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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
Sponsor:
Information provided by (Responsible Party):
Fundación Pública Andaluza para la gestión de la Investigación en Sevilla

Brief Summary:
The purpose of this study is to determine whether vitamin D is effective in the prevention of graft-versus-host-disease after completion of allogeneic transplant.

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

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Vitamin D
Drug Information available for: Vitamin D

Arm Intervention/treatment
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)




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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+


  3. 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-


  4. 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+


  5. NK markers [ Time Frame: Day +21,+56 and +100 post-transplant ]

    using the following combinations:

    CD94-FITC/CD56-PE/CD3-PerCP-Cy5.5/HLADR-APC

    CD11a-FITC/CD16-PE/CD3-PerCP-Cy5.5/CD56-APC

    CD158a-FITC/CD161-PE/CD3-PerCP-Cy5.5/CD56-APC

    CDNKB1-FITC/NKAT-PE/CD3-PerCP-Cy5.5/CD56-APC

    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.


  6. 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).

  7. Peak Plasma Concentration (Cmax) of Vitamin D [ Time Frame: Day -5 pre-transplant and +1, +7 and +21 post-transplant ]
    Peak Plasma Concentration (Cmax)

  8. 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)

  9. 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



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥ 18 years
  • The patient should accomplish all the criteria to proceed to an allogeneic transplant
  • The patient or their legal guardians should signed the informed consent approved by the Ethics Committees of Clinical Trials

Exclusion Criteria:

  • Hypercalcemia ≥ 10.5 mg/dl
  • Renal insufficiency with creatinine level ≥ 2 x upper limit of normal (1,1 mg/dl)
  • Participation in others Clinical Trials in which the intervention may affect the result of the study.
  • Patients receiving GVHD immunoprophylaxis with thymoglobuline or GVHD prophylaxis including in vitro or in vivo lymphocytes T depletion (anti-lymphocyte T globulin, ALG)
  • Patients receiving a transplant from an haploidentical donor

Information from the National Library of Medicine

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


Locations
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Spain
Christelle Ferrà i Coll
Badalona, Barcelona, Spain
Raquel Saldaña Moreno
Jerez de la Frontera, Cádiz, Spain
Carmen Martínez
Barcelona, Spain
David Valcárcel Ferreiras
Barcelona, Spain
Manuel Jurado Chacón
Granada, Spain
Mª Ángeles Cuesta
Málaga, Spain
Fermín Martín Sánchez- Guijo
Salamanca, Spain
Sponsors and Collaborators
Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
Investigators
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Study Chair: José Antonio Pérez-Simón, MD-PhD Head of haematology department

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
ClinicalTrials.gov Identifier: NCT02600988     History of Changes
Other Study ID Numbers: Alovita-1
First Posted: November 10, 2015    Key Record Dates
Last Update Posted: November 10, 2015
Last Verified: November 2015
Keywords provided by Fundación Pública Andaluza para la gestión de la Investigación en Sevilla:
Graft-Versus-Host-Disease
post-allogeneic transplant
haematopoietic progenitors
Additional relevant MeSH terms:
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Vitamin D
Ergocalciferols
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents
Calcium-Regulating Hormones and Agents