Clinical trial NCT03188601: α1-antitrypsin (AAT) Levels and Functions in Allogeneic Bone Marrow Transplantation and Throughout Progression Into GVHD
Official title: Relative Inactivity of Alpha-1-antitrypsin After Bone Marrow Transplantation as a Dynamic Biomarker for GVHD and Prognosis: a Prospective Cohort Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: GVHD
Bone Marrow Transplant Failure
Alpha 1-Antitrypsin
Keywords: Graft vs Host Disease
Immune System Diseases
Protease Inhibitors
Alpha 1-Antitrypsin
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Trypsin Inhibitors
Serine Proteinase Inhibitors
Lead sponsor: Rambam Health Care Campus
Sponsor class: OTHER
Collaborators: name: Soroka University Medical Center
name: Tel-Aviv Sourasky Medical Center
name: Hadassah Medical Organization
First posted: 2017-06-15
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: In every medical center in which a bone marrow transplantation is performed, allogeneic transplantation recipients will be recruited for the trial.

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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of patients progressing into acute or chronic GVHD
timeFrame: Up to 1 year
Secondary outcomes:
measure: Correlation between AAT pattern and survivability, response to immunosuppressive treatment. liver functions, immunocyte activities.
timeFrame: Up to 1 year
Other outcomes:
Locations:
city: Jerusalem
country: Israel
facility: Hadassah
state: Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center - Ichilov Hospital
state: Center
city: Haifa
country: Israel
facility: Rambam MC
state: North
city: Beer sheva
country: Israel
facility: Soroka Medical Center
state: South
Study officials:
affiliation: Ben-Gurion University of the Negev
name: Eli Lewis, Professor
role: PRINCIPAL_INVESTIGATOR
References: