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

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ClinicalTrials.gov Identifier: NCT03415139
Recruitment Status : Recruiting
First Posted : January 30, 2018
Last Update Posted : February 5, 2019
Sponsor:
Information provided by (Responsible Party):
Brian Engelhardt, MD, Vanderbilt-Ingram Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment
Diabetes Mellitus Cancer Drug: Oral Glucose Tolerance Test (OGTT) Drug: 2 OGTTs with and without GLP-1 Drug: Hyperglycemic clamp procedure

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.


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Study Type : Observational
Estimated Enrollment : 60 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Islet Cell and ST2 Axis Dysregulation in Post-Transplant Diabetes Mellitus
Actual Study Start Date : January 31, 2019
Estimated Primary Completion Date : April 2023
Estimated Study Completion Date : April 2025

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 infusion) 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
A standard OGTT will be performed and a second OGTT procedure will be repeated on a different day with exogenous GLP-1 infusion.




Primary Outcome Measures :
  1. 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). [ Time Frame: Up to 28 days pre-transplant ]
    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.

  2. 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). [ Time Frame: Up to 28 days pre-transplant ]
    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.

  3. Post-transplant glucagon secretion will be measured during the oral glucose tolerance test among patients who do or do not develop PTDM (univariable analysis). [ Time Frame: Up to 100 days after transplant ]
    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.

  4. Post-transplant glucagon secretion will be measured during the oral glucose tolerance test among patients who do or do not develop PTDM (multivariable analysis). [ Time Frame: Up to 100 days after transplant ]
    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.

  5. Plasma IL-33 levels will be measured among patients who do or do not develop PTDM (univariable analysis). [ Time Frame: Up to 100 days after transplant ]
    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.

  6. Plasma IL-33 levels will be measured among patients who do or do not develop PTDM (multivariable analysis). [ Time Frame: Up to 100 days after transplant ]
    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.


Biospecimen Retention:   Samples Without DNA
Serum / plasma and peripheral blood mononuclear cells will be collected before and after hematopoietic stem cell transplant (HCT)


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Patients without a history of diabetes mellitus undergoing matched related donor (MRD) allogeneic hematopoietic stem cell transplantation (HCT).
Criteria

Inclusion Criteria for Patients:

  • Patients undergoing matched related donor (MRD) 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
  • 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 (> 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 2Aim 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 match 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

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): NCT03415139


Contacts
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Contact: VICC Clinical Trials Information Program 800-811-8480 brian.engelhardt@vanderbilt.edu
Contact: Brian G Engelhardt, MD 615 936-0381 brian.engelhardt@vanderbilt.edu

Locations
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United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: VICC Clinical Trials Information Program    800-811-8480      
Contact: Brian G Engelhardt, MD    615-936-0381    brian.engelhardt@vanderbilt.edu   
Sponsors and Collaborators
Vanderbilt-Ingram Cancer Center
Investigators
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Principal Investigator: Brian G Engelhardt, MD Vanderbilt University Medical Center
  Study Documents (Full-Text)

Documents provided by Brian Engelhardt, MD, Vanderbilt-Ingram Cancer Center:

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Responsible Party: Brian Engelhardt, MD, Associate Professor of Medicine, Vanderbilt-Ingram Cancer Center
ClinicalTrials.gov Identifier: NCT03415139     History of Changes
Other Study ID Numbers: VICC BMT 1836
First Posted: January 30, 2018    Key Record Dates
Last Update Posted: February 5, 2019
Last Verified: February 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

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