Effect of Red Blood Cell Survival on a Commonly Used Diabetes Lab Test-HbA1c

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2013 by University of Cincinnati
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Robert Cohen, M.D., University of Cincinnati
ClinicalTrials.gov Identifier:
NCT01204216
First received: September 15, 2010
Last updated: April 2, 2013
Last verified: April 2013
  Purpose

Prevention of complications in veterans with diabetes depends heavily on assessment of blood glucose and HbA1c. The HbA1c is a blood test that measures the exposure of hemoglobin (Hb) to a person's average blood glucose over the lifespan of a red blood cell (RBC). The test is heavily relied upon as a measure of blood glucose control. It is normally assumed that all people (those with and without diabetes) have a narrow range of red blood cell survival. It has been recently shown that this is not a valid assumption.

A more precise test of red blood cell survival, using a biotin label method, demonstrated a substantial difference of red blood cell survival among otherwise normal people. There is sufficient difference in red blood cell survival to alter the estimate of glycemic control from the HbA1c test by as much as 30 per cent. This introduces concern that HbA1c values do not mean the same thing in a significant number of people.

Although the evidence is clear that there is variation in RBC survival among people, attributing this variation to differences between individuals depends on answering several simple questions which surprisingly remain unanswered: whether RBC survival is stable over time within an individual and whether blood glucose control affects its stability. Therefore, the goal of the proposed studies is to define these characteristics.


Condition Intervention
Diabetes Mellitus
Impaired Fasting Glucose
Prediabetes
Biological: re-infusion of biotin labeled cells
Biological: Re-infusion of biotin labeled cells
Behavioral: Diabetes education/diabetes medication adjustment

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: Does Variation in Mean Red Cell Age Impact HbA1C Interpretation?

Resource links provided by NLM:


Further study details as provided by University of Cincinnati:

Primary Outcome Measures:
  • Specific Aim 1: To determine the stability of MRBC (mean RBC age)over time at stable glycemia. The hypothesis is MRBC will be stable in subjects without diabetes and in subjects with diabetes at stable glycemic control. [ Time Frame: Baseline and 8 months later ] [ Designated as safety issue: No ]
    We will determine MRBC and MBG (by both 7 point profile and continuous glucose monitoring), twice in 10 subjects without diabetes and in 10 subjects with diabetes at stable glycemic control. Since the time course study for following the disappearance of re-infused labeled RBCs is approximately 4 months, performing the biotin labeling of the cells for the second study at least 8 months after completion of sampling for the first, effectively samples MRBC at two time points at least one year apart.


Secondary Outcome Measures:
  • Specific Aim 2: To determine the impact of glycemic control on MRBC. The hypothesis is MRBC will be similar in subjects with diabetes studied initially in poor glycemic control compared to re-study after stable, improved glycemic control for >8 months. [ Time Frame: Baseline and 8 months later ] [ Designated as safety issue: No ]
    Up to 15 subjects participating in Aim 2 will be studied initially in poor glycemic control, while their second biotin/glucose monitoring study will be performed at least 8 months later after achieving stable glycemic control. If RBC survival varies, and in particular if it varies with glycemic control, then the relationship between HbA1c and MBG will change. Several studies have reported that HbA1c rises linearly with MBG until there is the appearance of a plateau suggesting a saturation maximum.


Estimated Enrollment: 35
Study Start Date: September 2010
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Aim 1 Arm
Subjects in this arm will be 10 people without diabetes as well as 10 people with diabetes and stable glycemic control. Subjects will participate in experiments involving re-infusion of biotin-labeled cells in which a small volume (< 10 ml) of autologous, biotinylated erythrocytes will be re-infused to determine cell lifespan and in vivo HbA1c formation rate.
Biological: re-infusion of biotin labeled cells

Subjects will participate in experiments involving re-infusion of biotin-labeled cells in which a small volume (< 10 ml) of autologous, biotinylated erythrocytes will be re-infused to determine cell lifespan and in vivo HbA1c formation rate.

These experiments require a series of small, precisely timed post-infusion blood samples over a period of 4 months, with each subject undergoing the procedure twice separated by an interval of at least 8 months.

Active Comparator: Aim 2
For Aim 2, 10 additional subjects with diabetes in poor glycemic control will be studied initially and then again in improved glycemic control after at least 8 months (with up to 5 additional subjects entered as needed to ensure 10 completed paired studies) to assess the potential role of MRBC variation in the discordances seen between HbA1c and blood glucose testing. Subjects will participate in experiments involving re-infusion of biotin-labeled cells in which a small volume (< 10 ml) of autologous, biotinylated erythrocytes will be re-infused to determine cell lifespan and in vivo HbA1c formation rate.
Biological: Re-infusion of biotin labeled cells

Subjects will participate in experiments involving re-infusion of biotin-labeled cells in which a small volume (< 10 ml) of autologous, biotinylated erythrocytes will be re-infused to determine cell lifespan and in vivo HbA1c formation rate.

