Metabolic and CD4+ T Cell Dysregulation in Post-Transplant Diabetes Mellitus
试验速览
- 阶段
- 不适用
- 状态
- 终止
- 入组人数
- 22
- 试验地点
- 2
- 主要终点
- 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
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Supportive Care
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients undergoing MRD allogeneic HCT
- •DONOR: Donors undergoing stem cell collection for match related allogeneic stem cell transplant
排除标准
- •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
研究组 & 干预措施
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.
干预措施: assessment of therapy complications (Procedure)
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.
干预措施: laboratory biomarker analysis (Other)
结局指标
主要结局
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
时间窗: Up to 21 days pre-transplant
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
时间窗: Up to day 100 after transplant
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
时间窗: Up to day 100 after transplant
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.
次要结局
- Changes in hepatic insulin sensitivity among patients with or without established PTDM(Baseline to day 90 after transplant)
- Changes in peripheral insulin sensitivity among patients with or without established PTDM(Baseline to day 90 after transplant)
- Changes in OGTT results among patients with or without established PTDM(Baseline to day 90 after transplant)
- Changes in hepatic insulin sensitivity among different groups(Baseline to day 90 after transplant)
- Changes in hepatic insulin sensitivity in the entire cohort(Baseline to day 90 after transplant)
- Changes in OGTT results among patients in the entire cohort(Baseline to day 90 after transplant)
- Changes in peripheral insulin sensitivity in the entire cohort(Baseline to day 90 after transplant)
- Th1/Treg frequencies(Up to day 100 after transplant)
- Pre-HCT Th1 and Treg tissue-specific subsets(Up to 100 days pre-transplant)
- Ability of alpha4beta7+ Tregs from patients with or without PTDM in suppressing the proliferation of allogeneic T cells(Up to day 90 after transplant)
- Ability of effector T cells from patients with PTDM to be resistant to suppression from Tregs obtained from healthy individuals(Up to day 100 after transplant)
- Post-HCT donor derived Th1 and Treg subsets(Up to 100 days pre-transplant)
- Changes in peripheral insulin sensitivity among different groups(Baseline to day 90 after transplant)
- Changes in OGTT results among different groups(Baseline to day 90 after transplant)
- Ability of pre-transplant or post-transplant tissue-specific Tregs or Th1 cells to predict the development of PTDM(Up to day 100 after transplant)
- Insulin clamp indices(Up to day 100 after transplant)
研究者
Brian Engelhardt, MD
Assistant Professor of Medicine, Hematologist/Oncologist, Principal Investigator
Vanderbilt-Ingram Cancer Center