Finding the Cause for Post-Transplant Diabetes Mellitus After Allogeneic Hematopoietic Cell Transplant

Islet Cell and ST2 Axis Dysregulation in Post-Transplant Diabetes Mellitus

This clinical research studies the physiology and immunology of new-onset post-transplant diabetes mellitus in patients undergoing allogeneic stem cell transplantation. Oral glucose tolerance tests (OGTT), hyperglycemic 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.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus; Cancer
• Intervention / Treatment: Drug: Oral Glucose Tolerance Test (OGTT); Drug: Hyperglycemic clamp procedure; Drug: 2 OGTTs with and without GLP-1 analogue

Detailed Description

PRIMARY OBJECTIVES:

I. To determine if changes in islet cell physiology are detectable before or after matched related donor (MRD) hematopoietic stem cell transplant (HCT) in patients developing new-onset post-transplant diabetes mellitus (PTDM).

1. To determine if a compensatory increase in glucose stimulated insulin secretion (GSIS) by β-cells precedes PTDM development in patients without diabetes undergoing MRD HCT.
2. To determine if excess glucagon secretion and impaired α-cell response to glucose or GLP-1 contributes to the hyperglycemia of PTDM.

II. To determine if the IL-33/ST2 axis promotes immune/islet cell dysregulation during PTDM.

OUTLINE:

Patients undergo 2 OGTTs and a standard hyperglycemic clamp procedure prior to HCT. Patients then undergo repeat OGTTs and a hyperglycemic clamp procedure once after HCT between days 80-100.

• Study Type: Observational
• Enrollment (Anticipated): 120

Contacts and Locations

• Study Contact: Name: VICC Clinical Trials Information Program; Phone Number: 800-811-8480; Email: brian.engelhardt@vumc.org
• Study Contact Backup: Name: Brian G. Engelhardt, M.D.; Phone Number: 615 936-0381; Email: brian.engelhardt@vumc.org

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Vanderbilt University Medical Center
      • Contact: Brian G. Engelhardt, M.D.; Phone Number: 615-936-0381; Email: brian.engelhardt@vumc.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients without a history of diabetes mellitus undergoing allogeneic hematopoietic stem cell transplantation (HCT).

Description

Inclusion Criteria for Patients:

• Patients undergoing allogeneic hematopoietic stem cell transplantation (HCT).

Exclusion Criteria for Patients:

• 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
• Umbilical cord blood transplants
• Patients on established, chronic corticosteroid therapy (> 10 mg /day of prednisone or prednisone equivalent) prior to transplant; established, chronic corticosteroid therapy is defined as daily dosing of > 10 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 (> 10 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

Additional exclusion criteria (Arms 1 and 2 Aim 1 only):

-Diagnosis of diabetes by standard oral glucose tolerance testing prior to transplant (2-hour plasma glucose value ≥ 200 mg/dL) in either Arm 1 or 2 will exclude further testing as per Aim 1. Immunological / metabolic testing as per Aim 2 will still be allowed

DONORS Inclusion Criteria for Donors (Arm 1 and Arm 2) Donors undergoing stem cell collection for related allogeneic stem cell transplant

Exclusion Criteria for Donors (Arms 1 and 2):

• Individuals not donating stem cells
• Pregnancy or breastfeeding
• Inability to give informed consent
• Any condition which, in the opinion of the investigator, might interfere with study objective

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Arm 1 for MRD HCT Recipients; Patients undergo an Oral Glucose Tolerance Test (OGTT) and 1 hyperglycemic clamp will be performed on separate days prior to transplant and then each procedure will be repeated once between day+80 to day+100 (+/- 10 days) after transplant.	Drug: Oral Glucose Tolerance Test (OGTT); A standard OGTT will be performed. During OGTT 75gm of glucose will be given followed by phlebotomy.; Drug: Hyperglycemic clamp procedure; During the hyperglycemic clamp procedure, D20 will given, followed by phlebotomy.
Arm 2 for MRD HCT Recipients; Patients undergo 2 Oral Glucose Tolerance Test (OGTTs) (with and without GLP-1 analogue) will be performed on separate days prior to transplant and then each procedure will be repeated once between day+80 to day+100 (+/- 10 days) after transplant.	Drug: 2 OGTTs with and without GLP-1 analogue; A standard OGTT will be performed and a second OGTT procedure will be repeated on a different day with GLP-1 analogue.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pre-transplant insulin secretion will be measured as glucose stimulated insulin secretion (GSIS) during a hyperglycemic clamp procedure among patients who do or do not go on to develop PTDM (univariable analysis).	A hyperglycemic clamp procedure will be performed pre-transplant. Pre-transplant will be defined as no more than 28 days before allogeneic hematopoietic cell transplantation. Patients will then be followed for 100 days after transplant for development of diabetes. In univariable analysis, a Wilcoxon rank sum test will be applied to compare the population mean difference in GSIS between these two groups.	Up to 28 days pre-transplant
Pre-transplant insulin secretion will be measured as glucose stimulated insulin secretion (GSIS) during a hyperglycemic clamp procedure among patients who do or do not go on to develop PTDM (multivariable analysis).	A hyperglycemic clamp procedure will be performed pre-transplant. Pre-transplant will be defined as no more than 28 days before allogeneic hematopoietic cell transplantation. Patients will then be followed for 100 days after transplant for development of diabetes. In multivariable analysis, logistic regression will evaluate whether GSIS is an independent predictor of PTDM after adjusting for the following covariates: gender, 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.	Up to 28 days pre-transplant
Post-transplant glucagon secretion will be measured during the oral glucose tolerance test among patients who do or do not develop PTDM (univariable analysis).	Patients will be followed for 100 days after transplant for development of diabetes. In univariable analysis, a Wilcoxon rank sum test will be applied to compare the population mean difference in glucagon secretion between these two groups.	Up to 100 days after transplant
Post-transplant glucagon secretion will be measured during the oral glucose tolerance test among patients who do or do not develop PTDM (multivariable analysis).	Patients will be followed for 100 days after transplant for development of diabetes. In multivariable analysis, a logistic regression will evaluate whether glucagon secretion is independently associated with PTDM after adjusting for the following covariates: gender, 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.	Up to 100 days after transplant
Plasma IL-33 levels will be measured among patients who do or do not develop PTDM (univariable analysis).	Patients will be followed for 100 days after transplant for development of diabetes. In univariable analysis, a Wilcoxon rank sum test will be applied to compare the population mean difference in IL-33 between these two groups.	Up to 100 days after transplant
Plasma IL-33 levels will be measured among patients who do or do not develop PTDM (multivariable analysis).	In multivariable analysis, logistic regression will evaluate whether IL-33 is independently associated with PTDM after adjusting for the following covariates: gender, 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.	Up to 100 days after transplant

Collaborators and Investigators

• Sponsor: Vanderbilt-Ingram Cancer Center
• Investigators: Principal Investigator: Brian G. Engelhardt, M.D., Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2019
• Primary Completion (Anticipated): April 1, 2023
• Study Completion (Anticipated): April 1, 2025

Study Registration Dates

• First Submitted: January 15, 2018
• First Submitted That Met QC Criteria: January 22, 2018
• First Posted (Actual): January 30, 2018

Study Record Updates

• Last Update Posted (Actual): March 28, 2022
• Last Update Submitted That Met QC Criteria: March 10, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus
• Other Study ID Numbers: VICC CTT 1836

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No