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Efficacy of Single Dose Anti-thymocyte Globulin in the Modulation of T Lymphocytes in Kidney Transplantation

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ClinicalTrials.gov Identifier: NCT04835948
Recruitment Status : Completed
First Posted : April 8, 2021
Last Update Posted : April 19, 2021
Sponsor:
Information provided by (Responsible Party):
Fabiani Palagi Machado, Hospital de Clinicas de Porto Alegre

Brief Summary:

The use of polyclonal anti-T cell antibodies (ATG) has benefits in kidney transplantation, however, its use is associated mainly with hematological, infectious, and neoplastic complications. Monitoring T cells in patients receiving ATG was first proposed in 1975 to improve efficacy in preventing acute rejection and avoiding excessive immunosuppression. The dose regimen is guided by a daily count of TCD3+ lymphocytes. Monitoring the dose of thymoglobulin through its biological effects on T cells is a rational and safe method of titrating the dose of that antibody. This way, it is possible to reduce the total amount of drug administered to the patient and, consequently, reduce undesirable complications, as well as the cost of treatment, without losing effect on the benefit of immunosuppression.

Currently, the usual cumulative dose of ATG for induction in kidney transplant patients is 6mg/kg, in divided doses. However, the ideal dose and duration of therapy are still the subject of studies, with protocols between centers varying from total doses of 3 to 6 mg/kg, either fractionated or single, to achieve the lowest dose with fewer undesirable effects, and with reduced length of inpatient stay.

The use of ATG in a single dose of 3 mg/kg was successfully assessed for risks of infection and rejection in patients with low immunological risk.

This study proposes evaluating the efficacy and safety of a single 3mg/kg dose of ATG for patients with low and standard immune risk, with TCD3+ lymphocyte monitoring, to assess the duration of the TCD3+ cells in the peripheral blood.


Condition or disease Intervention/treatment
Kidney Transplant; Complications Immunosuppression Drug: single dose of Anti-thymocyte globulin

Detailed Description:

Kidney transplantation is one of the major advances in medicine in the past 60 years. Currently, is considered the best treatment for terminal chronic kidney disease in the medium and long term, and the least costly. To obtain these successful outcomes, the immune response to the graft must be properly controlled and monitored since its implantation. T and B lymphocytes are crucial in the alloimmune response by mediating cellular and antibody-mediated rejections, respectively, and along with anti-HLA antibodies are the main effectors of acute and chronic rejections.

Anti-thymocyte globulin (ATG) has a key role in the immunosuppressive induction regimens used in kidney transplants as well as in the treatment of acute rejections. It is a purified solution that contains a variety of T cell-specific immunoglobulins, including CD2, CD3, CD4, CD8, CD11a, CD18, CD25, HLA-DR, and class I HLA (human leukocyte antigen). This solution is produced by immunizing rabbits with human thymocytes. The use of these agents is particularly important in inducing patients who are more predisposed to the nephrotoxic effects of calcineurin inhibitors (CI), allowing the delayed introduction of the CI. Induction with antibodies is also of great value in patients with higher immunological risk, such as pediatric, Afro-descendants, re-transplanted, and previously sensitized to HLA antigens recipients.

Polyclonal antibodies have definite benefits in kidney transplantation, but their use is associated with hematological, infectious, and neoplastic complications. The use of reduced doses of ATG has been the subject of recent studies, but still with inconclusive results.

The concept of monitoring T cells in patients receiving ATG was first proposed in 1975 to improve efficacy in preventing acute rejection and avoiding excessive immunosuppression. The dose regimen is guided by a daily count of peripheral blood TCD3+ lymphocytes. Monitoring the dose of thymoglobulin through its biological effects on T cells is a rational and safe method of titrating the dose of that antibody. This way, it is possible to reduce the total amount of drug administered to the patient and, consequently, reduce undesirable complications, as well as the cost of treatment, hopefully without losing effect on the benefit of immunosuppression.

A 60% reduction in the total dose of ATG and 58% reduction in therapy cost was observed in patients who were monitored using TCD3+ cell counts. Currently, the usual total dose of ATG for induction in kidney transplant patients is 6mg/kg, divided into 4 doses, which can be administered from day zero until day 14 (maximum) of transplantation. However, the ideal dose and duration of therapy are still the subject of investigation, with protocols between centers varying from total doses of 3 to 6 mg/kg, fractionated or single, to attempt to achieve the lowest dose with fewer undesirable effects, and with reduced length of inpatient stay. The use of ATG in a single dose of 3 mg/kg was successfully assessed for risks of infection and rejection in patients with low immunological risk.

Considering that the adverse effects associated with the use of ATG are relevant in the clinical context of kidney transplantation, the use of a lower dose, keeping its immunomodulatory effect, with a safer profile, is desirable.

