Immunomodulatory Effect of Vitamin D in Allogenic Post-transplant (Alovita-1)
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|ClinicalTrials.gov Identifier: NCT02600988|
Recruitment Status : Completed
First Posted : November 10, 2015
Last Update Posted : November 10, 2015
|Condition or disease||Intervention/treatment||Phase|
|Hematopoietic Stem Cell Transplantation||Drug: 1000IU/day of Vitamine D Drug: 5000IU/day of Vitamine D||Phase 1 Phase 2|
The allogeneic transplant of haematopoietic cell is the only treatment option for many malignant blood diseases. Unfortunately, the progression free survival and the quality of life of transplanted patients is limited due to the development of graft-versus-host-disease (GVHD).
The development of new prophylaxis strategies of GVHD based in the use of immunomodulator agents (allowing the generation of an immunotolerance state and avoiding the use of immunosuppression) is essential.
The GVHD is due to the cytotoxic effect of the donor lymphocytes T against healthy organs and tissues of the receptor. Calcineurin inhibitor combined with methotrexate or antibodies anti-lymphocytes T are used as standard prophylaxis. This type of antibodies has demonstrated efficacy to reduce GVHD, but have not increased survival due to increasing the risk of relapses and serious post-transplant infections.
Due to its interactions with VDR (vitamin D receptor) present in immune system cells, vitamin D is able to inhibit the activation of dendritic cells and the proliferation and production of cytokines by lymphocytes T. Based on this effect, the peri- and post- transplant administration of vitamin D might decrease the risk of GVHD in allogeneic transplanted patients, subsequently decreasing the immunosuppressant treatment requirements and improving the prognosis of those patients.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||150 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Immunomodulatory Effect of Vitamin D in Allogenic Post-transplant|
|Study Start Date :||July 2011|
|Actual Primary Completion Date :||April 2015|
|Actual Study Completion Date :||April 2015|
No Intervention: Group 1: Control
Control group is composed by the first 50 patients included in the study. Those patients will not receive the treatment. Evaluations and follow-up will be the same as in the other groups.
Experimental: Group 2: 1000IU/day of Vitamine D
It is composed by the following 50 patients joining the study. They will take 1000 IU of vitamin D once a day.
Drug: 1000IU/day of Vitamine D
Administration of a specified dose of Vitamine D
Other Name: Vitamine D dose of 1000 international units (IU)
Experimental: Group 3: 5000IU/day of Vitamine D
It is composed by the last 50 patients joining the study. They will take 5000 IU of vitamin D once a day.
Drug: 5000IU/day of Vitamine D
Administration of a specified dose of Vitamine D
Other Name: Vitamine D dose of 5000 international units (IU)
- Incidence/severity of Graft-Versus-Host-Disease [ Time Frame: Day +150 post-transplant ]Number of cases of GVHD/Seriousness graded according to National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease
- Serum levels of Th1/Th2 cytokines [ Time Frame: Day -5 pre-transplant and +1, +7, +21,+56 and +100 post-transplant ](IL-2, IL-4, IL-6, IL-10, tumor necrosis factor alfa (TNF)-α and interferon gamma (IFN-g)) are determined by flow cytometry using the BD Human Th1/Th2 Cytokine CBA
- Dendritic cells [ Time Frame: Day +21,+56 and +100 post-transplant ]
The following markers were used to identify different subpopulations
CD16-PB, CD45-V500, HLADR-FITC, BDCA-PE, CD11c-PerCP-Cy5.5, CD86-PE-Cy7, CD123-APC and CD14-APC-H7.
Plasmacytoid dendritic cells: HLADR+ CD123++ CD11c- CD16- CD14- BDCA1- CD45+.
Monocyte-derived dendritic cells: HLADR+ CD123+d CD11c+ CD16++ CD14-/+d BDCA- CD45+.
Myeloid BDCA1 dendritic cells : HLADR+ CD123- CD11c+ CD16- CD14- BDCA+ CD45+
- Subpopulations of lymphocytes [ Time Frame: Day +21,+56 and +100 post-transplant ]
To be identified using the combination CD19+CD8-FITC, CD3+CD56-PE, CD4- PerCP-Cy5.5, HLADR-APC T cells: CD3+ (CD3+CD4+CD8-, CD3+CD4-CD8+, CD3+CD4+CD8+, CD3+CD4-CD8+)
B cells: CD19+ HLADR+
NK cells: CD3- CD19- CD56+
CD45RA-FITC and CCR7-PE were used to distinguish the repertory of naive/effector/memory of CD4 and CD8 cells.
-naive T cells: CD45RA+CCR7+
-effector T cells: CD45RA+CCR7-
-central memory T cells: CD45RA-CCR7+
-Peripheral memory T cells: CD45RA-CCR7-
- Regulatory T cells [ Time Frame: Day +21,+56 and +100 post-transplant ]
after incubation of surface antigens (CD25-FITC, CD127-PE and CD4-PerCP-Cy5.5), cells were washed in PBS and then fixed and permeabilized with FoxP3 Staining Buffer Set (eBiosciences) for FOXP3 staining.
phenotype of Treg: CD4+CD25+CD127-/+wFoxP3+
- NK markers [ Time Frame: Day +21,+56 and +100 post-transplant ]
using the following combinations:
We identify NK cells with weak expression of CD56 (CD56 called " weak) and those expressing more intensely this marker CD56 "bright ". In addition the expression of different KIR receptor as CD158a , CD161 , and NKAT2 NKB1 were reported.
- Activation of T cells [ Time Frame: Day +21,+56 and +100 post-transplant ]Activation assays are performed on 500 µl of peripheral blood added in 48-well plates. Peripheral blood is stimulated or not with PMA (20µg/2ml) and ionomycin (0.91 µg/ml).
- Peak Plasma Concentration (Cmax) of Vitamin D [ Time Frame: Day -5 pre-transplant and +1, +7 and +21 post-transplant ]Peak Plasma Concentration (Cmax)
- Area under the plasma concentration of Vitamin D [ Time Frame: Day -5 pre-transplant and +1, +7 and +21 post-transplant ]Area under the plasma concentration versus time curve (AUC)
- Bone densitometry changes carried out by protocol in post-transplant period [ Time Frame: Day +150 post-transplant ]Treatment effect in the subsequent development of osteoporosis
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02600988
|Christelle Ferrà i Coll|
|Badalona, Barcelona, Spain|
|Raquel Saldaña Moreno|
|Jerez de la Frontera, Cádiz, Spain|
|David Valcárcel Ferreiras|
|Manuel Jurado Chacón|
|Mª Ángeles Cuesta|
|Fermín Martín Sánchez- Guijo|
|Study Chair:||José Antonio Pérez-Simón, MD-PhD||Head of haematology department|