Diabetes MellitusNCT03288233
Exhaled Carbon Monoxide and Red Blood Cell Turnover
An observational study of Diabetes Mellitus and Healthy, run by University of Cincinnati at 1 site in United States.
Trial summary
Hemoglobin A1C (HbA1c) is the cornerstone of blood sugar monitoring. As HbA1c is formed by the covalent reaction of glucose with hemoglobin throughout the lifespan of the red blood cell (RBC), it is used as a surrogate marker for integrated mean blood glucose over time. Read more about this study
- Who is it for?
- Ages 18 to 75 yearsHealthy volunteers can take part
- Conditions the study is for
- Diabetes Mellitus, Healthy
- What is being tested?
- Breath carbon monoxide measurement
- How many people
- 30 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2015to Aug 2018
- Phase
- Observational
- Are there results?
- None posted in the registry
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 75 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: Healthy adults with Diabetes aged 18 to 75 years previously measured for red blood cell lifespan
Who may be able to join
- Subjects will be between age 18 and 75 years, non-pregnant, with a goal of equal gender and race (Caucasian vs. African-American) distribution
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 13Show 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
- lung transplantation, irradiation, recent surgery, recent intensive care admission, asthma, COPD, cystic fibrosis, smoking, recent hematoma, uncontrolled hypo- or hyperthyroidism or an underlying illness known to be associated with either body wasting or changes in serum proteins (e.g. certain malignancies including multiple myeloma or tuberculosis).
Trial locations and contacts
1 site in 1 country.
United States1 site, 1 recruiting
- Recruiting
University of Cincinnati
Cincinnati, Ohio, 45220
Colleen Rogge, BSN, 513-475-6478, marycolleenrogge@va.gov
Stephanie Donnelly, MBA, 513-558-2639, donnelsi@ucmail.uc.edu
About this study
Official title: Measurement of Exhaled Lower Respiratory Carbon Monoxide and Correlation With Previous Measures of Red Cell Lifespan
Hemoglobin A1C (HbA1c) is the cornerstone of blood sugar monitoring. As HbA1c is formed by the covalent reaction of glucose with hemoglobin throughout the lifespan of the red blood cell (RBC), it is used as a surrogate marker for integrated mean blood glucose over time. The HbA1c value therefore is dependent on the average amount of time the RBC spends in the circulation (mean RBC age or MRBC). However, our previous studies measuring red cell lifespan using either an age cohort label (ex vivo labeling with biotin) or a population label (stable isotope) have demonstrated, contrary to established dogma, that the MRBC varies substantially among individuals and is sufficiently variable to affect HA1c interpretation in a significant percentage of individuals with diabetes. Although the stable isotope method is suitable for clinical studies, it has limited potential for application to large population of subjects. A potential alternative to the stable isotope approach that could be applied routinely to the average patient in the clinic is measurement of exhaled carbon monoxide (eCO) concentration, a reflection of RBC heme turnover. In general, the primary advantage of applying exhaled breath analyses to human clinical diagnostics and therapeutic monitoring is that this technique is noninvasive, safe, simple, and provides near-real time measurements. The purpose of this observational study is to optimize the collection of eCO in a normal control population followed by measurement in a cohort of subjects previously assessed by either the SI or biotin methods for comparison.
Read the detailed description
Recently Investigators have demonstrated that RBC lifespan has substantial inter-individual variation even in people without diabetes or obvious hematologic diseases affecting RBC lifespan (5,6). Investigators combined Endocrinology-Hematology research group has taken a leading role in applying state-of-the-art methods for RBC survival measurement.The published articles articles are now cited when investigators refer to the state of the art understanding of true RBC lifespan (7). Using a biotin labeling method that involves ex vivo labeling of cells with biotin and then re-infusion of those cells, Investigators were able to demonstrate that RBC lifespan is sufficiently heterogeneous even in the hematologically normal population with normal reticulocyte count to significantly affect HbA1c interpretation (5). Recognizing the limitations of the safe but relatively invasive biotin technique, Investigators more recently developed a stable isotope (SI) in which RBC heme is labeled with orally administered 15N-glycine (6). This is a benign and noninvasive technique and expands the scope of RBC lifespan studies to sizable epidemiologic and physiologic studies, a number of which investigators are initiating and planning.
