Trial record 2 of 4 for:    Tregs | Diabetes

Predicting Development of Diabetes Mellitus in Patients Undergoing Allogeneic Stem Cell Transplant

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified September 2014 by Vanderbilt-Ingram Cancer Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Brian Engelhardt, MD, Vanderbilt-Ingram Cancer Center
ClinicalTrials.gov Identifier:
NCT02240381
First received: August 28, 2014
Last updated: October 8, 2014
Last verified: September 2014
  Purpose

This clinical trial studies the physiology and immunology of new-onset post-transplant diabetes mellitus in patients undergoing allogeneic stem cell transplantation. Oral glucose tolerance testing (OGTT), euglycemic hyperinsulinemic clamps, and immune assays will be used to define the mechanisms associated with abnormal glucose homeostasis following stem cell transplantation. Information from this clinical trial could be used to develop standardized screening procedures or to develop optimal treatment strategies for patients developing post-transplant diabetes mellitus.


Condition Intervention
Diabetes Mellitus
Malignant Neoplasm
Procedure: assessment of therapy complications
Other: laboratory biomarker analysis

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: Metabolic and CD4+ T Cell Dysregulation in Post-Transplant Diabetes Mellitus

Resource links provided by NLM:


Further study details as provided by Vanderbilt-Ingram Cancer Center:

Primary Outcome Measures:
  • Pre-transplant peripheral insulin sensitivity and glucose disposal as defined by the peripheral insulin sensitivity index among patients who do or do not go on to develop PTDM [ Time Frame: Up to 21 days pre-transplant ] [ Designated as safety issue: No ]
    Patients will be followed for 100 days after transplant for development of diabetes. Wilcoxon rank sum test will be applied to compare the population mean difference between these two groups. Multivariable logistic regression will evaluate whether the peripheral insulin sensitivity index is an independent predictor of PTDM after adjusting for the following covariates: fasting C-peptide level, conditioning (ablative vs. reduced intensity), or acute graft-versus-host disease (GVHD) requiring steroids. The estimated odds ratio (OR) and 95% confidence interval of the OR will be provided to measure the effect of the association.

  • Ratio of circulating, gut-homing (alpha4beta7+) Th1 subsets pre-transplant with the development of PTDM after HCT [ Time Frame: Up to day 100 after transplant ] [ Designated as safety issue: No ]
    Wilcoxon rank sum test will be applied to compare the mean difference between these two groups.

  • Expression of Helios or glycoprotein A repetitions predominant in alpha4beta7+Foxp3+ Tregs versus alpha4beta7+Foxp3- conventional T cells [ Time Frame: Up to day 100 after transplant ] [ Designated as safety issue: No ]
    Wilcoxon rank sum test or two-sample t-test will be applied to compare the mean difference between two groups. Data will be presented using means and standard deviations for continuous variables, as well as percentage and frequency for categorical variables.


Secondary Outcome Measures:
  • Changes in hepatic insulin sensitivity among patients with or without established PTDM [ Time Frame: Baseline to day 90 after transplant ] [ Designated as safety issue: No ]
    Comparison between two independent groups, e.g., with or without PTDM, will be carried out using either two-sample t-test or Wilcoxon rank sum test for continuous variables and Chi-square test or Fisher's exact test for categorical variables.

  • Changes in peripheral insulin sensitivity among patients with or without established PTDM [ Time Frame: Baseline to day 90 after transplant ] [ Designated as safety issue: No ]
    Comparison between two independent groups, e.g., with or without PTDM, will be carried out using either two-sample t-test or Wilcoxon rank sum test for continuous variables and Chi-square test or Fisher's exact test for categorical variables.

  • Changes in OGTT results among patients with or without established PTDM [ Time Frame: Baseline to day 90 after transplant ] [ Designated as safety issue: No ]
    Comparison between two independent groups, e.g., with or without PTDM, will be carried out using either two-sample t-test or Wilcoxon rank sum test for continuous variables and Chi-square test or Fisher's exact test for categorical variables.

  • Changes in hepatic insulin sensitivity in the entire cohort [ Time Frame: Baseline to day 90 after transplant ] [ Designated as safety issue: No ]
    For the comparison of the changes between baseline and day+90 after transplant in the entire cohort, the mean difference will be compared with paired Student's t-test or Wilcoxon signed rank test for continuous variables and a McNemar's test for categorical variables.