The study evaluates the efficacy and safety of a single dose of 3mg/kg ATG for patients with low and standard immune risk, with TCD3+ lymphocyte monitoring, to assess the clinical efficacy and the modulation of the T cell response.

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Study Type : Observational
Actual Enrollment : 200 participants
Observational Model: Case-Control
Time Perspective: Retrospective
Official Title: Study of the Efficacy of Single Dose Anti-thymocyte Globulin in the Modulation of T Lymphocytes in Kidney Transplant Outcomes
Actual Study Start Date : October 20, 2018
Actual Primary Completion Date : March 31, 2020
Actual Study Completion Date : April 13, 2021

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Multiple doses of anti-thymocyte globulin (ATG)
Control group that received fractionated doses of 1.5 mg/kg adding up to a total of 6 mg/kg
Drug: single dose of Anti-thymocyte globulin
Used anti-thymocyte globulin (ATG) in a single dose of 3 mg/kg for immunosuppression induction in the immediate postoperative period




Primary Outcome Measures :
  1. Immunomodulatory effect [ Time Frame: one year ]
    Immunomodulatory effect of a single dose of 3mg/kg ATG on TCD3+ lymphocytes in kidney transplant patients by comparing it with the effect of the regular fractionated dose of 6 mg/kg by counting daily the number of TCD3+ lymphocytes in peripheral blood.


Secondary Outcome Measures :
  1. Incidence of acute rejection [ Time Frame: one year ]
    Number of patients with acute rejection diagnosed by renal biopsy with the single-dose ATG strategy.

  2. Occurence of cytomegalovirus infection [ Time Frame: One year ]
    Number of patients with cytomegalovirus infection (positive detection through polymerase chain reaction or active disease).

  3. Incidence of delayed graft function [ Time Frame: one year ]
    Number of patients with delayed graft function (DGF) through the number of dialysis needed in the first week after kidney transplantation.

  4. One year survival of kidney grafts [ Time Frame: One year ]
    Survival of kidney grafts at 1 year after receiving a single dose of ATG.

  5. One year survival graft grafts [ Time Frame: one year ]
    Patient survival at the end of 1 year of a single dose of ATG.


Other Outcome Measures:
  1. Occurence of infections and neoplasms [ Time Frame: One year ]
    Number of patients with development of other infections and neoplasms of any etiology within one year proven by clinical features and laboratory or anatomopathological tests in the study patients.

  2. Hematological effects of the drug. [ Time Frame: One year ]
    Number of patients with hematological effects (laboratory analysis of anemia, leukopenia and thrombocytopenia) of ATG.

  3. Time of inpatient stay (days). [ Time Frame: One year ]
    Length of stay in days between groups with a single and fractionated dose of atg.



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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
The study population will consist of patients who received a kidney transplant at a single institution between October 2018 and March 2020 and received ATG at a single dose of 3 mg/kg for induction of immunosuppression in the immediate postoperative period and a control group that received fractionated doses of 1.5 mg/kg adding up to a total of 6 mg/kg.
Criteria

Inclusion Criteria:

  • Kidney transplant patients from Hospital de Clínicas de Porto Alegre (HCPA) between October 2018 to March 2020 who received a single 3 mg/kg ATG dose at the immediate postoperative period. Recipients of standard and low immunological risk (PRA - panel reactive antibodies <50% and without donor-specific antibodies), regardless of the time of cold ischemia and the presence of kidney failure in the donor.
  • Control group consisting of patients from the same and previous period, who received fractionated ATG dosing up to 6 mg/kg total dose.

Exclusion Criteria:

  • Patients who used other induction strategies that did not include ATG in a single dose of 3 mg/kg or the fractionated dose of 6 mg/kg.
  • Patients who died within 24 hours after transplantation.
  • Patients who had a transplant nephrectomy within 24 hours after transplantation.
  • Pediatric recipients (< 14 years old).
  • Recipients with incomplete data.

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): NCT04835948


Locations
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Brazil
Hospital de Clínicas de Porto Alegre
Porto Alegre, RS, Brazil
Sponsors and Collaborators
Hospital de Clinicas de Porto Alegre
Publications:

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Responsible Party: Fabiani Palagi Machado, Principal Investigator, Hospital de Clinicas de Porto Alegre
ClinicalTrials.gov Identifier: NCT04835948    
Other Study ID Numbers: 38361620.0.0000.5327
First Posted: April 8, 2021    Key Record Dates
Last Update Posted: April 19, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Fabiani Palagi Machado, Hospital de Clinicas de Porto Alegre:
Immunosuppression
kidney transplantation
CD3+ T lymphocytes
Anti-thymocyte globulin
Rejection
Additional relevant MeSH terms:
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Antilymphocyte Serum
Immunologic Factors
Physiological Effects of Drugs
Immunosuppressive Agents