However, the feasibility of making the findings translatable to widespread patient care has been perceived as a limitation to the merit of answering these scientific questions. The SI approach still requires multiple blood measurements over months (6). This proposed project is designed to test the feasibility of a method to satisfy the unmet clinical need for measuring RBC survival easily, noninvasively, and inexpensively. The goal is to access most individuals with or at risk for diagnosis of diabetes in or near most doctors' offices. Over the next year Investigators intend to determine whether exhaled alveolar carbon monoxide (eCO), a measure of heme breakdown and hence of RBC turnover, can be used in this manner to provide a single point measure of RBC lifespan. Interestingly, heme metabolism is the only known endogenous source of carbon monoxide in people (8) and there are recent studies by others suggesting its potential for measuring RBC lifespan (9,10) Now that technology has advanced to measure CO with sufficient sensitivity and cost, investigators will explore the use of instrumentation at the same time investigators expand their studies using the SI approach. The results from this method will be compared with a previous small population of subjects that had lifespan measured by biotin and/or SI technique.
- Conditions
- Diabetes Mellitus, Healthy
- Being tested
- Breath carbon monoxide measurement
- Keywords
- Hemoglobin A1c, HbA1c, End tidal carbon monoxide
- Medical subject headings
- Diabetes Mellitus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Breath carbon monoxide measurementDiagnostic test
Participants will be asked to breath in designed breathing circuits or hold their breath for short period of time and then their breath samples will be collected in special bags and the carbon monoxide and carbon dioxide will be measured with electrochemical techniques.
| Study group | Role | What they receive |
|---|---|---|
| Primary Group | Not described Receives: Diagnostic Test: Breath carbon monoxide measurement |
What is being measured
The primary outcome is the main question the study is designed to answer.
Average end expiratory alveolar concentration of Carbon monoxide (ppm) in morning before breakfast
In this preliminary phase of the study we use a device that has not been used in the United States before (Carbolyzer II, Taiyo, Japan) as a surrogate marker for red blood cell (RBC) removal or turnover in human subjects. Published studies and the company literature for the Carbolyzer mBA-2000 would suggest sufficient capability for the purposes of such measurements. This project will test more rigorously the validity of these specifications for this application. First, the detector will be standardized in more detail with measurement of the CO content of defined mixtures in the range needed for sufficient sensitivity. The device will calibrated prior with known concentrations of a mixture of carbon monoxide in air at three points (0-3-12 ppm). In addition, investigators will evaluate alternative CO detection devices for suitability which do not alter the experience of the participating subject or the accompanying risks and benefits.
Measured: four consecutive weeks
Average end expiratory alveolar concentration of CO (ppm) in morning 30 min after breakfast
similar to outcome 1
Measured: four consecutive weeks
Average end expiratory alveolar concentration of CO (ppm) 30 min after lunch
similar to outcome 1
Measured: one day sampling
Average end expiratory alveolar concentration of CO (ppm) 5 hours after lunch
similar to outcome 1
Measured: one day sampling
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Sep 2017
- Study startApr 2015
- Primary completionMay 2018 (estimated)
- Study completionAug 2018 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)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 University of CincinnatiThe 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
- Observational
- Observational model
- Other
- Time perspective
- Cross-sectional
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Cincinnati
- Sponsor type
- University, hospital or other
- Collaborators
- VA Office of Research and Development
- Responsible party
- Principal investigator, Robert Cohen, M.D., University of Cincinnati
- Investigators
- Robert Cohen, MD, Principal investigator, University of Cincinnati
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03288233
- Sponsor's protocol ID
- CR2_2015-1070
- Status last verified
- Sep 2017
- First submitted
- 8 Jun 2017
- Last updated
- 20 Sep 2017
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: No plan to share the IPD
Publications
Khera PK, Smith EP, Lindsell CJ, Rogge MC, Haggerty S, Wagner DA, Palascak MB, Mehta S, Hibbert JM, Joiner CH, Franco RS, Cohen RM. Use of an oral stable isotope label to confirm variation in red blood cell mean age that influences HbA1c interpretation. Am J Hematol. 2015 Jan;90(1):50-55. doi: 10.1002/ajh.23866.
