Immunomodulatory Effect of Vitamin D in Allogenic Post-transplant (Alovita-1)

November 5, 2015 updated by: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

150

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Spain
      • Barcelona, Spain
        • Carmen Martínez
      • Barcelona, Spain
        • David Valcárcel Ferreiras
      • Granada, Spain
        • Manuel Jurado Chacón
      • Málaga, Spain
        • Mª Ángeles Cuesta
      • Salamanca, Spain
        • Fermín Martín Sánchez- Guijo
    • Barcelona
      • Badalona, Barcelona, Spain
        • Christelle Ferrà i Coll
    • Cádiz
      • Jerez de la Frontera, Cádiz, Spain
        • Raquel Saldaña Moreno

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: PREVENTION
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / 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 Names:
  • 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 Names:
  • Vitamine D dose of 5000 international units (IU)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Day +150 post-transplant

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Day -5 pre-transplant and +1, +7, +21,+56 and +100 post-transplant
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+
Day +21,+56 and +100 post-transplant
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-
Day +21,+56 and +100 post-transplant
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+
Day +21,+56 and +100 post-transplant
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.
Day +21,+56 and +100 post-transplant
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).
Day +21,+56 and +100 post-transplant
Peak Plasma Concentration (Cmax) of Vitamin D
Time Frame: Day -5 pre-transplant and +1, +7 and +21 post-transplant
Peak Plasma Concentration (Cmax)
Day -5 pre-transplant and +1, +7 and +21 post-transplant
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)
Day -5 pre-transplant and +1, +7 and +21 post-transplant
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
Day +150 post-transplant

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fundación Pública Andaluza para la gestión de la Investigación en Sevilla

Investigators

  • Study Chair: José Antonio Pérez-Simón, MD-PhD, Head of haematology department

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2011

Primary Completion (Actual)

April 1, 2015

Study Completion (Actual)

April 1, 2015

Study Registration Dates

First Submitted

June 9, 2015

First Submitted That Met QC Criteria

November 5, 2015

First Posted (Estimate)

November 10, 2015

Study Record Updates

Last Update Posted (Estimate)

November 10, 2015

Last Update Submitted That Met QC Criteria

November 5, 2015

Last Verified

November 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Alovita-1

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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