planned.
Soroka Approximately 10 patients in total.No intervention planned.
Tel Aviv Souraski Approximately 40 patients in total.No intervention planned.
Jerusalem Hadassah Approximately 50 patients in total. No intervention planned.

Outcome Measures

Primary Outcome Measures

Number of patients progressing into acute or chronic GVHD [Up to 1 year]
Evaluation of patient circulating alpha-1-antitrypsin levels and enzymatic functions as a bio-marker for GVHD progression and grading

Secondary Outcome Measures

Correlation between AAT pattern and survivability, response to immunosuppressive treatment. liver functions, immunocyte activities. [Up to 1 year]
Correlation between AAT patterns and: Circulating immune cell activation profiles on day of ablation, 28 days from HSCT and once GVHD is diagnosed. Patient survival Liver function tests GVHD grade: skin manifestations, weight, GI and liver histopathology Graft-versus-leukemia effect

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Candidates for allogeneic transplantation for the first time, scheduled to receive HSCT from HLA-matched sibling or an unrelated matched donor
Signed informed consent by the donor(Healthy volunteers) and the patient

Exclusion Criteria:

Patients undergoing immunosuppressive treatment prior to preparation for bone-marrow transplantation.
Pregnant and disabled patients.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hadassah	Jerusalem	Center	Israel	91120
2	Tel Aviv Sourasky Medical Center - Ichilov Hospital	Tel Aviv	Center	Israel	6423906
3	Rambam MC	Haifa	North	Israel	3525408
4	Soroka Medical Center	Beer sheva	South	Israel	8410101