PubMed 25293624Coburn RF. The measurement of endogenous carbon monoxide production. J Appl Physiol (1985). 2012 Jun;112(11):1949-55. doi: 10.1152/japplphysiol.00174.2012. Epub 2012 Mar 22.
PubMed 22442030Strocchi A, Schwartz S, Ellefson M, Engel RR, Medina A, Levitt MD. A simple carbon monoxide breath test to estimate erythrocyte turnover. J Lab Clin Med. 1992 Sep;120(3):392-9.
PubMed 1517686
Study at a glance
From the registry record, last updated by the sponsor on 20 Sep 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Measurement of Exhaled Lower Respiratory Carbon Monoxide and Correlation With Previous Measures of Red Cell Lifespan
- ClinicalTrials.gov ID
- NCT03288233
- Acronym / sponsor ID
- CR2_2015-1070
- Conditions
- Diabetes Mellitus, Healthy
- Keywords
- Hemoglobin A1c, HbA1c, End tidal carbon monoxide
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 30 participants (estimated)
- Lead sponsor
- University of CincinnatiUniversity, hospital or other
- Collaborators
- VA Office of Research and Development
- Study start
- Apr 2015 (actual)
- Primary completion
- May 2018 (estimated)
- Study completion
- Aug 2018 (estimated)
- First posted
- 20 Sep 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Hemoglobin A1C (HbA1c) is the cornerstone of blood sugar monitoring. As HbA1c is formed by the covalent reaction of glucose with hemoglobin throughout the lifespan of the red blood cell (RBC), it is used as a surrogate marker for integrated mean blood glucose over time. The HbA1c value therefore is dependent on the average amount of time the RBC spends in the circulation (mean RBC age or MRBC). However, our previous studies measuring red cell lifespan using either an age cohort label (ex vivo labeling with biotin) or a population label (stable isotope) have demonstrated, contrary to established dogma, that the MRBC varies substantially among individuals and is sufficiently variable to affect HA1c interpretation in a significant percentage of individuals with diabetes. Although the stable isotope method is suitable for clinical studies, it has limited potential for application to large population of subjects. A potential alternative to the stable isotope approach that could be applied routinely to the average patient in the clinic is measurement of exhaled carbon monoxide (eCO) concentration, a reflection of RBC heme turnover. In general, the primary advantage of applying exhaled breath analyses to human clinical diagnostics and therapeutic monitoring is that this technique is noninvasive, safe, simple, and provides near-real time measurements. The purpose of this observational study is to optimize the collection of eCO in a normal control population followed by measurement in a cohort of subjects previously assessed by either the SI or biotin methods for comparison.
Detailed description
Recently Investigators have demonstrated that RBC lifespan has substantial inter-individual variation even in people without diabetes or obvious hematologic diseases affecting RBC lifespan (5,6). Investigators combined Endocrinology-Hematology research group has taken a leading role in applying state-of-the-art methods for RBC survival measurement.The published articles articles are now cited when investigators refer to the state of the art understanding of true RBC lifespan (7). Using a biotin labeling method that involves ex vivo labeling of cells with biotin and then re-infusion of those cells, Investigators were able to demonstrate that RBC lifespan is sufficiently heterogeneous even in the hematologically normal population with normal reticulocyte count to significantly affect HbA1c interpretation (5). Recognizing the limitations of the safe but relatively invasive biotin technique, Investigators more recently developed a stable isotope (SI) in which RBC heme is labeled with orally administered 15N-glycine (6). This is a benign and noninvasive technique and expands the scope of RBC lifespan studies to sizable epidemiologic and physiologic studies, a number of which investigators are initiating and planning.