  • Changes in peripheral insulin sensitivity in the entire cohort [ Time Frame: Baseline to day 90 after transplant ] [ Designated as safety issue: No ]
    For the comparison of the changes between baseline and day+90 after transplant in the entire cohort, the mean difference will be compared with paired Student's t-test or Wilcoxon signed rank test for continuous variables and a McNemar's test for categorical variables.

  • Changes in OGTT results among patients in the entire cohort [ Time Frame: Baseline to day 90 after transplant ] [ Designated as safety issue: No ]
    For the comparison of the changes between baseline and day+90 after transplant in the entire cohort, the mean difference will be compared with paired Student's t-test or Wilcoxon signed rank test for continuous variables and a McNemar's test for categorical variables.

  • Changes in hepatic insulin sensitivity among different groups [ Time Frame: Baseline to day 90 after transplant ] [ Designated as safety issue: No ]
    To compare the differences between baseline (pre-transplant) and day +90 test results among various groups, linear mixed model will be applied to continuous outcomes (i.e., peripheral insulin sensitivity and hepatic glucose production) and generalized linear mixed model to noncontinuous outcomes (i.e., OGTT results). Groups of interest will be created by stratifying patients based on PTDM, conditioning regimen (ablative vs. reduced intensity) or acute GVHD treated with steroids.

  • Changes in peripheral insulin sensitivity among different groups [ Time Frame: Baseline to day 90 after transplant ] [ Designated as safety issue: No ]
    To compare the differences between baseline (pre-transplant) and day +90 test results among various groups, linear mixed model will be applied to continuous outcomes (i.e., peripheral insulin sensitivity and hepatic glucose production) and generalized linear mixed model to noncontinuous outcomes (i.e., OGTT results). Groups of interest will be created by stratifying patients based on PTDM, conditioning regimen (ablative vs. reduced intensity) or acute GVHD treated with steroids.

  • Changes in OGTT results among different groups [ Time Frame: Baseline to day 90 after transplant ] [ Designated as safety issue: No ]
    To compare the differences between baseline (pre-transplant) and day +90 test results among various groups, linear mixed model will be applied to continuous outcomes (i.e., peripheral insulin sensitivity and hepatic glucose production) and generalized linear mixed model to noncontinuous outcomes (i.e., OGTT results). Groups of interest will be created by stratifying patients based on PTDM, conditioning regimen (ablative vs. reduced intensity) or acute GVHD treated with steroids.

  • Ability of pre-transplant or post-transplant tissue-specific Tregs or Th1 cells to predict the development of PTDM [ Time Frame: Up to day 100 after transplant ] [ Designated as safety issue: No ]
    The comparison between independent groups, e.g., with or without PTDM or the three OGTT groups (normal, impaired glucose tolerance, or diabetic), will be carried out using either Wilcoxon rank sum test or Kruskal-Wallis test, respectively.

  • Insulin clamp indices [ Time Frame: Up to day 100 after transplant ] [ Designated as safety issue: No ]
    Spearman correlation will be used to evaluate the correlation between insulin clamp indices and Th1/Treg frequencies.

  • Th1/Treg frequencies [ Time Frame: Up to day 100 after transplant ] [ Designated as safety issue: No ]
    Spearman correlation will be used to evaluate the correlation between insulin clamp indices and Th1/Treg frequencies.

  • Pre-HCT Th1 and Treg tissue-specific subsets [ Time Frame: Up to 100 days pre-transplant ] [ Designated as safety issue: No ]
    Spearman correlation will evaluate the association between pre-HCT Th1 and Treg tissue-specific subsets with post-HCT donor derived Th1 and Treg.

  • Ability of alpha4beta7+ Tregs from patients with or without PTDM in suppressing the proliferation of allogeneic T cells [ Time Frame: Up to day 90 after transplant ] [ Designated as safety issue: No ]
    Wilcoxon rank sum test or two-sample t-test will be applied to compare the mean difference between two groups. Data will be presented using means and standard deviations for continuous variables, as well as percentage and frequency for categorical variables. Investigations for outliers and assumptions for statistical analysis, e.g., normality and homoscedasticity will be made for the parametric test such as t-test and mixed model. If necessary, data will be transformed utilizing appropriate transformations such as the log or square root.