These experiments require a series of small, precisely timed post-infusion blood samples over a period of 4 months, with each subject undergoing the procedure twice separated by an interval of at least 8 months.

small volume (< 10 ml) of autologous, biotinylated erythrocytes will be re-infused to determine cell lifespan and in vivo HbA1c formation rate.

Behavioral: Diabetes education/diabetes medication adjustment
Between the initial 3-4 month trial period and the second infusion of biotin labeled cells approximately 8 months later,subjects will receive diabetes education from a CDE. In addition,if needed, diabetes medications may be adjusted by the study endocrinologist to improve subject's glycemic control.

Detailed Description:

The first Specific Aim tests the hypothesis that mean RBC age is stable in subjects without diabetes and in subjects with diabetes at stable glycemic control. The second Specific Aim tests the hypothesis that mean RBC age will not change in subjects with diabetes studied initially in poor glycemic control, and again after being treated to stable, improved glycemic control for >8 months. To accomplish the two aims, RBC survival and mean blood glucose will be determined at two times separated by at least eight months in 10 subjects without diabetes, 10 subjects with diabetes and stable glycemic control, and up to 15 subjects with diabetes in initial poor glycemic control in order to re-study 10 subjects subsequently in improved glycemic control. The RBC survival will be measured using the same novel biotin RBC label in conjunction with mean glucose determination by continuous glucose monitoring. Mean blood glucose will be assessed using blood glucose testing meter , continuous glucose monitoring equipment, HbA1c, fructosamine and glycated albumin determinations HbA1c is the most highly valued clinical test for long term monitoring of glycemic control and the prediction of diabetes complications risk is relied upon for hundreds of thousands of clinical decisions made every year in veterans with diabetes. The proposed studies, by further defining RBC survival stability necessary to develop a new approach to HbA1c interpretation, therefore has the potential to dramatically support the Department of Veterans Affairs in its mission to reduce the burden of diabetes and its complications

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subjects will be between ages 18 and 85 for Aim 1 and between 18 and 80 years for Aim 2 and non-pregnant
  • Subjects with both types 1 and 2 diabetes
  • Subjects without diabetes (as determined by an OGTT test at screening)
  • veterans receiving care at VAMC will be given preference but open to both veterans and non-veterans.

Exclusion Criteria:

  • known hemoglobinopathy or RBC disorder
  • positive pregnancy test (in women of child-bearing potential or are breast feeding or planning pregnancy during the course of the study;
  • baseline serum creatinine >1.5 mg/dl
  • CBC outside the normal range
  • history of GI blood loss or coagulopathy
  • urine microalbumin >100 mcg/mg creatinine (spot collection);
  • transaminases >3 X the upper limit of normal
  • presence of serum antibodies to biotinylated proteins (which could interfere with the biotin RBC labeling protocol)
  • greater than or equal to NYHA stage 3 heart failure;
  • active infection;
  • known rheumatologic disease
  • uncontrolled hypo-or hyperthyroidism or an underlying illness known to be associated with either body wasting or changes in serum proteins
  • plans to move out of the area within the time frame of the Aim for which they are recruited
  • unwillingness to perform self monitoring of blood glucose
  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: NCT01204216

Contacts
Contact: Mary C Rogge, BSN 513-487-6078 marycolleenrogge@va.gov

Locations
United States, Ohio
Clinical research unit, VAMC Recruiting
Cincinnati, Ohio, United States, 45220
Contact: Colleen Rogge, BSN    513-475-6478    MaryColleenRogge@va.gov   
Contact: Paramjit K Khera, PhD    513-558-0464    kherapk@uc.edu   
Principal Investigator: Robert M Cohen, MD         
Clinical Research Unit, VAMC Recruiting
Cincinnati, Ohio, United States, 45220
Contact: Colleen Rogge, BSN         
Contact: Kathy Burton, MS    513-861-3100 ext 4715    Kathy.Burton@va.gov   
Principal Investigator: Robert M Cohen, M D         
Sponsors and Collaborators
Robert Cohen, M.D.
Investigators
Principal Investigator: Robert M Cohen, M D University of Cincinnati
  More Information

Publications:
Responsible Party: Robert Cohen, M.D., Professor of Medicine, University of Cincinnati
ClinicalTrials.gov Identifier: NCT01204216     History of Changes
Other Study ID Numbers: 09100601
Study First Received: September 15, 2010
Last Updated: April 2, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Cincinnati:
Hemoglobin A1c
HbA1c
glycated serum proteins
fructosamine
glycated albumin
glycation gap

Additional relevant MeSH terms:
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Biotin
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 19, 2014