However, the feasibility of making the findings translatable to widespread patient care has been perceived as a limitation to the merit of answering these scientific questions. The SI approach still requires multiple blood measurements over months (6). This proposed project is designed to test the feasibility of a method to satisfy the unmet clinical need for measuring RBC survival easily, noninvasively, and inexpensively. The goal is to access most individuals with or at risk for diagnosis of diabetes in or near most doctors' offices. Over the next year Investigators intend to determine whether exhaled alveolar carbon monoxide (eCO), a measure of heme breakdown and hence of RBC turnover, can be used in this manner to provide a single point measure of RBC lifespan. Interestingly, heme metabolism is the only known endogenous source of carbon monoxide in people (8) and there are recent studies by others suggesting its potential for measuring RBC lifespan (9,10) Now that technology has advanced to measure CO with sufficient sensitivity and cost, investigators will explore the use of instrumentation at the same time investigators expand their studies using the SI approach. The results from this method will be compared with a previous small population of subjects that had lifespan measured by biotin and/or SI technique.
Study design
- Observational model
- Other
- Time perspective
- Cross-sectional
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Primary Group | – | Diagnostic Test: Breath carbon monoxide measurement |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- Healthy adults with Diabetes aged 18 to 75 years previously measured for red blood cell lifespan
Key inclusion criteria (1 listed)
- Subjects will be between age 18 and 75 years, non-pregnant, with a goal of equal gender and race (Caucasian vs. African-American) distribution
Key exclusion criteria (13 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 |
|---|---|---|
| Breath carbon monoxide measurementParticipants will be asked to breath in designed breathing circuits or hold their breath for short period of time and then their breath samples will be collected in special bags and the carbon monoxide and carbon dioxide will be measured with electrochemical techniques. | Diagnostic test | Primary Group |
Primary outcome
Average end expiratory alveolar concentration of Carbon monoxide (ppm) in morning before breakfast
Time frame: four consecutive weeks
In this preliminary phase of the study we use a device that has not been used in the United States before (Carbolyzer II, Taiyo, Japan) as a surrogate marker for red blood cell (RBC) removal or turnover in human subjects. Published studies and the company literature for the Carbolyzer mBA-2000 would suggest sufficient capability for the purposes of such measurements. This project will test more rigorously the validity of these specifications for this application. First, the detector will be standardized in more detail with measurement of the CO content of defined mixtures in the range needed for sufficient sensitivity. The device will calibrated prior with known concentrations of a mixture of carbon monoxide in air at three points (0-3-12 ppm). In addition, investigators will evaluate alternative CO detection devices for suitability which do not alter the experience of the participating subject or the accompanying risks and benefits.
Average end expiratory alveolar concentration of CO (ppm) in morning 30 min after breakfast
Time frame: four consecutive weeks
similar to outcome 1
Average end expiratory alveolar concentration of CO (ppm) 30 min after lunch
Time frame: one day sampling
similar to outcome 1
Average end expiratory alveolar concentration of CO (ppm) 5 hours after lunch
Time frame: one day sampling
similar to outcome 1
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Sep 2017.
- Background: PubMed 25293624Khera PK, Smith EP, Lindsell CJ, Rogge MC, Haggerty S, Wagner DA, Palascak MB, Mehta S, Hibbert JM, Joiner CH, Franco RS, Cohen RM. Use of an oral stable isotope label to confirm variation in red blood cell mean age that influences HbA1c interpretation. Am J Hematol. 2015 Jan;90(1):50-55. doi: 10.1002/ajh.23866.
- Background: PubMed 22442030Coburn RF. The measurement of endogenous carbon monoxide production. J Appl Physiol (1985). 2012 Jun;112(11):1949-55. doi: 10.1152/japplphysiol.00174.2012. Epub 2012 Mar 22.
- Background: PubMed 1517686Strocchi A, Schwartz S, Ellefson M, Engel RR, Medina A, Levitt MD. A simple carbon monoxide breath test to estimate erythrocyte turnover. J Lab Clin Med. 1992 Sep;120(3):392-9.
- Individual participant dataSharing planned: No. No plan to share the IPD
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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 Cohen, MD principal investigator
University of Cincinnati
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Diabetes Mellitus and Healthy, run by University of Cincinnati 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 1 inclusion and 13 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: status not confirmed, as of the sponsor's last update on 20 Sep 2017. 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Shahriar Arbabi, MD (513-558-3088, shahriar.arbabi@uc.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Average end expiratory alveolar concentration of Carbon monoxide (ppm) in morning before breakfast (time frame: four consecutive weeks). The study lists 4 primary outcomes in all. 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 NCT03288233, which also lists 3 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 20 Sep 2017.