Diabetes MellitusNCT01204216
Effect of Red Blood Cell Survival on a Commonly Used Diabetes Lab Test-HbA1c
A study testing re-infusion of biotin labeled cells and Diabetes education/diabetes medication adjustment in people with Diabetes Mellitus and Impaired Fasting Glucose, run by VA Office of Research and Development at 1 site in United States.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 to 85 yearsHealthy volunteers can take part
- Conditions the study is for
- Diabetes Mellitus, Impaired Fasting Glucose, Prediabetes
- What is being tested?
- re-infusion of biotin labeled cells and Diabetes education/diabetes medication adjustment
- Type of treatment
- Injection or infusion, Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 3 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Sep 2010to 1 Sep 2016
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 85 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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);
Show all 14Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Cincinnati VA Medical Center, Cincinnati, OH
Cincinnati, Ohio, 45220
About this study
Official title: Does Variation in Mean Red Cell Age Impact HbA1C Interpretation?
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.
Read the 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
- Conditions
- Diabetes Mellitus, Impaired Fasting Glucose, Prediabetes
- Being tested
- re-infusion of biotin labeled cells, Diabetes education/diabetes medication adjustment
- Keywords
- Hemoglobin A1c, HbA1c, glycated serum proteins, fructosamine, glycated albumin, glycation gap
- Medical subject headings
- Diabetes Mellitus, Prediabetic State
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
re-infusion of biotin labeled cellsBiological
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 month
Re-infusion of biotin labeled cellsBiological
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.
Diabetes education/diabetes medication adjustmentBehavioural
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.
| Study group | Role | What they receive |
|---|---|---|
| Aim 1 | Active comparator | 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. Receives: Biological: re-infusion of biotin labeled cells |
| Aim 2 | Active comparator | 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. Receives: Biological: Re-infusion of biotin labeled cells; Behavioral: Diabetes education/diabetes medication adjustment |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
The investigators 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.
Measured: Baseline and 8 months later
Secondary outcomes (1)
Specific Aim 2: To Determine the Impact of Glycemic Control on MRBC.
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.
Measured: Baseline and 8 months later
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Sep 2010 (estimated)
- Study start1 Sep 2010
- Primary completion1 Jul 2016
- Study completion1 Sep 2016
Why it stopped: technical barriers to completing the original design within the funding period
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Diabetes MellitusStudies of the same condition, open and under way.
- More trials run by VA Office of Research and DevelopmentThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Diagnosis
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 3 participants (actual)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Collaborators
- University of Cincinnati
- Responsible party
- Sponsor
- Investigators
- Robert M Cohen, MD, Principal investigator, Cincinnati VA Medical Center, Cincinnati, OH
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01204216
- Sponsor's protocol ID
- ENDA-006-09S
- Other IDs
- 09100601
- Status last verified
- May 2023
- First submitted
- 15 Sep 2010
- Last updated
- 31 May 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Cohen RM, Franco RS, Khera PK, Smith EP, Lindsell CJ, Ciraolo PJ, Palascak MB, Joiner CH. Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c. Blood. 2008 Nov 15;112(10):4284-91. doi: 10.1182/blood-2008-04-154112. Epub 2008 Aug 11.
PubMed 18694998Cohen RM, Lindsell CJ. When the blood glucose and the HbA(1c) don't match: turning uncertainty into opportunity. Diabetes Care. 2012 Dec;35(12):2421-3. doi: 10.2337/dc12-1479. No abstract available.
PubMed 23173128
Study at a glance
From the registry record, last updated by the sponsor on 31 May 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Does Variation in Mean Red Cell Age Impact HbA1C Interpretation?
- ClinicalTrials.gov ID
- NCT01204216
- Acronym / sponsor ID
- ENDA-006-09S
- Conditions
- Diabetes Mellitus, Impaired Fasting Glucose, Prediabetes
- Keywords
- Hemoglobin A1c, HbA1c, glycated serum proteins, fructosamine, glycated albumin, glycation gap
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: technical barriers to completing the original design within the funding period
- Enrolment
- 3 participants (actual)
- Lead sponsor
- VA Office of Research and DevelopmentUS federal agency
- Collaborators
- University of Cincinnati
- Study start
- 1 Sep 2010 (actual)
- Primary completion
- 1 Jul 2016 (actual)
- Study completion
- 1 Sep 2016 (actual)
- First posted
- 17 Sep 2010 (estimated)
- Results
- Posted 31 May 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
Study design
- Primary purpose
- Diagnosis
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Aim 1 | Active comparator | Biological: re-infusion of biotin labeled cellsSubjects 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. |
| Aim 2 | Active comparator | Biological: Re-infusion of biotin labeled cells, Behavioral: Diabetes education/diabetes medication adjustmentFor 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. |
Who may qualify
- Ages
- 18 to 85 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (14 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| re-infusion of biotin labeled cellsSubjects 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 month | Biological | Aim 1 |
| Re-infusion of biotin labeled cellsSubjects 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. | Biological | Aim 2 |
| Diabetes education/diabetes medication adjustmentBetween 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. | Behavioural | Aim 2 |
Primary outcome
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
The investigators 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.
1 secondary outcome
Specific Aim 2: To Determine the Impact of Glycemic Control on MRBC.
Time frame: Baseline and 8 months later
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 May 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 18694998Cohen RM, Franco RS, Khera PK, Smith EP, Lindsell CJ, Ciraolo PJ, Palascak MB, Joiner CH. Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c. Blood. 2008 Nov 15;112(10):4284-91. doi: 10.1182/blood-2008-04-154112. Epub 2008 Aug 11.
- Background: PubMed 23173128Cohen RM, Lindsell CJ. When the blood glucose and the HbA(1c) don't match: turning uncertainty into opportunity. Diabetes Care. 2012 Dec;35(12):2421-3. doi: 10.2337/dc12-1479. No abstract available.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robert M Cohen, MD principal investigator
Cincinnati VA Medical Center, Cincinnati, OH
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing re-infusion of biotin labeled cells and Diabetes education/diabetes medication adjustment in people with Diabetes Mellitus and Impaired Fasting Glucose, run by VA Office of Research and Development at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 31 May 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 31 May 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01204216, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 May 2023.