  • Ability of effector T cells from patients with PTDM to be resistant to suppression from Tregs obtained from healthy individuals [ Time Frame: Up to day 100 after transplant ] [ Designated as safety issue: No ]
    Wilcoxon rank sum test or two-sample t-test will be applied to compare the mean difference between two groups. Data will be presented using means and standard deviations for continuous variables, as well as percentage and frequency for categorical variables.

  • Post-HCT donor derived Th1 and Treg subsets [ Time Frame: Up to 100 days pre-transplant ] [ Designated as safety issue: No ]
    Spearman correlation will evaluate the association between pre-HCT Th1 and Treg tissue-specific subsets with post-HCT donor derived Th1 and Treg.


Estimated Enrollment: 40
Study Start Date: October 2014
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Diagnostic (OGTT, euglycemic hyperinsulinemic clamp)
Patients undergo OGTT and a standard 2-step euglycemic hyperinsulinemic clamp procedure prior to HCT. Patients then undergo repeat OGTT and a 2-step euglycemic hyperinsulinemic clamp procedure once after HCT between days 90-100.
Procedure: assessment of therapy complications
During OGTT 75gm of glucose will be given followed by phlebotomy
Procedure: assessment of therapy complications
During clamp procedure tritiated glucose, D20, regular insulin will be given, followed by phlebotomy.
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine whether pre-transplant insulin resistance predicts for the development of new onset post-transplant diabetes mellitus (PTDM) in individuals without diabetes undergoing matched related donor (MRD) hematopoietic stem cell transplant (HCT).

II. To define the role of circulating tissue-specific Th1 cells in the development of PTDM.

III. To characterize the phenotype and function of circulating tissue-specific regulatory T cells (Tregs) in HCT recipients with or without PTDM.

OUTLINE:

Patients undergo OGTT and a standard 2-step euglycemic hyperinsulinemic clamp procedure prior to HCT. Patients then undergo repeat OGTT and a 2-step euglycemic hyperinsulinemic clamp procedure once after HCT between days 90-100.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients undergoing MRD allogeneic HCT
  • DONOR: Donors undergoing stem cell collection for match related allogeneic stem cell transplant

Exclusion Criteria:

  • Patients who have not received an allogeneic HCT
  • Recent or current history of diabetes mellitus, defined as:1) diabetes therapy within 6 months of enrollment, or 2) fasting blood glucose at "pre-admit" (screening) visit >= 126 mg/dL
  • Pregnancy or breastfeeding
  • Unrelated donor, umbilical cord blood, mismatched, or haploidentical transplants
  • Patients receiving T cell depletion or thymoglobulin as part of their transplant
  • Patients on established, chronic corticosteroid therapy (> 5 mg /day of prednisone or prednisone equivalent) prior to transplant; established, chronic corticosteroid therapy is defined as daily dosing of > 5 mg/day of prednisone or prednisone equivalent for at least 2 weeks prior to the start of conditioning/chemotherapy or plans to continue pre-transplant corticosteroids (> 5 mg/day of prednisone or prednisone equivalent) indefinitely after transplantation
  • Inability to give informed consent
  • Any condition which, in the opinion of the investigator, might interfere with study objective
  • Any reason which, in the opinion of the investigator, adds additional risk to the patient
  • DONOR: Individuals not donating stem cells
  • DONOR: Pregnancy or breastfeeding
  • DONOR: Inability to give informed consent
  • DONOR: Any condition which, in the opinion of the investigator, might interfere with study objective
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02240381

Contacts
Contact: VICC Clinical Trials Information Program 800-811-8480

Locations
United States, Tennessee
Vanderbilt-Ingram Cancer Center Not yet recruiting
Nashville, Tennessee, United States, 37232
Contact: VICC Clinical Trials Information Program    800-811-8480      
Principal Investigator: Brian G. Engelhardt         
Sponsors and Collaborators
Vanderbilt-Ingram Cancer Center
Investigators
Principal Investigator: Brian Engelhardt Vanderbilt-Ingram Cancer Center
  More Information

No publications provided

Responsible Party: Brian Engelhardt, MD, Assistant Professor of Medicine, Hematologist/Oncologist, Principal Investigator, Vanderbilt-Ingram Cancer Center
ClinicalTrials.gov Identifier: NCT02240381     History of Changes
Other Study ID Numbers: VICC BMT 1426, NCI-2014-01250, P30CA068485
Study First Received: August 28, 2014
Last Updated: October 8, 2014
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Diabetes Mellitus
Neoplasms
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases

ClinicalTrials.gov processed this record on October 22, 2014